血脂易感基因多态性及mRNA水平与北京市儿童脂代谢的相关性研究
|
摘要
背景：血脂异常是冠心病的重要的独立危险因子,血脂水平除了受环境因素影响,也和遗传相关。多种基因参与调节血脂代谢,基因的一般变异和罕见变异影响血脂浓度。GWAS相关基因的筛选验证分析,对于了解血脂代谢机制具有重要的意义。通过对遗传易感基因的分析,了解血脂代谢的遗传机制,获得有用的可干预靶点,可提供对脂代谢紊乱以及代谢综合征其他危险因子的预防和治疗策略。由于儿童期血脂水平与成人期密切相关,所以在儿童人群鉴别与血脂相关的基因多态性及其表达状态将增加对血脂代谢机制的了解。
目的：探讨1.血脂易感基因单核苷酸多态性位点(Single nucleotide polymorphisms, SNP)(GALNT2:rs2144300,GCKR:rs1260333, rs1260326,LPL: rs10105606, TRIB1: rs2954029,ANGPTL3: rs1748195和APOA5-A4-C3-A1cluster-: rs964184)与学龄儿童血脂水平及脂代谢紊乱的关联性；
2.血脂易感基因多态性对信使RNA (mRNA)表达的影响；
3.基因一环境交互作用对学龄儿童脂代谢紊乱的影响。
方法：
1.研究对象：
1)基因型与血脂水平的相关性研究：来源于2004年4-10月进行的以人群为基础的横断面研究：北京市儿童青少年代谢综合征(BCAMS)研究。BCAMS人群包括有代表性的北京市城乡地区6-18岁学龄儿童的19593人,其中男生占50%。进行人体测量,按照中国肥胖问题工作组(WGOC)推荐的“中国学龄儿童青少年超重、肥胖筛查体重指数值分类标准”评价体重状态,招募同意接受静脉采血的儿童总计3518人,其中肥胖组1229人,超重组655人,正常体重组1620人,其余14人因缺失部分数据未分组。采集空腹12小时静脉血,进行医学检查和生活行为因素问卷调查。
2)mRNA表达实验：来源于2013年1-3月从首都儿科研究所附属医院病房入选50名5周岁以上儿童,经诊断无心、肺、肝、肾等重要脏器的慢性疾病、身体重要残疾(如脊柱和下肢残疾)、无内分泌类疾病以及药物性肥胖。测量身高、体重、腰围数据,评价体重状态,记录病历号。采集空腹血。
2.基因型检测实验：采用盐析法或商品试剂盒从外周血白细胞中提取DNA。通过查阅文献和专家研讨,确定6个基因的7个多态性位点(SNP)(GALNT2: rs2144300, GCKR:rs1260333, rs1260326, LPL:rs10105606, TRIB1:rs2954029,ANGPTL3:rs1748195和APOA5-A4-C3-A1cluster:rs964184),采用TaqMan探针法检测基因型。
3. mRNA表达实验：提取全血总RNA采用实时荧光定量聚合酶链反应(RTQ-PCR)技术检测上述6个血脂候选基因(GALNT2, GCKR, LPL, TRIB1, ANGPTL3和APOA5-A4-C3-A1cluster)的mRNA表达水平,看家基因选择GAPDHo
4.统计分析：使用Access软件进行数据录入,统计分析采用SPSS13.0软件,主要统计方法包括ANCOVA,多元线性回归分析、多元logistic回归分析。
结果：
应用遗传加性模型,调整年龄、性别、体重指数和青春期,并进行FDR校正(标准为0.05)。6个SNP (rs2144300,rs1260333,rs1260326,rs10105606,rs748195和rs964184)与甘油三酯相关(p<0.05)。两个SNP (rs2954029口rs964184)与总胆固醇相关(p<0.05)。两个SNP (rs10105606和rs964184)与高密度脂蛋白胆固醇相关(p<0.05)。4个SNP (rs1260333, rs1260326, rs2954029和rs964184)与低密度脂蛋白胆固醇相关(p<0.05)。调整年龄、性别、BMI和青春期后,与儿童血脂代谢紊乱相关的SNP有3个,rs1260333(OR=1.22,95%CI1.09-1.36),rs1260326(OR=1.21,95%CI1.09-1.39)和rs964184(OR=1.37,95%CI1.20-1.55)。5个SNP与高甘油三酯血症相关,rs2144300, rs1260333, rs1260326, rs1748195和rs964184,OR值分别为1.42(95%CI1.12-1.80),1.34(95%CI1.13-1.59),1.31(95%CI1.11-1.55),1.31(95%CI1.07-1.61)和1.71(95%CI1.43-2.06)。仅一个SNP rs964184与低HDL-C血症相关,OR=1.34,95%CI1.12-1.61。
随着遗传危险得分(GRSs)增加,TG, TC, HDL-C, LDL-C的水平呈线性相关,有统计学意义(p<0.05)每增加一个危险等位基因,可以引起脂代谢紊乱、高甘油三酯、高胆固醇、低高密度脂蛋白和高低密度脂蛋白血症的的风险分别增加17%,40%,9%,10%和11%。
RTQ-PCR结果显示,GCKR mRNA随着rs1260333和rs1260326危险等位基因数目增加表达水平呈线性降低；ANGPTL3的mRNA表达是随着rs1748195危险等位基因数目增加而呈线性升高；APOA5-A4-C3-Al cluster上的rs964184无RR基因型,含有一个危险等位基因的杂合子CR型的APOA5-A4-C3-Al cluster的mRNA水平低于无危险等位基因的CC型。
采用因子分析方法,共提取脂肪蛋白类食物、果蔬、烟酒、静态生活方式和业余体育活动5个公因子。脂代谢紊乱的基因—环境相互作用分析结果显示,GCKR位点rs1260333变异与烟酒、静态生活方式和运动三个因素存在交互作用,归因危险度百分比(AP)分别为2.61%、7.56%和3.89%。rs1260326与烟酒、静态生活方式和运动存在交互作用,AP分别为9.60%、6.95和0.35%。APOA5-A4-C3-A1cluster位点rs964184与脂肪蛋白类食物、蔬果、静态生活方式和运动存在交互作用,AP分别为15.73%、6.82%、2.15%和26.07%。
血脂易感SNP与生活行为因素对于高甘油三酯血症的交互作用结果显示,rs2144300与烟酒、蔬果、静态生活方式和运动存在交互作用,AP分别为21.41%、18.88%、2.71%和25.58%；GCKR的两个SNPrs1260333和rs1260326仅与脂肪蛋白类食物存在交互作用,AP分别为8.30%和13.34%。ANGPTL3上的SNP rs1748195与脂肪蛋白类食物和静态生活方式存在交互作用,AP分别为4.04%和32.76%。rs964184与脂肪蛋白类食物、烟酒、蔬果、静态生活方式和运动都存在交互作用,AP分别为27.70%、5.39%、3.67%、8.35%和27.02%。
结论：本研究首次在北京儿童人群中验证了血脂相关易感基因的多态性位点与血脂水平以及脂代谢紊乱存在关联。
与血脂水平和脂代谢紊乱相关的基因多态性存在累积效应,随等位基因风险值增大,血脂水平升高,脂代谢紊乱和高甘油三酯血症患病率上升。
血脂易感基因的mRNA表达水平在肥胖和非肥胖儿童中的差异表明,基因表达与肥胖可能存在关联；其次,基因型间的mRNA差异趋势提示,这些单核苷酸多态性位点可能通过影响基因的表达水平对血脂代谢进行调节。
易感基因与环境之间存在交互作用,其中高脂高蛋白食物、低果蔬类摄入、运动较少和烟酒摄入均可影响易感基因与血脂紊乱的关系。
Backgrounds:Epidemiological evidences indicated that abnormal lipids are strong independent risk factor for cardiovascular disease. Genetic and environmental factors contribute to the lipid levels. It is known that multiple genes participate into the regulation of lipid metabolism, common and rare variants in lipid-susceptibility genes may collectively determine blood lipid levels. Genome-wide association studies have identified association signals containing both classically established genes and previously unknown genomic regions as determinants of lipid levels, which is helpful to understand the mechanism of lipid metabolism, and get diagnosis goals from these identified locus. Levels of lipids variables in childhood were associated with levels in adulthood, identifying genes and genetic variants associated with blood lipids will enrich our understanding of blood lipid metabolism.
Objective:1. In the current study, we aimed to test the associations between seven variants (GALNT2(rs2144300), GCKR (rs1260326, rs1260333), LPL (rs10105606), TRIB1(rs2954029), ANGPTL3(rs1748195), and APOA5-A4-C3-A1cluster (rs964184)) and levels of triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) as continuous traits in Chinese Han children population. Then we estimated the association of variants with risks of dyslipidemia as dichotomized traits.
2. To test the relationship between genotypes of lipid-susceptibility loci and message RNA (mRNA).
3. To investigate the effect of genes-environment interaction on dyslipidemia in Chinese Han children.
Methods:1. Subjects:1) Association study:Subjects were recruited from the BCAMS study, a cross-sectional population-based survey carried out in2004. The survey included a questionnaire, medical examination, anthropometric measurement, and finger capillary blood tests among a representative sample (n=19593, boys accounted for50%of the sample) of Beijing school-age children aged6to18years from urban and rural districts. Anthropometric measurement included weight, height, waist circumference, and FMP by bioimpedance analysis. Birth weight was collected based on a self-report questionnaire, which was completed by parents or guardians. Within this large group of children,1229obese,655overweight and1620normal weight children were recruited and diagnosed by the Chinese age-and sex-specific BMI cutoffs, there were14un-grouped by the diagnosis criteria for missing data. Venipuncture blood samples were collected after a12-hour overnight fast.2) mRNA expression study: Children aged5to15years were recruited from patient wards in Capital Institute of Pediatrics from January to March in2013. The participants was diagnosed without chronic diseases of heart, lung, liver, kidney and other vital organs, without major physical disabilities, such as spinal and lower limb disability, and without endocrine diseases and drug-induced obesity. Anthropometric measurement included weight, height, waist circumference. The medical identification numbers were recorded and venipuncture blood samples were collected after a12-hour overnight fast.
2. Genotyping:Genomic DNA was isolated from peripheral blood white cells using the salt fractionation method or commercial kit. Seven variants (GALNT2(rs2144300), GCKR (rs1260326, rs1260333), LPL (rs10105606), TRIB1(rs2954029), ANGPTL3(rs1748195), and APOA5-A4-C3-A1cluster (rs964184)) were selected from previous GWAS studies. All genotyping were performed by TaqMan probes Allelic Discrimination Assays with the GeneAmp7900Sequence Detection System.
3. mRNA expression:Total RNA from venipuncture blood was extracted, and mRNA levels of GALNT2, GCKR, LPL, TRIB1, ANGPTL3and APOA5-A4-C3-A1cluster were detected by real time quantitative polymerase chain reaction (RTQ-PCR). The house-keeping gene is GAPDH.
4. Statistical analysis:Access2003was used for data entry and SPSS, version13.0(SPSS Inc., Chicago, Illinois) was used for data analysis. The statistical methods included ANCOVA, multiple linear regression, multiple logistic regression.
Results:With genetic additive model, after age, sex, BMI, and puberty stage, and correction with FDR (p<0.05), six SNPs(rs2144300,rs1260333,rs1260326,rs10105606, rs1748195and rs964184) associated with triglycerides (p<0.05). Two SNPs (rs2954029and rs964184) associated with total cholesterol (p<0.05). Two SNP (rs10105606and rs964184) associated with HDL-C(p<0.05). Four SNPs (rs1260333, rs1260326, rs2954029and rs964184) associated with LDL-C (p<0.05)).
After adjustment for age, sex, BMI, and puberty stage, there were significant associations between rs1260333(OR=1.22,95%CI1.09-1.36), rs1260326(OR=1.21,95%CI1.09-1.39), rs964184(OR=1.37,95%CI1.20-1.55) and dyslipidemia. Five SNPs, rs2144300(OR=1.42,95%C11.12-1.80), rs1260333(OR=1.34,95%CI1.13-1.59), rs1260326(OR=1.31,95%CI1.11-1.55), rs1748195(OR=1.31,95%CI1.07-1.61), and rs964184(OR=1.71,95%CI1.43-2.06) associated with hypertriglyceridemia. Only rs964184associated with low HDL-C (OR=1.34,95%CI1.12-1.61).
With the increased genetic risk scores (GRSs), there were a significant increasing in the lipid traits (TG, TC, HDL-C and LDL-C levels) with a significant stepwise manner (p<0.05). And with risk scores increased, the risks of dislipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL-C and high LDL-C is increasing with17%,40%,9%,10%and11%.
