过氧化物酶体增殖物激活受体γ基因多态性与非酒精性脂肪性肝病相关性研究
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摘要
背景与目的:
非酒精性脂肪性肝病(NAFLD,俗称脂肪肝)的发病与胰岛素抵抗(IR)密切相关,胰岛素抵抗可能是NAFLD发病机制的中心环节。近年来,有研究表明,过氧化物酶体增殖物激活受体γ(PPARγ)的激活能改善机体对胰岛素的敏感性。PPARγ的基因多态性与代谢综合征(MS)显著相关,而IR是NAFLD与MS的共同发病机制。单体型(Haplotype)分析能揭示复杂基因疾病与遗传的相关性。NAFLD是一种与遗传相关的复杂基因疾病,发病机制尚未完全清楚,本文通过研究广东汉族人群过PPARγ的单体型分布情况,探讨PPARγ基因多态性与NAFLD发病易感性之间的关系,从分子生物学角度探讨NAFLD的发病机制。
对象与方法:
按照病例-对照设计,从2009年我们在广东省汉族人群NAFLD流行病学调查中,筛选出中、重度脂肪肝232例,去除因涉及饮酒、病毒性肝炎、药物性肝病等原因的63例后,纳入169例NAFLD患者作为病例组,按病例组与对照组比例为1:3比例从非脂肪肝人群1174例随机抽取699例入选对照组。使用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测PPARγ四个位点:C-681G、C-689T、Pro12Ala及C1431T的单核苷酸多态性(SNP),生化方法检测空腹血糖、血脂等指标,测量腰围、臀围、身高、体重、血压等临床参数,问卷调查年龄、饮酒、生活习惯等情况。Hardy-Weinberg定律检验群体代表性;连锁不平衡分析检验连锁强度;单个突变分析和单体型分析检验SNP与NAFLD的相关性。
结果:
1.病例组与对照组的临床参数比较,体重、BMI、腰围、臀围、腰臀比、收缩压、舒张压、空腹血糖、空腹胰岛素、胰岛素抵抗指数、甘油三酯、总胆固醇、谷丙转氨酶、谷草转氨酶均显著高于对照组(P<0.05),而高密度脂蛋白胆固醇显著低于对照组(P<0.05)。
2. NAFLD组的MS患病率(60.94%)显著高于正常人群(7.43%)(P<0.01)。
3.四个位点中只有C-681G的基因型频率(CC,CG,GG)在病例组(0.349,0.479,
0.172)及对照组(0.415,0.473,0.112)中的分布有显著性差异(P=0.03),其它位点差异不显著(P>0.05)。
4. C-681G的GG基因型是NAFLD患病的危险因素(OR=2.04,95%CI:1.11-3.77,P=0.02)。
5.单体型分析显示GCCT单体型是NAFLD的危险因素(OR=1.38, 95%CI:
1.04-1.83,P=0.03)。
结论:
1 NAFLD和MS的临床表现重叠。
2 PPARγC-681G基因变异是NAFLD患病的危险因素。
3 PPARγC-689T、Pro12Ala及C1431T基因多态性与NAFLD发病易感性不相关。
4 PPARγ基因GCCT单体型与NAFLD发病易感性相关。
Objective:
Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin-resistance (IR), Studies have shown that IR plays a primary role in NAFLD pathogenesis. Recently it was reported that higher receptor activity of peroxisome proliferator-activated receptorγ(PPARγ) improved the body's sensitivity to insulin. Single nucleotide polymorphism (SNP) of PPARγis associated with metabolic syndrome (MS). As it is well known that NAFLD and MS share the same pathogeneses (IR), it is important to investigate the association between genetic and hereditary diseases with haplotype analysis. NAFLD is a kind of complicated gene disease, and the pathogeneses of NAFLD are still unclear. The aims of this study were to investigate the distributions of the PPARγhaplotypes of Cantonese Han patients with NAFLD and to explore the relationship between PPARγgene polymorphisms and NAFLD susceptibility.