Under the genetic additive model of the loci genotyping, mRNA of GCKR gene decreased with the number of risk allele of rs1260333and rs1260326; mRNA of ANGPTL3increased with the number of risk allele of rs1748195; we didn't found the RR homozygotes for the risk allele for APOA5-A4-C3-A1cluster SNP rs964184, mRNA level of heterozygotes with one risk allele (CR) was lower than non-risk allele homozygotes (CC).
Using factor analysis methodology, five main factors, including lipid-protein, fruits&vegetable, smoke&drinking, sedentary behavior and physical exercise in spare time were extracted. We analyzed the interaction between gene and environment for dyslipidemia. The SNP rs1260333in GCKR interacted with smoke&drinking, sedentary behavior and physical exercise in spare time, and the attributable percent (AP) is2.61%,7.56%and3.89%, respectively. rs1260326interacted with smoke&drinking, sedentary behavior and physical exercise in spare time,too. And the AP is9.60%,6.95%and0.35%, respectively. APOA5-A4-C3-A1cluster SNP rs964184interacted with lipid-protein, vegetables&fruits, sedentary behavior and physical exercise in spare time, the AP is15.73%,6.82%,2.15%and26.07%.
For hypertriglyceridemia, GALNT2SNP rs2144300interacted with smoke&drinking, fruits&vegetable, sedentary behavior and physical exercise in spare time, the AP is21.41%,18.88%,2.71%and25.58%, respectively. GCKR SNP rs1260333and rs1260326interacted with lipid-protein, the AP is8.30%and13.34%, respectively. ANGPTL3SNP rs1748195interacted with lipid-protein and sedentary behavior. The AP is4.04%and32.76%, respectively. APOA5-A4-C3-A1cluster SNP rs964184interacted with all five main factors, the AP is27.70%、5.39%、3.67%、8.35%and27.02%for lipid-protein, fruits&vegetable, smoke&drinking, sedentary behavior and physical exercise in spare time, respectively.
Conclusions:Our study firstly validated the association of seven variants with blood lipids and risk of dyslipidemia among the Chinese Beijing children and adolescents.
There were accumulative risk effects of these seven variants on lipid traits, risks of dislipidemia and hypertriglyceridemia.
The trends between genotype and mRNA levels, implied that the genes expression might be influenced by the lipid-susceptibility SNPs.
There were interactions between lipid-susceptible SNPs and environmental factors. Low vegetables&fruits, less physical exercise and smoke&drinking might co-mordify the effects of lipid-susceptibility genes on the risk of dyslipidemia.
目的：探讨1.血脂易感基因单核苷酸多态性位点(Single nucleotide polymorphisms, SNP)(GALNT2:rs2144300,GCKR:rs1260333, rs1260326,LPL: rs10105606, TRIB1: rs2954029,ANGPTL3: rs1748195和APOA5-A4-C3-A1cluster-: rs964184)与学龄儿童血脂水平及脂代谢紊乱的关联性；
2.血脂易感基因多态性对信使RNA (mRNA)表达的影响；
3.基因一环境交互作用对学龄儿童脂代谢紊乱的影响。
方法：
1.研究对象：
1)基因型与血脂水平的相关性研究：来源于2004年4-10月进行的以人群为基础的横断面研究：北京市儿童青少年代谢综合征(BCAMS)研究。BCAMS人群包括有代表性的北京市城乡地区6-18岁学龄儿童的19593人,其中男生占50%。进行人体测量,按照中国肥胖问题工作组(WGOC)推荐的“中国学龄儿童青少年超重、肥胖筛查体重指数值分类标准”评价体重状态,招募同意接受静脉采血的儿童总计3518人,其中肥胖组1229人,超重组655人,正常体重组1620人,其余14人因缺失部分数据未分组。采集空腹12小时静脉血,进行医学检查和生活行为因素问卷调查。
2)mRNA表达实验：来源于2013年1-3月从首都儿科研究所附属医院病房入选50名5周岁以上儿童,经诊断无心、肺、肝、肾等重要脏器的慢性疾病、身体重要残疾(如脊柱和下肢残疾)、无内分泌类疾病以及药物性肥胖。测量身高、体重、腰围数据,评价体重状态,记录病历号。采集空腹血。
2.基因型检测实验：采用盐析法或商品试剂盒从外周血白细胞中提取DNA。通过查阅文献和专家研讨,确定6个基因的7个多态性位点(SNP)(GALNT2: rs2144300, GCKR:rs1260333, rs1260326, LPL:rs10105606, TRIB1:rs2954029,ANGPTL3:rs1748195和APOA5-A4-C3-A1cluster:rs964184),采用TaqMan探针法检测基因型。
3. mRNA表达实验：提取全血总RNA采用实时荧光定量聚合酶链反应(RTQ-PCR)技术检测上述6个血脂候选基因(GALNT2, GCKR, LPL, TRIB1, ANGPTL3和APOA5-A4-C3-A1cluster)的mRNA表达水平,看家基因选择GAPDHo
4.统计分析：使用Access软件进行数据录入,统计分析采用SPSS13.0软件,主要统计方法包括ANCOVA,多元线性回归分析、多元logistic回归分析。
结果：
应用遗传加性模型,调整年龄、性别、体重指数和青春期,并进行FDR校正(标准为0.05)。6个SNP (rs2144300,rs1260333,rs1260326,rs10105606,rs748195和rs964184)与甘油三酯相关(p<0.05)。两个SNP (rs2954029口rs964184)与总胆固醇相关(p<0.05)。两个SNP (rs10105606和rs964184)与高密度脂蛋白胆固醇相关(p<0.05)。4个SNP (rs1260333, rs1260326, rs2954029和rs964184)与低密度脂蛋白胆固醇相关(p<0.05)。调整年龄、性别、BMI和青春期后,与儿童血脂代谢紊乱相关的SNP有3个,rs1260333(OR=1.22,95%CI1.09-1.36),rs1260326(OR=1.21,95%CI1.09-1.39)和rs964184(OR=1.37,95%CI1.20-1.55)。5个SNP与高甘油三酯血症相关,rs2144300, rs1260333, rs1260326, rs1748195和rs964184,OR值分别为1.42(95%CI1.12-1.80),1.34(95%CI1.13-1.59),1.31(95%CI1.11-1.55),1.31(95%CI1.07-1.61)和1.71(95%CI1.43-2.06)。仅一个SNP rs964184与低HDL-C血症相关,OR=1.34,95%CI1.12-1.61。
随着遗传危险得分(GRSs)增加,TG, TC, HDL-C, LDL-C的水平呈线性相关,有统计学意义(p<0.05)每增加一个危险等位基因,可以引起脂代谢紊乱、高甘油三酯、高胆固醇、低高密度脂蛋白和高低密度脂蛋白血症的的风险分别增加17%,40%,9%,10%和11%。
RTQ-PCR结果显示,GCKR mRNA随着rs1260333和rs1260326危险等位基因数目增加表达水平呈线性降低；ANGPTL3的mRNA表达是随着rs1748195危险等位基因数目增加而呈线性升高；APOA5-A4-C3-Al cluster上的rs964184无RR基因型,含有一个危险等位基因的杂合子CR型的APOA5-A4-C3-Al cluster的mRNA水平低于无危险等位基因的CC型。
采用因子分析方法,共提取脂肪蛋白类食物、果蔬、烟酒、静态生活方式和业余体育活动5个公因子。脂代谢紊乱的基因—环境相互作用分析结果显示,GCKR位点rs1260333变异与烟酒、静态生活方式和运动三个因素存在交互作用,归因危险度百分比(AP)分别为2.61%、7.56%和3.89%。rs1260326与烟酒、静态生活方式和运动存在交互作用,AP分别为9.60%、6.95和0.35%。APOA5-A4-C3-A1cluster位点rs964184与脂肪蛋白类食物、蔬果、静态生活方式和运动存在交互作用,AP分别为15.73%、6.82%、2.15%和26.07%。
血脂易感SNP与生活行为因素对于高甘油三酯血症的交互作用结果显示,rs2144300与烟酒、蔬果、静态生活方式和运动存在交互作用,AP分别为21.41%、18.88%、2.71%和25.58%；GCKR的两个SNPrs1260333和rs1260326仅与脂肪蛋白类食物存在交互作用,AP分别为8.30%和13.34%。ANGPTL3上的SNP rs1748195与脂肪蛋白类食物和静态生活方式存在交互作用,AP分别为4.04%和32.76%。rs964184与脂肪蛋白类食物、烟酒、蔬果、静态生活方式和运动都存在交互作用,AP分别为27.70%、5.39%、3.67%、8.35%和27.02%。
结论：本研究首次在北京儿童人群中验证了血脂相关易感基因的多态性位点与血脂水平以及脂代谢紊乱存在关联。
与血脂水平和脂代谢紊乱相关的基因多态性存在累积效应,随等位基因风险值增大,血脂水平升高,脂代谢紊乱和高甘油三酯血症患病率上升。
血脂易感基因的mRNA表达水平在肥胖和非肥胖儿童中的差异表明,基因表达与肥胖可能存在关联；其次,基因型间的mRNA差异趋势提示,这些单核苷酸多态性位点可能通过影响基因的表达水平对血脂代谢进行调节。
易感基因与环境之间存在交互作用,其中高脂高蛋白食物、低果蔬类摄入、运动较少和烟酒摄入均可影响易感基因与血脂紊乱的关系。
Backgrounds:Epidemiological evidences indicated that abnormal lipids are strong independent risk factor for cardiovascular disease. Genetic and environmental factors contribute to the lipid levels. It is known that multiple genes participate into the regulation of lipid metabolism, common and rare variants in lipid-susceptibility genes may collectively determine blood lipid levels. Genome-wide association studies have identified association signals containing both classically established genes and previously unknown genomic regions as determinants of lipid levels, which is helpful to understand the mechanism of lipid metabolism, and get diagnosis goals from these identified locus. Levels of lipids variables in childhood were associated with levels in adulthood, identifying genes and genetic variants associated with blood lipids will enrich our understanding of blood lipid metabolism.
Objective:1. In the current study, we aimed to test the associations between seven variants (GALNT2(rs2144300), GCKR (rs1260326, rs1260333), LPL (rs10105606), TRIB1(rs2954029), ANGPTL3(rs1748195), and APOA5-A4-C3-A1cluster (rs964184)) and levels of triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) as continuous traits in Chinese Han children population. Then we estimated the association of variants with risks of dyslipidemia as dichotomized traits.
2. To test the relationship between genotypes of lipid-susceptibility loci and message RNA (mRNA).
3. To investigate the effect of genes-environment interaction on dyslipidemia in Chinese Han children.
Methods:1. Subjects:1) Association study:Subjects were recruited from the BCAMS study, a cross-sectional population-based survey carried out in2004. The survey included a questionnaire, medical examination, anthropometric measurement, and finger capillary blood tests among a representative sample (n=19593, boys accounted for50%of the sample) of Beijing school-age children aged6to18years from urban and rural districts. Anthropometric measurement included weight, height, waist circumference, and FMP by bioimpedance analysis. Birth weight was collected based on a self-report questionnaire, which was completed by parents or guardians. Within this large group of children,1229obese,655overweight and1620normal weight children were recruited and diagnosed by the Chinese age-and sex-specific BMI cutoffs, there were14un-grouped by the diagnosis criteria for missing data. Venipuncture blood samples were collected after a12-hour overnight fast.2) mRNA expression study: Children aged5to15years were recruited from patient wards in Capital Institute of Pediatrics from January to March in2013. The participants was diagnosed without chronic diseases of heart, lung, liver, kidney and other vital organs, without major physical disabilities, such as spinal and lower limb disability, and without endocrine diseases and drug-induced obesity. Anthropometric measurement included weight, height, waist circumference. The medical identification numbers were recorded and venipuncture blood samples were collected after a12-hour overnight fast.
2. Genotyping:Genomic DNA was isolated from peripheral blood white cells using the salt fractionation method or commercial kit. Seven variants (GALNT2(rs2144300), GCKR (rs1260326, rs1260333), LPL (rs10105606), TRIB1(rs2954029), ANGPTL3(rs1748195), and APOA5-A4-C3-A1cluster (rs964184)) were selected from previous GWAS studies. All genotyping were performed by TaqMan probes Allelic Discrimination Assays with the GeneAmp7900Sequence Detection System.
3. mRNA expression:Total RNA from venipuncture blood was extracted, and mRNA levels of GALNT2, GCKR, LPL, TRIB1, ANGPTL3and APOA5-A4-C3-A1cluster were detected by real time quantitative polymerase chain reaction (RTQ-PCR). The house-keeping gene is GAPDH.
4. Statistical analysis:Access2003was used for data entry and SPSS, version13.0(SPSS Inc., Chicago, Illinois) was used for data analysis. The statistical methods included ANCOVA, multiple linear regression, multiple logistic regression.
Results:With genetic additive model, after age, sex, BMI, and puberty stage, and correction with FDR (p<0.05), six SNPs(rs2144300,rs1260333,rs1260326,rs10105606, rs1748195and rs964184) associated with triglycerides (p<0.05). Two SNPs (rs2954029and rs964184) associated with total cholesterol (p<0.05). Two SNP (rs10105606and rs964184) associated with HDL-C(p<0.05). Four SNPs (rs1260333, rs1260326, rs2954029and rs964184) associated with LDL-C (p<0.05)).
After adjustment for age, sex, BMI, and puberty stage, there were significant associations between rs1260333(OR=1.22,95%CI1.09-1.36), rs1260326(OR=1.21,95%CI1.09-1.39), rs964184(OR=1.37,95%CI1.20-1.55) and dyslipidemia. Five SNPs, rs2144300(OR=1.42,95%C11.12-1.80), rs1260333(OR=1.34,95%CI1.13-1.59), rs1260326(OR=1.31,95%CI1.11-1.55), rs1748195(OR=1.31,95%CI1.07-1.61), and rs964184(OR=1.71,95%CI1.43-2.06) associated with hypertriglyceridemia. Only rs964184associated with low HDL-C (OR=1.34,95%CI1.12-1.61).
With the increased genetic risk scores (GRSs), there were a significant increasing in the lipid traits (TG, TC, HDL-C and LDL-C levels) with a significant stepwise manner (p<0.05). And with risk scores increased, the risks of dislipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL-C and high LDL-C is increasing with17%,40%,9%,10%and11%.
Under the genetic additive model of the loci genotyping, mRNA of GCKR gene decreased with the number of risk allele of rs1260333and rs1260326; mRNA of ANGPTL3increased with the number of risk allele of rs1748195; we didn't found the RR homozygotes for the risk allele for APOA5-A4-C3-A1cluster SNP rs964184, mRNA level of heterozygotes with one risk allele (CR) was lower than non-risk allele homozygotes (CC).
Using factor analysis methodology, five main factors, including lipid-protein, fruits&vegetable, smoke&drinking, sedentary behavior and physical exercise in spare time were extracted. We analyzed the interaction between gene and environment for dyslipidemia. The SNP rs1260333in GCKR interacted with smoke&drinking, sedentary behavior and physical exercise in spare time, and the attributable percent (AP) is2.61%,7.56%and3.89%, respectively. rs1260326interacted with smoke&drinking, sedentary behavior and physical exercise in spare time,too. And the AP is9.60%,6.95%and0.35%, respectively. APOA5-A4-C3-A1cluster SNP rs964184interacted with lipid-protein, vegetables&fruits, sedentary behavior and physical exercise in spare time, the AP is15.73%,6.82%,2.15%and26.07%.
For hypertriglyceridemia, GALNT2SNP rs2144300interacted with smoke&drinking, fruits&vegetable, sedentary behavior and physical exercise in spare time, the AP is21.41%,18.88%,2.71%and25.58%, respectively. GCKR SNP rs1260333and rs1260326interacted with lipid-protein, the AP is8.30%and13.34%, respectively. ANGPTL3SNP rs1748195interacted with lipid-protein and sedentary behavior. The AP is4.04%and32.76%, respectively. APOA5-A4-C3-A1cluster SNP rs964184interacted with all five main factors, the AP is27.70%、5.39%、3.67%、8.35%and27.02%for lipid-protein, fruits&vegetable, smoke&drinking, sedentary behavior and physical exercise in spare time, respectively.
Conclusions:Our study firstly validated the association of seven variants with blood lipids and risk of dyslipidemia among the Chinese Beijing children and adolescents.
There were accumulative risk effects of these seven variants on lipid traits, risks of dislipidemia and hypertriglyceridemia.
The trends between genotype and mRNA levels, implied that the genes expression might be influenced by the lipid-susceptibility SNPs.
There were interactions between lipid-susceptible SNPs and environmental factors. Low vegetables&fruits, less physical exercise and smoke&drinking might co-mordify the effects of lipid-susceptibility genes on the risk of dyslipidemia.
引文
1. Forrester JS:Triglycerides:risk factor or fellow traveler? Curr Opin Cardiol 2001; 16:261-264
2. Malloy MJ, Kane JP:A risk factor for atherosclerosis:triglyceride-rich lipoproteins. Adv Intern Med 2001;47:111-136
3. Keith SW, Redden DT, Katzmarzyk PT, Boggiano MM, Hanlon EC, Benca RM, Ruden D, Pietrobelli A, Barger JL, Fontaine KR, Wang C, Aronne LJ, Wright SM, Baskin M, Dhurandhar NV, Lijoi MC, Grilo CM, DeLuca M, Westfall AO, Allison DB:Putative contributors to the secular increase in obesity:exploring the roads less traveled. Int J Obes (Lond) 2006;30:1585-1594
4.米杰,程红,侯冬青,段佳丽,滕红红,王友发：北京市2004年2-18岁儿童青少年超重和肥胖流行现状.中华流行病学杂志2006；27：469-474
5.刘颖,米杰,杜军保：北京地区6-18岁儿童血脂紊乱现况调查.中国实用儿科杂志2007；22：101-102
6.万乃君,米杰,王天有,段佳丽,黎明,巩纯秀,杜军保,赵小元,程红,侯冬青,王俐：北京市超重和肥胖学龄儿童中代谢综合征的流行特征.中华儿科杂志2007；45：417-421
7. Miller NE, Miller GJ:Letter:High-density lipoprotein and atherosclerosis. Lancet 1975;1:1033
8. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J,3rd:Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study. Ann Intern Med 1961;55:33-50
9. Pilia G, Chen WM, Scuteri A, Orru M, Albai G, Dei M, Lai S, Usala G, Lai M, Loi P, Mameli C, Vacca L, Deiana M, Olla N, Masala M, Cao A, Najjar SS, Terracciano A, Nedorezov T, Sharov A, Zonderman AB, Abecasis GR, Costa P, Lakatta E, Schlessinger D:Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2006;2:e132
10. Berenson GS:Childhood risk factors predict adult risk associated with subclinical cardiovascular disease. The Bogalusa Heart Study. Am J Cardiol 2002;90:3L-7L
11. Kathiresan S, Musunuru K, Orho-Melander M:Defining the spectrum of alleles that contribute to blood lipid concentrations in humans. Curr Opin Lipidol 2008;19:122-127
12. Friedlander Y, Austin MA, Newman B, Edwards K, Mayer-Davis El, King MC: Heritability of longitudinal changes in coronary-heart-disease risk factors in women twins. Am J Hum Genet 1997;60:1502-1512
13. Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, Girardet JP, Bonnet D:Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children:a prospective study. Lancet 2001;358:1400-1404
14. Bao W, Srinivasan SR, Wattigney WA, Berenson GS:Usefulness of childhood low-density lipoprotein cholesterol level in predicting adult dyslipidemia and other cardiovascular risks. The Bogalusa Heart Study. Arch Intern Med 1996; 156:1315-1320
15. Srinivasan SR, Berenson GS:Childhood lipoprotein profiles and implications for adult coronary artery disease:the Bogalusa Heart Study. Am J Med Sci 1995;310 Suppl 1:S62-67
16. Kort EN, Ballinger DG, Ding W, Hunt SC, Bowen BR, Abkevich V, Bulka K, Campbell B, Capener C, Gutin A, Harshman K, McDermott M, Thorne T, Wang H, Wardell B, Wong J, Hopkins PN, Skolnick M, Samuels M:Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23. Am J Hum Genet 2000;66:1845-1856
17. Manolio TA, Brooks LD, Collins FS:A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008;118:1590-1605
18. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee JY, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, et al:Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707-713
19. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, Strait J, Duren WL, Maschio A, Busonero F, Mulas A, Albai G, Swift AJ, Morken MA, Narisu N, Bennett D, Parish S, Shen H, Galan P, Meneton P, Hercberg S, Zelenika D, Chen WM, Li Y, Scott LJ, Scheet PA, Sundvall J, Watanabe RM, Nagaraja R, Ebrahim S, Lawlor DA, Ben-Shlomo Y, Davey-Smith G, Shuldiner AR, Collins R, Bergman RN, Uda M, Tuomilehto J, Cao A, Collins FS, Lakatta E, Lathrop GM, Boehnke M, Schlessinger D, Mohlke KL, Abecasis GR:Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161-169
20. Waterworth DM, Ricketts SL, Song K, Chen L, Zhao JH, Ripatti S, Aulchenko YS, Zhang W, Yuan X, Lim N, Luan J, Ashford S, Wheeler E, Young EH, Hadley D, Thompson JR, Braund PS, Johnson T, Struchalin M, Surakka I, Luben R, Khaw KT, Rodwell SA, Loos RJ, Boekholdt SM, Inouye M, Deloukas P, Elliott P, Schlessinger D, Sanna S, Scuteri A, Jackson A, Mohlke KL, Tuomilehto J, Roberts R, Stewart A, Kesaniemi YA, Mahley RW, Grundy SM, McArdle W, Cardon L, Waeber G, Vollenweider P, Chambers JC, Boehnke M, Abecasis GR, Salomaa V, Jarvelin MR, Ruokonen A, Barroso I, Epstein SE, Hakonarson HH, Rader DJ, Reilly MP, Witteman JC, Hall AS, Samani NJ, Strachan DP, Barter P, van Duijn CM, Kooner JS, Peltonen L, Wareham NJ, McPherson R, Mooser V, Sandhu MS:Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vase Bio12010;30:2264-2276
21. Wallace C, Newhouse SJ, Braund P, Zhang F, Tobin M, Falchi M, Ahmadi K, Dobson RJ, Marcano AC, Hajat C, Burton P, Deloukas P, Brown M, Connell JM, Dominiczak A5 Lathrop GM, Webster J, Farrall M, Spector T, Samani NJ, Caulfield MJ, Munroe PB:Genome-wide association study identifies genes for biomarkers of cardiovascular disease:serum urate and dyslipidemia. Am J Hum Genet 2008;82:139-149
22. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Kottgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O'Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM:Genome-wide association study of blood pressure and hypertension. Nat Genet 2009;41:677-687
23. Lettre G, Palmer CD, Young T, Ejebe KG, Allayee H, Benjamin EJ, Bennett F, Bowden DW, Chakravarti A, Dreisbach A, Farlow DN, Folsom AR, Fornage M, Forrester T, Fox E, Haiman CA, Hartiala J, Harris TB, Hazen SL, Heckbert SR, Henderson BE, Hirschhorn JN, Keating BJ, Kritchevsky SB, Larkin E, Li M, Rudock ME, McKenzie CA, Meigs JB, Meng YA, Mosley TH, Newman AB, Newton-Cheh CH, Paltoo DN, Papanicolaou GJ, Patterson N, Post WS, Psaty BM, Qasim AN, Qu L, Rader DJ, Redline S, Reilly MP, Reiner AP, Rich SS, Rotter JI, Liu Y, Shrader P, Siscovick DS, Tang WH, Taylor HA, Tracy RP, Vasan RS, Waters KM, Wilks R, Wilson JG, Fabsitz RR, Gabriel SB, Kathiresan S, Boerwinkle E:Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans:the NHLBI CARe Project. PLoS Genet 2011;7:el001300
24. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O'Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA: Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41:56-65
25. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189-197
26. Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, Roos C, Hirschhorn JN, Berglund G, Hedblad B, Groop L, Altshuler DM, Newton-Cheh C, Orho-Melander M: Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 2008;358:1240-1249
27. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Magi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song K, Goel A, Perry JR, Egan JM, Lajunen T, Grarup N, Sparso T, Doney A, Voight BF, Stringham HM, Li M, Kanoni S, Shrader P, Cavalcanti-Proenca C, Kumari M, Qi L, Timpson NJ, Gieger C, Zabena C, Rocheleau G, et al.:New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010;42:105-116
28. Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, Falchi M, Willemsen G, Hottenga JJ, de Geus EJ, Montgomery GW, Whitfield J, Magnusson P, Saharinen J, Perola M, Silander K, Isaacs A, Sijbrands EJ, Uitterlinden AG, Witteman JC, Oostra BA, Elliott P, Ruokonen A, Sabatti C, Gieger C, Meitinger T, Kronenberg F, Doring A, Wichmann HE, Smit JH, McCarthy MI, van Duijn CM, Peltonen L:Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009;41:47-55