Methods:
On the basis of our epidemiological survey in 2009, 232 moderate and severe fatty liver disease patients were selected. After removed 63 cases who were involved in drinking, viral hepatitis and drug-induced liver disease, this case-controlled study enrolled 169 Cantonese Han subjects with NAFLD as cases. According to the case for 1:3 proportion ratio, 699 subjects were randomly selected as controls among 1174 non-fatty liver disease persons. Polymerase chain reaction-restricted fragments length polymorphism (PCR-RFLP) was used to determine the single nucleotide polymorphisms (SNPs) in the four sites of PPARγgene (C-681G C-689T Pro12Ala and C1431T). Fasting plasma glucose (FPG), total cholesterol (CHOL) and triglyceride (TG) were tested by biochemistry. Anthropometrical parameters such as waist circumference, hip circumference, body height, body weight, blood pressure were measured. Age, drinking and living habits were collected in a standard questionnaire. Hardy-Weinberg law was used to confirm the sampling representatives. Linkage disequilibrium law was used to detect linkage strength. Logistic regression analysis was used to investigate the association between PPARγSNPs and NAFLD susceptibility. Haplotypes analysis was used to investigate the association of haplotypes with NAFLD susceptibility.
Results:
1. As compared with controls, body weight, BMI, waist circumference, hip circumference, WHR, SBP, DBP, FPG, fasting insulin, HOMA-IR, TG, CHOL, AST and ALT levels of NAFLD group were significantly increased, and HLDL level of which was significantly decreased.(P<0.05).
2. The prevalence of MS in NAFLD group (60.94%) was significantly higher than that in controls (7.43%) (P<0.01).
3. The CC,CG,GG genotype frequencies of C-681G polymorphisms in NAFLD group that were 0.349,0.479 and 0.172 differed significantly from those in controls that were 0.415,0.473 and 0.112. The SNPs in other three sites (C-689T, Pro12Ala, C1431T) were not significantly different from those of controls (P=0.03).
4. The GG genotype of C-681G was an independent risk factor for NAFLD susceptibility (OR=2.04,95%CI:1.11-3.77,P=0.02).
5. In haplotype analysis, GCCT haplotype was a risk factor for NAFLD susceptibility (OR=1.38, 95%CI:1.04-1.83,P=0.03).
Conclusion:
1. The clinical manifestations NAFLD and MS overlapped.
2. PPARγgene C-681G polymorphism was closly associated with NAFLD
3. PPARγgene C-689T, Pro12Ala and C1431T polymorphisms were not associated with NAFLD susceptibility.
4. PPARγgene GCCT haplotype was associated with NAFLD susceptibility.
非酒精性脂肪性肝病(NAFLD,俗称脂肪肝)的发病与胰岛素抵抗(IR)密切相关,胰岛素抵抗可能是NAFLD发病机制的中心环节。近年来,有研究表明,过氧化物酶体增殖物激活受体γ(PPARγ)的激活能改善机体对胰岛素的敏感性。PPARγ的基因多态性与代谢综合征(MS)显著相关,而IR是NAFLD与MS的共同发病机制。单体型(Haplotype)分析能揭示复杂基因疾病与遗传的相关性。NAFLD是一种与遗传相关的复杂基因疾病,发病机制尚未完全清楚,本文通过研究广东汉族人群过PPARγ的单体型分布情况,探讨PPARγ基因多态性与NAFLD发病易感性之间的关系,从分子生物学角度探讨NAFLD的发病机制。
对象与方法:
按照病例-对照设计,从2009年我们在广东省汉族人群NAFLD流行病学调查中,筛选出中、重度脂肪肝232例,去除因涉及饮酒、病毒性肝炎、药物性肝病等原因的63例后,纳入169例NAFLD患者作为病例组,按病例组与对照组比例为1:3比例从非脂肪肝人群1174例随机抽取699例入选对照组。使用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测PPARγ四个位点:C-681G、C-689T、Pro12Ala及C1431T的单核苷酸多态性(SNP),生化方法检测空腹血糖、血脂等指标,测量腰围、臀围、身高、体重、血压等临床参数,问卷调查年龄、饮酒、生活习惯等情况。Hardy-Weinberg定律检验群体代表性;连锁不平衡分析检验连锁强度;单个突变分析和单体型分析检验SNP与NAFLD的相关性。
结果:
1.病例组与对照组的临床参数比较,体重、BMI、腰围、臀围、腰臀比、收缩压、舒张压、空腹血糖、空腹胰岛素、胰岛素抵抗指数、甘油三酯、总胆固醇、谷丙转氨酶、谷草转氨酶均显著高于对照组(P<0.05),而高密度脂蛋白胆固醇显著低于对照组(P<0.05)。
2. NAFLD组的MS患病率(60.94%)显著高于正常人群(7.43%)(P<0.01)。
3.四个位点中只有C-681G的基因型频率(CC,CG,GG)在病例组(0.349,0.479,
0.172)及对照组(0.415,0.473,0.112)中的分布有显著性差异(P=0.03),其它位点差异不显著(P>0.05)。
4. C-681G的GG基因型是NAFLD患病的危险因素(OR=2.04,95%CI:1.11-3.77,P=0.02)。
5.单体型分析显示GCCT单体型是NAFLD的危险因素(OR=1.38, 95%CI:
1.04-1.83,P=0.03)。
结论:
1 NAFLD和MS的临床表现重叠。
2 PPARγC-681G基因变异是NAFLD患病的危险因素。
3 PPARγC-689T、Pro12Ala及C1431T基因多态性与NAFLD发病易感性不相关。
4 PPARγ基因GCCT单体型与NAFLD发病易感性相关。
Objective:
Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin-resistance (IR), Studies have shown that IR plays a primary role in NAFLD pathogenesis. Recently it was reported that higher receptor activity of peroxisome proliferator-activated receptorγ(PPARγ) improved the body's sensitivity to insulin. Single nucleotide polymorphism (SNP) of PPARγis associated with metabolic syndrome (MS). As it is well known that NAFLD and MS share the same pathogeneses (IR), it is important to investigate the association between genetic and hereditary diseases with haplotype analysis. NAFLD is a kind of complicated gene disease, and the pathogeneses of NAFLD are still unclear. The aims of this study were to investigate the distributions of the PPARγhaplotypes of Cantonese Han patients with NAFLD and to explore the relationship between PPARγgene polymorphisms and NAFLD susceptibility.
Methods:
On the basis of our epidemiological survey in 2009, 232 moderate and severe fatty liver disease patients were selected. After removed 63 cases who were involved in drinking, viral hepatitis and drug-induced liver disease, this case-controlled study enrolled 169 Cantonese Han subjects with NAFLD as cases. According to the case for 1:3 proportion ratio, 699 subjects were randomly selected as controls among 1174 non-fatty liver disease persons. Polymerase chain reaction-restricted fragments length polymorphism (PCR-RFLP) was used to determine the single nucleotide polymorphisms (SNPs) in the four sites of PPARγgene (C-681G C-689T Pro12Ala and C1431T). Fasting plasma glucose (FPG), total cholesterol (CHOL) and triglyceride (TG) were tested by biochemistry. Anthropometrical parameters such as waist circumference, hip circumference, body height, body weight, blood pressure were measured. Age, drinking and living habits were collected in a standard questionnaire. Hardy-Weinberg law was used to confirm the sampling representatives. Linkage disequilibrium law was used to detect linkage strength. Logistic regression analysis was used to investigate the association between PPARγSNPs and NAFLD susceptibility. Haplotypes analysis was used to investigate the association of haplotypes with NAFLD susceptibility.
Results:
1. As compared with controls, body weight, BMI, waist circumference, hip circumference, WHR, SBP, DBP, FPG, fasting insulin, HOMA-IR, TG, CHOL, AST and ALT levels of NAFLD group were significantly increased, and HLDL level of which was significantly decreased.(P<0.05).
2. The prevalence of MS in NAFLD group (60.94%) was significantly higher than that in controls (7.43%) (P<0.01).
3. The CC,CG,GG genotype frequencies of C-681G polymorphisms in NAFLD group that were 0.349,0.479 and 0.172 differed significantly from those in controls that were 0.415,0.473 and 0.112. The SNPs in other three sites (C-689T, Pro12Ala, C1431T) were not significantly different from those of controls (P=0.03).
4. The GG genotype of C-681G was an independent risk factor for NAFLD susceptibility (OR=2.04,95%CI:1.11-3.77,P=0.02).
5. In haplotype analysis, GCCT haplotype was a risk factor for NAFLD susceptibility (OR=1.38, 95%CI:1.04-1.83,P=0.03).
Conclusion:
1. The clinical manifestations NAFLD and MS overlapped.
2. PPARγgene C-681G polymorphism was closly associated with NAFLD
3. PPARγgene C-689T, Pro12Ala and C1431T polymorphisms were not associated with NAFLD susceptibility.
4. PPARγgene GCCT haplotype was associated with NAFLD susceptibility.
引文
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[2] Willner IR,Waters B,Patil SR et al.Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease[J].Am J Gastroenterol,2001, 96(10): 2957-61
[3] Farrell GC,Chitturi S,Lau GK,Sollano JD.Asia-Pacific Working Party for NAFLD Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary[J].Gastroenterol Hepatol, 2007,22:775–7
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