29. Sandhu MS, Waterworth DM, Debenham SL, Wheeler E, Papadakis K, Zhao JH, Song K, Yuan X, Johnson T, Ashford S, Inouye M, Luben R, Sims M, Hadley D, McArdle W, Barter P, Kesaniemi YA, Mahley RW, McPherson R, Grundy SM, Bingham SA> Khaw KT, Loos RJ, Waeber G, Barroso I, Strachan DP, Deloukas P, Vollenweider P, Wareham NJ, Mooser V:LDL-cholesterol concentrations:a genome-wide association study. Lancet 2008;371:483-491
30. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Bostrom K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S:Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-1336
31. De Franca E, Alves JG, Hutz MH:Apolipoprotein E polymorphism and its association with serum lipid levels in Brazilian children. Hum Biol 2004;76:267-275
32. Tikkanen E, Tuovinen T, Widen E, Lehtimaki T, Viikari J, Kahonen M, Peltonen L, Raitakari OT, Ripatti S:Association of known loci with lipid levels among children and prediction of dyslipidemia in adults. Circ Cardiovasc Genet 2011;4:673-680
33. Murphy LD, Herzog CE, Rudick JB, Fojo AT, Bates SE:Use of the polymerase chain reaction in the quantitation of mdr-1 gene expression. Biochemistry 1990;29:10351-10356
34.郭杨,陈世界,郭万柱,李璟[3]：荧光定量PCR技术及其应用研究进展.动物医学进展2009；30：78-82
35.李洁：实时荧光定量PCR技术及实例分析.中国现代教育装备2009：47-50
36. Winer J, Jung CK, Shackel I, Williams PM:Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem 1999;270:41-49
37. Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S, Mullikin JC, Mortimore BJ, Willey DL, Hunt SE, Cole CG, Coggill PC, Rice CM, Ning Z, Rogers J, Bentley DR, Kwok PY, Mardis ER, Yeh RT, Schultz B, Cook L, Davenport R, Dante M, Fulton L, Hillier L, Waterston RH, McPherson JD, Gilman B, Schafner S, Van Etten WJ, Reich D, Higgins J, Daly MJ, Blumenstiel B, Baldwin J, Stange-Thomann N, Zody MC, Linton L, Lander ES, Altshuler D:A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001;409:928-933
38. Cheung VG, Spielman RS:The genetics of variation in gene expression. Nat Genet 2002;32 Suppl:522-525
39. Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, Burdick JT:Mapping determinants of human gene expression by regional and genome-wide association. Nature 2005;437:1365-1369
40. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS, Cheung VG:Genetic analysis of genome-wide variation in human gene expression. Nature 2004;430:743-747
41. Spielman RS, Bastone LA, Burdick JT, Morley M, Ewens WJ, Cheung VG:Common genetic variants account for differences in gene expression among ethnic groups. Nat Genet 2007;39:226-231
42. Zimmermann MB, Aeberli I:Dietary determinants of subclinical inflammation, dyslipidemia and components of the metabolic syndrome in overweight children:a review. Int J Obes (Lond) 2008;32 Supp16:S11-18
43. McCarty MF:Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increased glucagon activity. Med Hypotheses 1999;53:459-485
44. McCarty MF:The origins of western obesity:a role for animal protein? Med Hypotheses 2000;54:488-494
45. Parra D, Bandarra NM, Kiely M, Thorsdottir I, Martinez JA:Impact of fish intake on oxidative stress when included into a moderate energy-restricted program to treat obesity. Eur J Nutr 2007;46:460-467
46. Kavey RE, Daniels SR, Lauer RM, Atkins DL, Hayman LL, Taubert K:American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation 2003;107:1562-1566
47. Jebb SA, Lovegrove JA, Griffin BA, Frost GS, Moore CS, Chatfield MD, Bluck LJ, Williams CM, Sanders TA:Effect of changing the amount and type of fat and carbohydrate on insulin sensitivity and cardiovascular risk:the RISCK (Reading, Imperial, Surrey, Cambridge, and Kings) trial. Am J Clin Nutr 2010;92:748-758
48. Keys A, Parlin RW:Serum cholesterol response to changes in dietary lipids. Am J Clin Nutr 1966; 19:175-181
49. Corella D, Ordovas JM:SINGLE NUCLEOTIDE POLYMORPHISMS THAT INFLUENCE LIPID METABOLISM:Interaction with Dietary Factors. Annu Rev Nutr 2005;25:341-390
50. Masson LF, McNeill G, Avenell A:Genetic variation and the lipid response to dietary intervention:a systematic review. Am J Clin Nutr 2003;77:1098-1111
51. Ordovas JM, Corella D, Cupples LA, Demissie S, Kelleher A, Coltell O, Wilson PW, Schaefer EJ, Tucker K:Polyunsaturated fatty acids modulate the effects of the APOA1 G-A polymorphism on HDL-cholesterol concentrations in a sex-specific manner:the Framingham Study. Am J Clin Nutr 2002;75:38-46
52. Ordovas JM, Corella D, Demissie S, Cupples LA, Couture P, Coltell O, Wilson PW, Schaefer EJ, Tucker KL:Dietary fat intake determines the effect of a common polymorphism in the hepatic lipase gene promoter on high-density lipoprotein metabolism:evidence of a strong dose effect in this gene-nutrient interaction in the Framingham Study. Circulation 2002; 106:2315-2321
53. Petot GJ, Traore F, Debanne SM, Lerner AJ, Smyth KA, Friedland RP:Interactions of apolipoprotein E genotype and dietary fat intake of healthy older persons during mid-adult life. Metabolism 2003;52:279-281
54. Corella D, Carrasco P, Amiano P, Arriola L, Chirlaque MD, Huerta JM, Martinez C, Martinez-Camblor P, Molina E, Navarro C, Quiros JR, Rodriguez L, Sanchez MJ, Ortega-Azorin C, Ros E, Sala N, Gonzalez CA, Moreno C:Common cholesteryl ester transfer protein gene variation related to high-density lipoprotein cholesterol is not associated with decreased coronary heart disease risk after a 10-year follow-up in a Mediterranean cohort:Modulation by alcohol consumption. Atherosclerosis 2010;211:531-538
55. [Experts consensus for prevention and treatment of dyslipidemia in children and adolescents]. Zhonghua Er Ke Za Zhi 2009;47:426-428
56. Benjamini Y, Hochberg Y:Controlling the False Discovery Rate:a Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society B 1995;57:289-300
57. Shi YY, He L:SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 2005;15:97-98
58. Weedon MN, McCarthy MI, Hitman G, Walker M, Groves CJ, Zeggini E, Rayner NW, Shields B, Owen KR, Hattersley AT, Frayling TM:Combining information from common type 2 diabetes risk polymorphisms improves disease prediction. PLoS Med 2006;3:e374
59. Andersson T, Alfredsson L, Kallberg H, Zdravkovic S, Ahlbom A:Calculating measures of biological interaction. Eur J Epidemiol 2005;20:575-579
60. Holleboom AG, Karlsson H, Lin RS, Beres TM, Sierts JA, Herman DS, Stroes ES, Aerts JM, Kastelein JJ, Motazacker MM, Dallinga-Thie GM, Levels JH, Zwinderman AH, Seidman JG, Seidman CE, Ljunggren S, Lefeber DJ, Morava E, Wevers RA, Fritz TA, Tabak LA, Lindahl M, Hovingh GK, Kuivenhoven JA:Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man. Cell Metab 2011;14:811-818
61. Li Q, Yin RX, Yan TT, Miao L, Cao XL, Hu XJ, Aung LH, Wu DF, Wu JZ, Lin WX: Association of the GALNT2 gene polymorphisms and several environmental factors with serum lipid levels in the Mulao and Han populations. Lipids Health Dis 2011;10:160
62. Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PR, Orho-Melander M, Gloyn AL:The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 2009; 18:4081-4088
63. Tang W, Basu S, Kong X, Pankow JS, Aleksic N, Tan A, Cushman M, Boerwinkle E, Folsom AR:Genome-wide association study identifies novel loci for plasma levels of protein C:the ARIC study. Blood 2010;116:5032-5036
64. Saleheen D, Soranzo N, Rasheed A, Scharnagl H, Gwilliam R, Alexander M, Inouye M, Zaidi M, Potter S, Haycock P, Bumpstead S, Kaptoge S, Di Angelantonio E, Sarwar N, Hunt SE, Sheikh N, Shah N, Samuel M, Haider SR, Murtaza M, Thompson A, Gobin R, Butterworth A, Ahmad U, Hakeem A, Zaman KS, Kundi A, Yaqoob Z, Cheema LA, Qamar N, Faruqui A, Mallick NH3 Azhar M, Samad A, Ishaq M, Rasheed SZ, Jooma R, Niazi JH, Gardezi AR, Memon NA, Ghaffar A, Rehman FU, Hoffmann MM, Renner W, Kleber ME, Grammer TB, Stephens J, Attwood A, Koch K, Hussain M, Kumar K, Saleem A, Daood MS, Gul AA, Abbas S, Zafar J, Shahid F, Bhatti SM, Ali SS, Muhammad F, Sagoo G, Bray S, McGinnis R, Dudbridge F, Winkelmann BR, Boehm B, Thompson S, Ouwehand W, Marz W, Frossard P, Danesh J, Deloukas P:Genetic determinants of major blood lipids in Pakistanis compared with Europeans. Circ Cardiovasc Genet 2010;3:348-357
65. Merkel M, Weinstock PH, Chajek-Shaul T, Radner H, Yin B, Breslow JL, Goldberg IJ:Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia. J Clin Invest 1998; 102:893-901
66. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI:Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 2001;98:7522-7527
67. Burkhardt R, Toh SA, Lagor WR, Birkeland A, Levin M, Li X, Robblee M, Fedorov VD, Yamamoto M, Satoh T, Akira S, Kathiresan S, Breslow JL, Rader DJ:Tribl is a lipid-and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice. J Clin Invest 2010;120:4410-4414
68. Sabatti C, Service SK, Hartikainen AL, Pouta A, Ripatti S, Brodsky J, Jones CG, Zaitlen NA, Varilo T, Kaakinen M, Sovio U, Ruokonen A, Laitinen J, Jakkula E, Coin L, Hoggart C, Collins A, Turunen H, Gabriel S, Elliot P, McCarthy MI, Daly MJ, Jarvelin MR, Freimer NB, Peltonen L:Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 2009;41:35-46
69. Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK:Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J Clin Invest 1998;102:910-918
70. Schaap FG, Rensen PC, Voshol PJ, Vrins C, van der Vliet HN, Chamuleau RA, Havekes LM, Groen AK, van Dijk KW:ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. J Biol Chem 2004;279:27941-27947
71. Garces C, Oya I, Lasuncion MA, Lopez-Simon L, Cano B, de Oya M:Sex hormone-binding globulin and lipid profile in pubertal children. Metabolism 2010;59:166-171
72.叶葶葶：预防医学第3版.人民卫生出版社,2006,72-73
1. Forrester JS:Triglycerides:risk factor or fellow traveler? Curr Opin Cardiol 2001;16:261-264
2. Malloy MJ, Kane JP:A risk factor for atherosclerosis:triglyceride-rich lipoproteins. Adv Intern Med 2001;47:111-136
3. Kort EN, Ballinger DQ Ding W, Hunt SC, Bowen BR, Abkevich V, Bulka K, Campbell B, Capener C, Gutin A, Harshman K, McDermott M, Thorne T, Wang H, Wardell B, Wong J, Hopkins PN, Skolnick M, Samuels M:Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23. Am J Hum Genet 2000;66:1845-1856
4. Friedlander Y, Austin MA, Newman B, Edwards K, Mayer-Davis El, King MC: Heritability of longitudinal changes in coronary-heart-disease risk factors in women twins. Am J Hum Genet 1997;60:1502-1512
5. Kathiresan S, Musunuru K, Orho-Melander M:Defining the spectrum of alleles that contribute to blood lipid concentrations in humans. Curr Opin Lipidol 2008;19:122-127
6. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG:Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 2008;300:2142-2152
7. Marks D, Thorogood M, Neil HA, Humphries SE:A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 2003;168:1-14
8. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee JY, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, Zee RY, Wright AF, Witteman JC, Wilson JF, Willemsen G, Wichmann HE, Whitfield JB, Waterworth DM, Wareham NJ, Waeber G, Vollenweider P, Voight BF, Vitart V, Uitterlinden AG, Uda M, Tuomilehto J, Thompson JR, Tanaka T, Surakka I, Stringham HM, Spector TD, Soranzo N, Smit JH, Sinisalo J, Silander K, Sijbrands EJ, Scuteri A, Scott J, Schlessinger D, Sanna S, Salomaa V, Saharinen J, Sabatti C, Ruokonen A, Rudan I, Rose LM, Roberts R, Rieder M, Psaty BM, Pramstaller PP, Pichler I, Perola M, Penninx BW, Pedersen NL, Pattaro C, Parker AN, Pare G, Oostra BA, O'Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, Meitinger T, McPherson R, McCarthy MI, McArdle W, Masson D, Martin NG, Marroni F, Mangino M, Magnusson PK, Lucas G, Luben R, Loos RJ, Lokki ML, Lettre G, Langenberg C, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, Kronenberg F, Konig IR, Khaw KT, Kaprio J, Kaplan LM, Johansson A, Jarvelin MR, Janssens AC, Ingelsson E, Igl W, Kees Hovingh G, Hottenga JJ, Hofman A, Hicks AA, Hengstenberg C, Heid IM, Hayward C, Havulinna AS, Hastie ND, Harris TB, Haritunians T, Hall AS, Gyllensten U, Guiducci C, Groop LC, Gonzalez E, Gieger C, Freimer NB, Ferrucci L, Erdmann J, Elliott P, Ejebe KG, Doring A, Dominiczak AF, Demissie S, Deloukas P, de Geus EJ, de Faire U, Crawford G, Collins FS, Chen YD, Caulfield MJ, Campbell H, Burtt NP, Bonnycastle LL, Boomsma DI, Boekholdt SM, Bergman RN, Barroso I, Bandinelli S, Ballantyne CM, Assimes TL, Quertermous T, Altshuler D, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Adair LS, Taylor HA, Jr., Borecki IB, Gabriel SB, Wilson JG, Holm H, Thorsteinsdottir U, Gudnason V, Krauss RM, Mohlke KL, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE, Rotter JI, Boerwinkle E, Strachan DP, Mooser V, Stefansson K, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, van Duijn CM, Peltonen L, Abecasis GR, Boehnke M, Kathiresan S:Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707-713
9. Kathiresan S, Wilier CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O'Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA: Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41:56-65
10. Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, Li X, Li H, Kuperwasser N, Ruda VM, Pirruccello JP, Muchmore B, Prokunina-Olsson L, Hall JL, Schadt EE, Morales CR, Lund-Katz S, Phillips MC, Wong J, Cantley W, Racie T, Ejebe KG, Orho-Melander M, Melander O, Koteliansky V, Fitzgerald K, Krauss RM, Cowan CA, Kathiresan S, Rader DJ:From noncoding variant to phenotype via SORT1 at the Ip13 cholesterol locus. Nature 2010;466:714-719
11. Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S:Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010;363:2220-2227
12. Asselbergs FW, Guo Y, van Iperen EP, Sivapalaratnam S, Tragante V, Lanktree MB, Lange LA, Almoguera B, Appelman YE, Barnard J, Baumert J, Beitelshees AL, Bhangale TR, Chen YD, Gaunt TR, Gong Y, Hopewell JC, Johnson T, Kleber ME, Langaee TY, Li M, Li YR, Liu K, McDonough CW, Meijs MF, Middelberg RP, Musunuru K, Nelson CP, O'Connell JR, Padmanabhan S, Pankow JS, Pankratz N, Rafelt S, Rajagopalan R, Romaine SP, Schork NJ, Shaffer J, Shen H, Smith EN, Tischfield SE, van der Most PJ, van Vliet-Ostaptchouk JV, Verweij N, Volcik KA, Zhang L, Bailey KR, Bailey KM, Bauer F, Boer JM, Braund PS, Burt A, Burton PR, Buxbaum SG, Chen W, Cooper-Dehoff RM, Cupples LA, Dejong JS, Delles C, Duggan D, Fornage M, Furlong CE, Glazer N, Gums JG, Hastie C, Holmes MV, Illig T, Kirkland SA, Kivimaki M, Klein R, Klein BE, Kooperberg C, Kottke-Marchant K, Kumari M, Lacroix AZ, Mallela L, Murugesan G, Ordovas J, Ouwehand WH, Post WS, Saxena R, Scharnagl H, Schreiner PJ, Shah T, Shields DC, Shimbo D, Srinivasan SR, Stolk RP, Swerdlow DI, Taylor HA, Jr., Topol EJ, Toskala E, van Pelt JL, van Setten J, Yusuf S, Whittaker JC, Zwinderman AH, Anand SS, Balmforth AJ, Berenson GS, Bezzina CR, Boehm BO, Boerwinkle E, Casas JP, Caulfield MJ, Clarke R, Connell JM, Cruickshanks KJ, Davidson KW, Day IN, de Bakker PI, Doevendans PA, Dominiczak AF, Hall AS, Hartman CA, Hengstenberg C, Hillege HL, Hofker MH, Humphries SE, Jarvik GP, Johnson JA, Kaess BM, Kathiresan S, Koenig W, Lawlor DA, Marz W, Melander O, Mitchell BD, Montgomery GW, Munroe PB, Murray SS, Newhouse SJ, Onland-Moret NC, Poulter N, Psaty B, Redline S, Rich SS, Rotter JI, Schunkert H, Sever P, Shuldiner AR, Silverstein RL, Stanton A, Thorand B, Trip MD, Tsai MY, van der Harst P, van der Schoot E, van der Schouw YT, Verschuren WM, Watkins H, Wilde AA, Wolffenbuttel BH, Whitfield JB, Hovingh GK, Ballantyne CM, Wijmenga C, Reilly MP, Martin NG, Wilson JG Rader DJ, Samani NJ, Reiner AP, Hegele RA, Kastelein JJ, Hingorani AD, Talmud PJ, Hakonarson H, Elbers CC, Keating BJ, Drenos F:Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci. Am J Hum Genet 2012;91:823-838
13. Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, Falchi M, Willemsen G, Hottenga JJ, de Geus EJ, Montgomery GW, Whitfield J, Magnusson P, Saharinen J, Perola M, Silander K, Isaacs A, Sijbrands EJ, Uitterlinden AG, Witteman JC, Oostra BA, Elliott P, Ruokonen A, Sabatti C, Gieger C, Meitinger T, Kronenberg F, Doring A, Wichmann HE, Smit JH, McCarthy MI, van Duijn CM, Peltonen L:Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009;41:47-55
14. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189-197
15. Sabatti C, Service SK, Hartikainen AL, Pouta A, Ripatti S, Brodsky J, Jones CG, Zaitlen NA, Varilo T, Kaakinen M, Sovio U, Ruokonen A, Laitinen J, Jakkula E, Coin L, Hoggart C, Collins A, Turunen H, Gabriel S, Elliot P, McCarthy MI, Daly MJ, Jarvelin MR, Freimer NB, Peltonen L:Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 2009;41:35-46
16. Sandhu MS, Waterworth DM, Debenham SL, Wheeler E, Papadakis K, Zhao JH, Song K, Yuan X, Johnson T, Ashford S, Inouye M, Luben R, Sims M, Hadley D, McArdle W, Barter P, Kesaniemi YA, Mahley RW, McPherson R, Grundy SM, Bingham SA, Khaw KT, Loos RJ, Waeber G, Barroso I, Strachan DP, Deloukas P, Vollenweider P, Wareham NJ, Mooser V:LDL-cholesterol concentrations:a genome-wide association study. Lancet 2008;371:483-491
17. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Bostrom K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B? Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S:Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-1336
18. Wallace C, Newhouse SJ, Braund P, Zhang F, Tobin M, Falchi M, Ahmadi K, Dobson RJ, Marcano AC, Hajat C, Burton P, Deloukas P, Brown M, Connell JM, Dominiczak A, Lathrop GM, Webster J, Farrall M, Spector T, Samani NJ, Caulfield MJ, Munroe PB:Genome-wide association study identifies genes for biomarkers of cardiovascular disease:serum urate and dyslipidemia. Am J Hum Genet 2008;82:139-149
19. Waterworth DM, Ricketts SL, Song K, Chen L, Zhao JH, Ripatti S, Aulchenko YS, Zhang W, Yuan X, Lim N, Luan J, Ashford S, Wheeler E, Young EH, Hadley D, Thompson JR, Braund PS, Johnson T, Struchalin M, Surakka I, Luben R, Khaw KT, Rodwell SA, Loos RJ, Boekholdt SM, Inouye M, Deloukas P, Elliott P, Schlessinger D, Sanna S, Scuteri A, Jackson A, Mohlke KL, Tuomilehto J, Roberts R, Stewart A, Kesaniemi YA, Mahley RW, Grundy SM, McArdle W, Cardon L, Waeber G, Vollenweider P, Chambers JC, Boehnke M, Abecasis GR, Salomaa V, Jarvelin MR, Ruokonen A, Barroso I, Epstein SE, Hakonarson HH, Rader DJ, Reilly MP, Witteman JC, Hall AS, Samani NJ, Strachan DP, Barter P, van Duijn CM, Kooner JS, Peltonen L, Wareham NJ, McPherson R, Mooser V, Sandhu MS:Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vase Bio12010;30:2264-2276
20. Wilier CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, Strait J, Duren WL, Maschio A, Busonero F, Mulas A, Albai G, Swift AJ, Morken MA, Narisu N, Bennett D, Parish S, Shen H, Galan P, Meneton P, Hercberg S, Zelenika D, Chen WM, Li Y, Scott LJ, Scheet PA, Sundvall J, Watanabe RM, Nagaraja R, Ebrahim S, Lawlor DA, Ben-Shlomo Y, Davey-Smith G, Shuldiner AR, Collins R, Bergman RN, Uda M, Tuomilehto J, Cao A, Collins FS, Lakatta E, Lathrop GM, Boehnke M, Schlessinger D, Mohlke KL, Abecasis GR:Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161-169
21. Berenson GS:Childhood risk factors predict adult risk associated with subclinical cardiovascular disease. The Bogalusa Heart Study. Am J Cardiol 2002;90:3L-7L
22.米杰,程红,侯冬青,段佳丽,滕红红,王友发：北京市2004年2-18岁儿童青少 年超重和肥胖流行现状.中华流行病学杂志2006；27：469-474
23.刘颖,米杰,杜军保：北京地区6-18岁儿童血脂紊乱现况调查.中国实用儿科杂志2007；22：101-102
24.万乃君,米杰,王天有,段佳丽,黎明,巩纯秀,杜军保,赵小元,程红,侯冬青,王俐：北京市超重和肥胖学龄儿童中代谢综合征的流行特征.中华儿科杂志2007；45：417-421
25. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J,3rd:Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study. Ann Intern Med 1961;55:33-50
26. Pilia G, Chen WM, Scuteri A, Orru M, Albai G, Dei M, Lai S, Usala G, Lai M, Loi P, Mameli C, Vacca L, Deiana M, Olla N, Masala M, Cao A, Najjar SS, Terracciano A, Nedorezov T, Sharov A, Zonderman AB, Abecasis GR, Costa P, Lakatta E, Schlessinger D:Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2006;2:e132
27. Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, Girardet JP, Bonnet D:Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children:a prospective study. Lancet 2001;358:1400-1404
28. Bao W, Srinivasan SR, Wattigney WA, Berenson GS:Usefulness of childhood low-density lipoprotein cholesterol level in predicting adult dyslipidemia and other cardiovascular risks. The Bogalusa Heart Study. Arch Intern Med 1996;156:1315-1320
29. Srinivasan SR, Frontini MG, Xu J, Berenson GS:Utility of childhood non-high-density lipoprotein cholesterol levels in predicting adult dyslipidemia and other cardiovascular risks:the Bogalusa Heart Study. Pediatrics 2006; 118:201-206
30. Srinivasan SR, Berenson GS:Childhood lipoprotein profiles and implications for adult coronary artery disease:the Bogalusa Heart Study. Am J Med Sci 1995;310 Suppl 1:S62-67
31. Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, Dykas DJ, Bale AE, Giannini C, Pierpont B, Shaw MM, Groop L, Caprio S:Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 2012;55:781-789
32. Makimura M, Ihara K, Kojima-Ishii K, Nozaki T, Ohkubo K, Kohno H, Kishimoto J, Hara T:The signal transducer and activator of transcription 5B gene polymorphism contributes to the cholesterol metabolism in Japanese children with growth hormone deficiency. Clin Endocrinol (Oxf) 2011;74:611-617
33. Lee JC, Weissglas-Volkov D, Kyttala M, Dastani Z, Cantor RM, Sobel EM, Plaisier CL, Engert JC, van Greevenbroek MM, Kane JP, Malloy MJ, Pullinger CR, Huertas-Vazquez A, Aguilar-Salinas CA, Tusie-Luna T, de Bruin TW, Aouizerat BE, van der Kallen CC, Croce CM, Aqeilan RI, Marcil M, Viikari JS, Lehtimaki T, Raitakari OT, Kuusisto J, Laakso M, Taskinen MR, Genest J, Pajukanta P: WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels. Am J Hum Genet 2008;83:180-192
34. Wu J, Yan WJ, Mo J, Yang HB, Wang ZZ, Lei MX, Peng LW:[Association of adiponectin gene polymorphism with obesity in children]. Zhongguo Dang Dai Er Ke Za Zhi 2011;13:539-542
35. Mong JL, Ng MC, Guldan GS, Tam CH, Lee HM, Ma RC, So WY, Wong GW, Kong AP, Chan JC, Waye MM:Associations of the growth hormone receptor (GHR) gene polymorphisms with adiposity and IGF-I activity in adolescents. Clin Endocrinol (Oxf) 2010; 73:313-322
36. Brown MS, Goldstein JL:Expression of the familial hypercholesterolemia gene in heterozygotes:mechanism for a dominant disorder in man. Science 1974; 185:61-63
37. Linsel-Nitschke P, Gotz A, Erdmann J, Braenne I, Braund P, Hengstenberg C, Stark K, Fischer M, Schreiber S, El Mokhtari NE, Schaefer A, Schrezenmeir J, Rubin D, Hinney A, Reinehr T, Roth C, Ortlepp J, Hanrath P, Hall AS, Mangino M, Lieb W, Lamina C, Heid IM, Doering A, Gieger C, Peters A, Meitinger T, Wichmann HE, Konig IR, Ziegler A, Kronenberg F, Samani NJ, Schunkert H:Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study. PLoS One 2008;3:e2986
38. Hegele RA, Ramdath DD, Ban MR, Carruthers MN, Carrington CV, Cao H: Polymorphisms in PNLIP, encoding pancreatic lipase, and associations with metabolic traits. J Hum Genet 2001;46:320-324
39. Hamon SC, Kardia SL, Boerwinkle E, Liu K, Klos KL, Clark AG, Sing CF:Evidence for consistent intragenic and intergenic interactions between SNP effects in the APOA1/C3/A4/A5 gene cluster. Hum Hered 2006;61:87-96
40. Tam CH, Ma RC, So WY, Wang Y, Lam VK, Germer S, Martin M, Chan JC, Ng MC: Interaction effect of genetic polymorphisms in glucokinase (GCK) and glucokinase regulatory protein (GCKR) on metabolic traits in healthy Chinese adults and adolescents. Diabetes 2009;58:765-769
41.谭建新,孙玉洁：表观基因组学研究方法进展与评价.遗传2009；31：3-12
42. Sacco J, Adeli K:MicroRNAs:emerging roles in lipid and lipoprotein metabolism. Curr Opin Lipidol 2012;23:220-225
2. Malloy MJ, Kane JP:A risk factor for atherosclerosis:triglyceride-rich lipoproteins. Adv Intern Med 2001;47:111-136
3. Keith SW, Redden DT, Katzmarzyk PT, Boggiano MM, Hanlon EC, Benca RM, Ruden D, Pietrobelli A, Barger JL, Fontaine KR, Wang C, Aronne LJ, Wright SM, Baskin M, Dhurandhar NV, Lijoi MC, Grilo CM, DeLuca M, Westfall AO, Allison DB:Putative contributors to the secular increase in obesity:exploring the roads less traveled. Int J Obes (Lond) 2006;30:1585-1594
4.米杰,程红,侯冬青,段佳丽,滕红红,王友发：北京市2004年2-18岁儿童青少年超重和肥胖流行现状.中华流行病学杂志2006；27：469-474
5.刘颖,米杰,杜军保：北京地区6-18岁儿童血脂紊乱现况调查.中国实用儿科杂志2007；22：101-102
6.万乃君,米杰,王天有,段佳丽,黎明,巩纯秀,杜军保,赵小元,程红,侯冬青,王俐：北京市超重和肥胖学龄儿童中代谢综合征的流行特征.中华儿科杂志2007；45：417-421
7. Miller NE, Miller GJ:Letter:High-density lipoprotein and atherosclerosis. Lancet 1975;1:1033
8. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J,3rd:Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study. Ann Intern Med 1961;55:33-50
9. Pilia G, Chen WM, Scuteri A, Orru M, Albai G, Dei M, Lai S, Usala G, Lai M, Loi P, Mameli C, Vacca L, Deiana M, Olla N, Masala M, Cao A, Najjar SS, Terracciano A, Nedorezov T, Sharov A, Zonderman AB, Abecasis GR, Costa P, Lakatta E, Schlessinger D:Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2006;2:e132
10. Berenson GS:Childhood risk factors predict adult risk associated with subclinical cardiovascular disease. The Bogalusa Heart Study. Am J Cardiol 2002;90:3L-7L
11. Kathiresan S, Musunuru K, Orho-Melander M:Defining the spectrum of alleles that contribute to blood lipid concentrations in humans. Curr Opin Lipidol 2008;19:122-127
12. Friedlander Y, Austin MA, Newman B, Edwards K, Mayer-Davis El, King MC: Heritability of longitudinal changes in coronary-heart-disease risk factors in women twins. Am J Hum Genet 1997;60:1502-1512
13. Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, Girardet JP, Bonnet D:Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children:a prospective study. Lancet 2001;358:1400-1404
14. Bao W, Srinivasan SR, Wattigney WA, Berenson GS:Usefulness of childhood low-density lipoprotein cholesterol level in predicting adult dyslipidemia and other cardiovascular risks. The Bogalusa Heart Study. Arch Intern Med 1996; 156:1315-1320
15. Srinivasan SR, Berenson GS:Childhood lipoprotein profiles and implications for adult coronary artery disease:the Bogalusa Heart Study. Am J Med Sci 1995;310 Suppl 1:S62-67
16. Kort EN, Ballinger DG, Ding W, Hunt SC, Bowen BR, Abkevich V, Bulka K, Campbell B, Capener C, Gutin A, Harshman K, McDermott M, Thorne T, Wang H, Wardell B, Wong J, Hopkins PN, Skolnick M, Samuels M:Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23. Am J Hum Genet 2000;66:1845-1856
17. Manolio TA, Brooks LD, Collins FS:A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008;118:1590-1605
18. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee JY, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, et al:Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707-713
19. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, Strait J, Duren WL, Maschio A, Busonero F, Mulas A, Albai G, Swift AJ, Morken MA, Narisu N, Bennett D, Parish S, Shen H, Galan P, Meneton P, Hercberg S, Zelenika D, Chen WM, Li Y, Scott LJ, Scheet PA, Sundvall J, Watanabe RM, Nagaraja R, Ebrahim S, Lawlor DA, Ben-Shlomo Y, Davey-Smith G, Shuldiner AR, Collins R, Bergman RN, Uda M, Tuomilehto J, Cao A, Collins FS, Lakatta E, Lathrop GM, Boehnke M, Schlessinger D, Mohlke KL, Abecasis GR:Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161-169
20. Waterworth DM, Ricketts SL, Song K, Chen L, Zhao JH, Ripatti S, Aulchenko YS, Zhang W, Yuan X, Lim N, Luan J, Ashford S, Wheeler E, Young EH, Hadley D, Thompson JR, Braund PS, Johnson T, Struchalin M, Surakka I, Luben R, Khaw KT, Rodwell SA, Loos RJ, Boekholdt SM, Inouye M, Deloukas P, Elliott P, Schlessinger D, Sanna S, Scuteri A, Jackson A, Mohlke KL, Tuomilehto J, Roberts R, Stewart A, Kesaniemi YA, Mahley RW, Grundy SM, McArdle W, Cardon L, Waeber G, Vollenweider P, Chambers JC, Boehnke M, Abecasis GR, Salomaa V, Jarvelin MR, Ruokonen A, Barroso I, Epstein SE, Hakonarson HH, Rader DJ, Reilly MP, Witteman JC, Hall AS, Samani NJ, Strachan DP, Barter P, van Duijn CM, Kooner JS, Peltonen L, Wareham NJ, McPherson R, Mooser V, Sandhu MS:Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vase Bio12010;30:2264-2276
21. Wallace C, Newhouse SJ, Braund P, Zhang F, Tobin M, Falchi M, Ahmadi K, Dobson RJ, Marcano AC, Hajat C, Burton P, Deloukas P, Brown M, Connell JM, Dominiczak A5 Lathrop GM, Webster J, Farrall M, Spector T, Samani NJ, Caulfield MJ, Munroe PB:Genome-wide association study identifies genes for biomarkers of cardiovascular disease:serum urate and dyslipidemia. Am J Hum Genet 2008;82:139-149
22. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Kottgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O'Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM:Genome-wide association study of blood pressure and hypertension. Nat Genet 2009;41:677-687
23. Lettre G, Palmer CD, Young T, Ejebe KG, Allayee H, Benjamin EJ, Bennett F, Bowden DW, Chakravarti A, Dreisbach A, Farlow DN, Folsom AR, Fornage M, Forrester T, Fox E, Haiman CA, Hartiala J, Harris TB, Hazen SL, Heckbert SR, Henderson BE, Hirschhorn JN, Keating BJ, Kritchevsky SB, Larkin E, Li M, Rudock ME, McKenzie CA, Meigs JB, Meng YA, Mosley TH, Newman AB, Newton-Cheh CH, Paltoo DN, Papanicolaou GJ, Patterson N, Post WS, Psaty BM, Qasim AN, Qu L, Rader DJ, Redline S, Reilly MP, Reiner AP, Rich SS, Rotter JI, Liu Y, Shrader P, Siscovick DS, Tang WH, Taylor HA, Tracy RP, Vasan RS, Waters KM, Wilks R, Wilson JG, Fabsitz RR, Gabriel SB, Kathiresan S, Boerwinkle E:Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans:the NHLBI CARe Project. PLoS Genet 2011;7:el001300
24. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O'Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA: Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41:56-65
25. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189-197
26. Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, Roos C, Hirschhorn JN, Berglund G, Hedblad B, Groop L, Altshuler DM, Newton-Cheh C, Orho-Melander M: Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 2008;358:1240-1249
27. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Magi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song K, Goel A, Perry JR, Egan JM, Lajunen T, Grarup N, Sparso T, Doney A, Voight BF, Stringham HM, Li M, Kanoni S, Shrader P, Cavalcanti-Proenca C, Kumari M, Qi L, Timpson NJ, Gieger C, Zabena C, Rocheleau G, et al.:New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010;42:105-116
28. Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, Falchi M, Willemsen G, Hottenga JJ, de Geus EJ, Montgomery GW, Whitfield J, Magnusson P, Saharinen J, Perola M, Silander K, Isaacs A, Sijbrands EJ, Uitterlinden AG, Witteman JC, Oostra BA, Elliott P, Ruokonen A, Sabatti C, Gieger C, Meitinger T, Kronenberg F, Doring A, Wichmann HE, Smit JH, McCarthy MI, van Duijn CM, Peltonen L:Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009;41:47-55
29. Sandhu MS, Waterworth DM, Debenham SL, Wheeler E, Papadakis K, Zhao JH, Song K, Yuan X, Johnson T, Ashford S, Inouye M, Luben R, Sims M, Hadley D, McArdle W, Barter P, Kesaniemi YA, Mahley RW, McPherson R, Grundy SM, Bingham SA> Khaw KT, Loos RJ, Waeber G, Barroso I, Strachan DP, Deloukas P, Vollenweider P, Wareham NJ, Mooser V:LDL-cholesterol concentrations:a genome-wide association study. Lancet 2008;371:483-491
30. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Bostrom K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S:Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-1336
31. De Franca E, Alves JG, Hutz MH:Apolipoprotein E polymorphism and its association with serum lipid levels in Brazilian children. Hum Biol 2004;76:267-275
32. Tikkanen E, Tuovinen T, Widen E, Lehtimaki T, Viikari J, Kahonen M, Peltonen L, Raitakari OT, Ripatti S:Association of known loci with lipid levels among children and prediction of dyslipidemia in adults. Circ Cardiovasc Genet 2011;4:673-680
33. Murphy LD, Herzog CE, Rudick JB, Fojo AT, Bates SE:Use of the polymerase chain reaction in the quantitation of mdr-1 gene expression. Biochemistry 1990;29:10351-10356
34.郭杨,陈世界,郭万柱,李璟[3]：荧光定量PCR技术及其应用研究进展.动物医学进展2009；30：78-82
35.李洁：实时荧光定量PCR技术及实例分析.中国现代教育装备2009：47-50
36. Winer J, Jung CK, Shackel I, Williams PM:Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem 1999;270:41-49
37. Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S, Mullikin JC, Mortimore BJ, Willey DL, Hunt SE, Cole CG, Coggill PC, Rice CM, Ning Z, Rogers J, Bentley DR, Kwok PY, Mardis ER, Yeh RT, Schultz B, Cook L, Davenport R, Dante M, Fulton L, Hillier L, Waterston RH, McPherson JD, Gilman B, Schafner S, Van Etten WJ, Reich D, Higgins J, Daly MJ, Blumenstiel B, Baldwin J, Stange-Thomann N, Zody MC, Linton L, Lander ES, Altshuler D:A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001;409:928-933
38. Cheung VG, Spielman RS:The genetics of variation in gene expression. Nat Genet 2002;32 Suppl:522-525
39. Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, Burdick JT:Mapping determinants of human gene expression by regional and genome-wide association. Nature 2005;437:1365-1369
40. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS, Cheung VG:Genetic analysis of genome-wide variation in human gene expression. Nature 2004;430:743-747
41. Spielman RS, Bastone LA, Burdick JT, Morley M, Ewens WJ, Cheung VG:Common genetic variants account for differences in gene expression among ethnic groups. Nat Genet 2007;39:226-231
42. Zimmermann MB, Aeberli I:Dietary determinants of subclinical inflammation, dyslipidemia and components of the metabolic syndrome in overweight children:a review. Int J Obes (Lond) 2008;32 Supp16:S11-18
43. McCarty MF:Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increased glucagon activity. Med Hypotheses 1999;53:459-485
44. McCarty MF:The origins of western obesity:a role for animal protein? Med Hypotheses 2000;54:488-494
45. Parra D, Bandarra NM, Kiely M, Thorsdottir I, Martinez JA:Impact of fish intake on oxidative stress when included into a moderate energy-restricted program to treat obesity. Eur J Nutr 2007;46:460-467
46. Kavey RE, Daniels SR, Lauer RM, Atkins DL, Hayman LL, Taubert K:American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation 2003;107:1562-1566
47. Jebb SA, Lovegrove JA, Griffin BA, Frost GS, Moore CS, Chatfield MD, Bluck LJ, Williams CM, Sanders TA:Effect of changing the amount and type of fat and carbohydrate on insulin sensitivity and cardiovascular risk:the RISCK (Reading, Imperial, Surrey, Cambridge, and Kings) trial. Am J Clin Nutr 2010;92:748-758
48. Keys A, Parlin RW:Serum cholesterol response to changes in dietary lipids. Am J Clin Nutr 1966; 19:175-181
49. Corella D, Ordovas JM:SINGLE NUCLEOTIDE POLYMORPHISMS THAT INFLUENCE LIPID METABOLISM:Interaction with Dietary Factors. Annu Rev Nutr 2005;25:341-390
50. Masson LF, McNeill G, Avenell A:Genetic variation and the lipid response to dietary intervention:a systematic review. Am J Clin Nutr 2003;77:1098-1111
51. Ordovas JM, Corella D, Cupples LA, Demissie S, Kelleher A, Coltell O, Wilson PW, Schaefer EJ, Tucker K:Polyunsaturated fatty acids modulate the effects of the APOA1 G-A polymorphism on HDL-cholesterol concentrations in a sex-specific manner:the Framingham Study. Am J Clin Nutr 2002;75:38-46
52. Ordovas JM, Corella D, Demissie S, Cupples LA, Couture P, Coltell O, Wilson PW, Schaefer EJ, Tucker KL:Dietary fat intake determines the effect of a common polymorphism in the hepatic lipase gene promoter on high-density lipoprotein metabolism:evidence of a strong dose effect in this gene-nutrient interaction in the Framingham Study. Circulation 2002; 106:2315-2321
53. Petot GJ, Traore F, Debanne SM, Lerner AJ, Smyth KA, Friedland RP:Interactions of apolipoprotein E genotype and dietary fat intake of healthy older persons during mid-adult life. Metabolism 2003;52:279-281
54. Corella D, Carrasco P, Amiano P, Arriola L, Chirlaque MD, Huerta JM, Martinez C, Martinez-Camblor P, Molina E, Navarro C, Quiros JR, Rodriguez L, Sanchez MJ, Ortega-Azorin C, Ros E, Sala N, Gonzalez CA, Moreno C:Common cholesteryl ester transfer protein gene variation related to high-density lipoprotein cholesterol is not associated with decreased coronary heart disease risk after a 10-year follow-up in a Mediterranean cohort:Modulation by alcohol consumption. Atherosclerosis 2010;211:531-538
55. [Experts consensus for prevention and treatment of dyslipidemia in children and adolescents]. Zhonghua Er Ke Za Zhi 2009;47:426-428
56. Benjamini Y, Hochberg Y:Controlling the False Discovery Rate:a Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society B 1995;57:289-300
57. Shi YY, He L:SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 2005;15:97-98
58. Weedon MN, McCarthy MI, Hitman G, Walker M, Groves CJ, Zeggini E, Rayner NW, Shields B, Owen KR, Hattersley AT, Frayling TM:Combining information from common type 2 diabetes risk polymorphisms improves disease prediction. PLoS Med 2006;3:e374
59. Andersson T, Alfredsson L, Kallberg H, Zdravkovic S, Ahlbom A:Calculating measures of biological interaction. Eur J Epidemiol 2005;20:575-579
60. Holleboom AG, Karlsson H, Lin RS, Beres TM, Sierts JA, Herman DS, Stroes ES, Aerts JM, Kastelein JJ, Motazacker MM, Dallinga-Thie GM, Levels JH, Zwinderman AH, Seidman JG, Seidman CE, Ljunggren S, Lefeber DJ, Morava E, Wevers RA, Fritz TA, Tabak LA, Lindahl M, Hovingh GK, Kuivenhoven JA:Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man. Cell Metab 2011;14:811-818
61. Li Q, Yin RX, Yan TT, Miao L, Cao XL, Hu XJ, Aung LH, Wu DF, Wu JZ, Lin WX: Association of the GALNT2 gene polymorphisms and several environmental factors with serum lipid levels in the Mulao and Han populations. Lipids Health Dis 2011;10:160
62. Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PR, Orho-Melander M, Gloyn AL:The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 2009; 18:4081-4088
63. Tang W, Basu S, Kong X, Pankow JS, Aleksic N, Tan A, Cushman M, Boerwinkle E, Folsom AR:Genome-wide association study identifies novel loci for plasma levels of protein C:the ARIC study. Blood 2010;116:5032-5036
64. Saleheen D, Soranzo N, Rasheed A, Scharnagl H, Gwilliam R, Alexander M, Inouye M, Zaidi M, Potter S, Haycock P, Bumpstead S, Kaptoge S, Di Angelantonio E, Sarwar N, Hunt SE, Sheikh N, Shah N, Samuel M, Haider SR, Murtaza M, Thompson A, Gobin R, Butterworth A, Ahmad U, Hakeem A, Zaman KS, Kundi A, Yaqoob Z, Cheema LA, Qamar N, Faruqui A, Mallick NH3 Azhar M, Samad A, Ishaq M, Rasheed SZ, Jooma R, Niazi JH, Gardezi AR, Memon NA, Ghaffar A, Rehman FU, Hoffmann MM, Renner W, Kleber ME, Grammer TB, Stephens J, Attwood A, Koch K, Hussain M, Kumar K, Saleem A, Daood MS, Gul AA, Abbas S, Zafar J, Shahid F, Bhatti SM, Ali SS, Muhammad F, Sagoo G, Bray S, McGinnis R, Dudbridge F, Winkelmann BR, Boehm B, Thompson S, Ouwehand W, Marz W, Frossard P, Danesh J, Deloukas P:Genetic determinants of major blood lipids in Pakistanis compared with Europeans. Circ Cardiovasc Genet 2010;3:348-357
65. Merkel M, Weinstock PH, Chajek-Shaul T, Radner H, Yin B, Breslow JL, Goldberg IJ:Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia. J Clin Invest 1998; 102:893-901
66. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI:Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 2001;98:7522-7527
67. Burkhardt R, Toh SA, Lagor WR, Birkeland A, Levin M, Li X, Robblee M, Fedorov VD, Yamamoto M, Satoh T, Akira S, Kathiresan S, Breslow JL, Rader DJ:Tribl is a lipid-and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice. J Clin Invest 2010;120:4410-4414
68. Sabatti C, Service SK, Hartikainen AL, Pouta A, Ripatti S, Brodsky J, Jones CG, Zaitlen NA, Varilo T, Kaakinen M, Sovio U, Ruokonen A, Laitinen J, Jakkula E, Coin L, Hoggart C, Collins A, Turunen H, Gabriel S, Elliot P, McCarthy MI, Daly MJ, Jarvelin MR, Freimer NB, Peltonen L:Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 2009;41:35-46
69. Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK:Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J Clin Invest 1998;102:910-918
70. Schaap FG, Rensen PC, Voshol PJ, Vrins C, van der Vliet HN, Chamuleau RA, Havekes LM, Groen AK, van Dijk KW:ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. J Biol Chem 2004;279:27941-27947
71. Garces C, Oya I, Lasuncion MA, Lopez-Simon L, Cano B, de Oya M:Sex hormone-binding globulin and lipid profile in pubertal children. Metabolism 2010;59:166-171
72.叶葶葶：预防医学第3版.人民卫生出版社,2006,72-73
1. Forrester JS:Triglycerides:risk factor or fellow traveler? Curr Opin Cardiol 2001;16:261-264
2. Malloy MJ, Kane JP:A risk factor for atherosclerosis:triglyceride-rich lipoproteins. Adv Intern Med 2001;47:111-136
3. Kort EN, Ballinger DQ Ding W, Hunt SC, Bowen BR, Abkevich V, Bulka K, Campbell B, Capener C, Gutin A, Harshman K, McDermott M, Thorne T, Wang H, Wardell B, Wong J, Hopkins PN, Skolnick M, Samuels M:Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23. Am J Hum Genet 2000;66:1845-1856
4. Friedlander Y, Austin MA, Newman B, Edwards K, Mayer-Davis El, King MC: Heritability of longitudinal changes in coronary-heart-disease risk factors in women twins. Am J Hum Genet 1997;60:1502-1512
5. Kathiresan S, Musunuru K, Orho-Melander M:Defining the spectrum of alleles that contribute to blood lipid concentrations in humans. Curr Opin Lipidol 2008;19:122-127
6. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG:Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 2008;300:2142-2152
7. Marks D, Thorogood M, Neil HA, Humphries SE:A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 2003;168:1-14
8. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee JY, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, Zee RY, Wright AF, Witteman JC, Wilson JF, Willemsen G, Wichmann HE, Whitfield JB, Waterworth DM, Wareham NJ, Waeber G, Vollenweider P, Voight BF, Vitart V, Uitterlinden AG, Uda M, Tuomilehto J, Thompson JR, Tanaka T, Surakka I, Stringham HM, Spector TD, Soranzo N, Smit JH, Sinisalo J, Silander K, Sijbrands EJ, Scuteri A, Scott J, Schlessinger D, Sanna S, Salomaa V, Saharinen J, Sabatti C, Ruokonen A, Rudan I, Rose LM, Roberts R, Rieder M, Psaty BM, Pramstaller PP, Pichler I, Perola M, Penninx BW, Pedersen NL, Pattaro C, Parker AN, Pare G, Oostra BA, O'Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, Meitinger T, McPherson R, McCarthy MI, McArdle W, Masson D, Martin NG, Marroni F, Mangino M, Magnusson PK, Lucas G, Luben R, Loos RJ, Lokki ML, Lettre G, Langenberg C, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, Kronenberg F, Konig IR, Khaw KT, Kaprio J, Kaplan LM, Johansson A, Jarvelin MR, Janssens AC, Ingelsson E, Igl W, Kees Hovingh G, Hottenga JJ, Hofman A, Hicks AA, Hengstenberg C, Heid IM, Hayward C, Havulinna AS, Hastie ND, Harris TB, Haritunians T, Hall AS, Gyllensten U, Guiducci C, Groop LC, Gonzalez E, Gieger C, Freimer NB, Ferrucci L, Erdmann J, Elliott P, Ejebe KG, Doring A, Dominiczak AF, Demissie S, Deloukas P, de Geus EJ, de Faire U, Crawford G, Collins FS, Chen YD, Caulfield MJ, Campbell H, Burtt NP, Bonnycastle LL, Boomsma DI, Boekholdt SM, Bergman RN, Barroso I, Bandinelli S, Ballantyne CM, Assimes TL, Quertermous T, Altshuler D, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Adair LS, Taylor HA, Jr., Borecki IB, Gabriel SB, Wilson JG, Holm H, Thorsteinsdottir U, Gudnason V, Krauss RM, Mohlke KL, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE, Rotter JI, Boerwinkle E, Strachan DP, Mooser V, Stefansson K, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, van Duijn CM, Peltonen L, Abecasis GR, Boehnke M, Kathiresan S:Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707-713
9. Kathiresan S, Wilier CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O'Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA: Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41:56-65
10. Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, Li X, Li H, Kuperwasser N, Ruda VM, Pirruccello JP, Muchmore B, Prokunina-Olsson L, Hall JL, Schadt EE, Morales CR, Lund-Katz S, Phillips MC, Wong J, Cantley W, Racie T, Ejebe KG, Orho-Melander M, Melander O, Koteliansky V, Fitzgerald K, Krauss RM, Cowan CA, Kathiresan S, Rader DJ:From noncoding variant to phenotype via SORT1 at the Ip13 cholesterol locus. Nature 2010;466:714-719
11. Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S:Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010;363:2220-2227
12. Asselbergs FW, Guo Y, van Iperen EP, Sivapalaratnam S, Tragante V, Lanktree MB, Lange LA, Almoguera B, Appelman YE, Barnard J, Baumert J, Beitelshees AL, Bhangale TR, Chen YD, Gaunt TR, Gong Y, Hopewell JC, Johnson T, Kleber ME, Langaee TY, Li M, Li YR, Liu K, McDonough CW, Meijs MF, Middelberg RP, Musunuru K, Nelson CP, O'Connell JR, Padmanabhan S, Pankow JS, Pankratz N, Rafelt S, Rajagopalan R, Romaine SP, Schork NJ, Shaffer J, Shen H, Smith EN, Tischfield SE, van der Most PJ, van Vliet-Ostaptchouk JV, Verweij N, Volcik KA, Zhang L, Bailey KR, Bailey KM, Bauer F, Boer JM, Braund PS, Burt A, Burton PR, Buxbaum SG, Chen W, Cooper-Dehoff RM, Cupples LA, Dejong JS, Delles C, Duggan D, Fornage M, Furlong CE, Glazer N, Gums JG, Hastie C, Holmes MV, Illig T, Kirkland SA, Kivimaki M, Klein R, Klein BE, Kooperberg C, Kottke-Marchant K, Kumari M, Lacroix AZ, Mallela L, Murugesan G, Ordovas J, Ouwehand WH, Post WS, Saxena R, Scharnagl H, Schreiner PJ, Shah T, Shields DC, Shimbo D, Srinivasan SR, Stolk RP, Swerdlow DI, Taylor HA, Jr., Topol EJ, Toskala E, van Pelt JL, van Setten J, Yusuf S, Whittaker JC, Zwinderman AH, Anand SS, Balmforth AJ, Berenson GS, Bezzina CR, Boehm BO, Boerwinkle E, Casas JP, Caulfield MJ, Clarke R, Connell JM, Cruickshanks KJ, Davidson KW, Day IN, de Bakker PI, Doevendans PA, Dominiczak AF, Hall AS, Hartman CA, Hengstenberg C, Hillege HL, Hofker MH, Humphries SE, Jarvik GP, Johnson JA, Kaess BM, Kathiresan S, Koenig W, Lawlor DA, Marz W, Melander O, Mitchell BD, Montgomery GW, Munroe PB, Murray SS, Newhouse SJ, Onland-Moret NC, Poulter N, Psaty B, Redline S, Rich SS, Rotter JI, Schunkert H, Sever P, Shuldiner AR, Silverstein RL, Stanton A, Thorand B, Trip MD, Tsai MY, van der Harst P, van der Schoot E, van der Schouw YT, Verschuren WM, Watkins H, Wilde AA, Wolffenbuttel BH, Whitfield JB, Hovingh GK, Ballantyne CM, Wijmenga C, Reilly MP, Martin NG, Wilson JG Rader DJ, Samani NJ, Reiner AP, Hegele RA, Kastelein JJ, Hingorani AD, Talmud PJ, Hakonarson H, Elbers CC, Keating BJ, Drenos F:Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci. Am J Hum Genet 2012;91:823-838
13. Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, Falchi M, Willemsen G, Hottenga JJ, de Geus EJ, Montgomery GW, Whitfield J, Magnusson P, Saharinen J, Perola M, Silander K, Isaacs A, Sijbrands EJ, Uitterlinden AG, Witteman JC, Oostra BA, Elliott P, Ruokonen A, Sabatti C, Gieger C, Meitinger T, Kronenberg F, Doring A, Wichmann HE, Smit JH, McCarthy MI, van Duijn CM, Peltonen L:Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009;41:47-55
14. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189-197
15. Sabatti C, Service SK, Hartikainen AL, Pouta A, Ripatti S, Brodsky J, Jones CG, Zaitlen NA, Varilo T, Kaakinen M, Sovio U, Ruokonen A, Laitinen J, Jakkula E, Coin L, Hoggart C, Collins A, Turunen H, Gabriel S, Elliot P, McCarthy MI, Daly MJ, Jarvelin MR, Freimer NB, Peltonen L:Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 2009;41:35-46
16. Sandhu MS, Waterworth DM, Debenham SL, Wheeler E, Papadakis K, Zhao JH, Song K, Yuan X, Johnson T, Ashford S, Inouye M, Luben R, Sims M, Hadley D, McArdle W, Barter P, Kesaniemi YA, Mahley RW, McPherson R, Grundy SM, Bingham SA, Khaw KT, Loos RJ, Waeber G, Barroso I, Strachan DP, Deloukas P, Vollenweider P, Wareham NJ, Mooser V:LDL-cholesterol concentrations:a genome-wide association study. Lancet 2008;371:483-491
17. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Bostrom K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B? Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S:Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-1336
18. Wallace C, Newhouse SJ, Braund P, Zhang F, Tobin M, Falchi M, Ahmadi K, Dobson RJ, Marcano AC, Hajat C, Burton P, Deloukas P, Brown M, Connell JM, Dominiczak A, Lathrop GM, Webster J, Farrall M, Spector T, Samani NJ, Caulfield MJ, Munroe PB:Genome-wide association study identifies genes for biomarkers of cardiovascular disease:serum urate and dyslipidemia. Am J Hum Genet 2008;82:139-149
19. Waterworth DM, Ricketts SL, Song K, Chen L, Zhao JH, Ripatti S, Aulchenko YS, Zhang W, Yuan X, Lim N, Luan J, Ashford S, Wheeler E, Young EH, Hadley D, Thompson JR, Braund PS, Johnson T, Struchalin M, Surakka I, Luben R, Khaw KT, Rodwell SA, Loos RJ, Boekholdt SM, Inouye M, Deloukas P, Elliott P, Schlessinger D, Sanna S, Scuteri A, Jackson A, Mohlke KL, Tuomilehto J, Roberts R, Stewart A, Kesaniemi YA, Mahley RW, Grundy SM, McArdle W, Cardon L, Waeber G, Vollenweider P, Chambers JC, Boehnke M, Abecasis GR, Salomaa V, Jarvelin MR, Ruokonen A, Barroso I, Epstein SE, Hakonarson HH, Rader DJ, Reilly MP, Witteman JC, Hall AS, Samani NJ, Strachan DP, Barter P, van Duijn CM, Kooner JS, Peltonen L, Wareham NJ, McPherson R, Mooser V, Sandhu MS:Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vase Bio12010;30:2264-2276
20. Wilier CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, Strait J, Duren WL, Maschio A, Busonero F, Mulas A, Albai G, Swift AJ, Morken MA, Narisu N, Bennett D, Parish S, Shen H, Galan P, Meneton P, Hercberg S, Zelenika D, Chen WM, Li Y, Scott LJ, Scheet PA, Sundvall J, Watanabe RM, Nagaraja R, Ebrahim S, Lawlor DA, Ben-Shlomo Y, Davey-Smith G, Shuldiner AR, Collins R, Bergman RN, Uda M, Tuomilehto J, Cao A, Collins FS, Lakatta E, Lathrop GM, Boehnke M, Schlessinger D, Mohlke KL, Abecasis GR:Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161-169
21. Berenson GS:Childhood risk factors predict adult risk associated with subclinical cardiovascular disease. The Bogalusa Heart Study. Am J Cardiol 2002;90:3L-7L
22.米杰,程红,侯冬青,段佳丽,滕红红,王友发：北京市2004年2-18岁儿童青少 年超重和肥胖流行现状.中华流行病学杂志2006；27：469-474
23.刘颖,米杰,杜军保：北京地区6-18岁儿童血脂紊乱现况调查.中国实用儿科杂志2007；22：101-102
24.万乃君,米杰,王天有,段佳丽,黎明,巩纯秀,杜军保,赵小元,程红,侯冬青,王俐：北京市超重和肥胖学龄儿童中代谢综合征的流行特征.中华儿科杂志2007；45：417-421
25. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J,3rd:Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study. Ann Intern Med 1961;55:33-50
26. Pilia G, Chen WM, Scuteri A, Orru M, Albai G, Dei M, Lai S, Usala G, Lai M, Loi P, Mameli C, Vacca L, Deiana M, Olla N, Masala M, Cao A, Najjar SS, Terracciano A, Nedorezov T, Sharov A, Zonderman AB, Abecasis GR, Costa P, Lakatta E, Schlessinger D:Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2006;2:e132
27. Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, Girardet JP, Bonnet D:Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children:a prospective study. Lancet 2001;358:1400-1404
28. Bao W, Srinivasan SR, Wattigney WA, Berenson GS:Usefulness of childhood low-density lipoprotein cholesterol level in predicting adult dyslipidemia and other cardiovascular risks. The Bogalusa Heart Study. Arch Intern Med 1996;156:1315-1320
29. Srinivasan SR, Frontini MG, Xu J, Berenson GS:Utility of childhood non-high-density lipoprotein cholesterol levels in predicting adult dyslipidemia and other cardiovascular risks:the Bogalusa Heart Study. Pediatrics 2006; 118:201-206
30. Srinivasan SR, Berenson GS:Childhood lipoprotein profiles and implications for adult coronary artery disease:the Bogalusa Heart Study. Am J Med Sci 1995;310 Suppl 1:S62-67
31. Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, Dykas DJ, Bale AE, Giannini C, Pierpont B, Shaw MM, Groop L, Caprio S:Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 2012;55:781-789
32. Makimura M, Ihara K, Kojima-Ishii K, Nozaki T, Ohkubo K, Kohno H, Kishimoto J, Hara T:The signal transducer and activator of transcription 5B gene polymorphism contributes to the cholesterol metabolism in Japanese children with growth hormone deficiency. Clin Endocrinol (Oxf) 2011;74:611-617
33. Lee JC, Weissglas-Volkov D, Kyttala M, Dastani Z, Cantor RM, Sobel EM, Plaisier CL, Engert JC, van Greevenbroek MM, Kane JP, Malloy MJ, Pullinger CR, Huertas-Vazquez A, Aguilar-Salinas CA, Tusie-Luna T, de Bruin TW, Aouizerat BE, van der Kallen CC, Croce CM, Aqeilan RI, Marcil M, Viikari JS, Lehtimaki T, Raitakari OT, Kuusisto J, Laakso M, Taskinen MR, Genest J, Pajukanta P: WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels. Am J Hum Genet 2008;83:180-192
34. Wu J, Yan WJ, Mo J, Yang HB, Wang ZZ, Lei MX, Peng LW:[Association of adiponectin gene polymorphism with obesity in children]. Zhongguo Dang Dai Er Ke Za Zhi 2011;13:539-542
35. Mong JL, Ng MC, Guldan GS, Tam CH, Lee HM, Ma RC, So WY, Wong GW, Kong AP, Chan JC, Waye MM:Associations of the growth hormone receptor (GHR) gene polymorphisms with adiposity and IGF-I activity in adolescents. Clin Endocrinol (Oxf) 2010; 73:313-322
36. Brown MS, Goldstein JL:Expression of the familial hypercholesterolemia gene in heterozygotes:mechanism for a dominant disorder in man. Science 1974; 185:61-63
37. Linsel-Nitschke P, Gotz A, Erdmann J, Braenne I, Braund P, Hengstenberg C, Stark K, Fischer M, Schreiber S, El Mokhtari NE, Schaefer A, Schrezenmeir J, Rubin D, Hinney A, Reinehr T, Roth C, Ortlepp J, Hanrath P, Hall AS, Mangino M, Lieb W, Lamina C, Heid IM, Doering A, Gieger C, Peters A, Meitinger T, Wichmann HE, Konig IR, Ziegler A, Kronenberg F, Samani NJ, Schunkert H:Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study. PLoS One 2008;3:e2986
38. Hegele RA, Ramdath DD, Ban MR, Carruthers MN, Carrington CV, Cao H: Polymorphisms in PNLIP, encoding pancreatic lipase, and associations with metabolic traits. J Hum Genet 2001;46:320-324
39. Hamon SC, Kardia SL, Boerwinkle E, Liu K, Klos KL, Clark AG, Sing CF:Evidence for consistent intragenic and intergenic interactions between SNP effects in the APOA1/C3/A4/A5 gene cluster. Hum Hered 2006;61:87-96
40. Tam CH, Ma RC, So WY, Wang Y, Lam VK, Germer S, Martin M, Chan JC, Ng MC: Interaction effect of genetic polymorphisms in glucokinase (GCK) and glucokinase regulatory protein (GCKR) on metabolic traits in healthy Chinese adults and adolescents. Diabetes 2009;58:765-769
41.谭建新,孙玉洁：表观基因组学研究方法进展与评价.遗传2009；31：3-12
42. Sacco J, Adeli K:MicroRNAs:emerging roles in lipid and lipoprotein metabolism. Curr Opin Lipidol 2012;23:220-225