9p21上位点多态性与糖尿病下肢血管病变的关联研究及其与相关因素的交互作用探讨
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摘要
下肢血管病变（Peripheral arterial disease，PAD）是一种由环境和遗传因素共同作用的复杂慢性病变，能明显增加心血管事件、心血管死亡和全因死亡的风险。与非糖尿病患者相比，2型糖尿病患者PAD患病风险明显增加，而且发病年龄提前，病变进展更加迅速。由于大多数糖尿病PAD患者缺乏明显的临床症状，使得糖尿病人群普遍存在PAD诊断不足的现象。
在糖尿病患者中，许多非遗传因素（如年龄、吸烟、血脂异常、高血压、高血糖和糖尿病病程）在PAD发生中扮演着重要角色。流行病学调查显示，不同种族的糖尿病人群PAD患病率明显不同，提示遗传因素在糖尿病人群PAD的发生中可能占有重要角色。
目前多数全基因组研究表明9号染色体短臂21号区域（9p21）基因变异与动脉粥样硬化疾病如冠心病、心肌梗死和脑中风密切相关。在这个风险序列中具有代表性的两个位点rs10757274和rs10757278的单核苷酸多态性（single nucleotide polymorphism，SNP）与冠心病的相关性尤其突出。同时这两个位点与缺血性脑中风的风险增加也显著相关。PAD作为一种普通的动脉粥样硬化病变与冠心病和缺血性脑中风分享着相似或相同的病因和发病机制。据我们目前所知，关于9p21上动脉粥样硬化病变易感位点与PAD相关性探讨甚少，无论如何，9p21与糖尿病人群PAD的关联研究尚未见文献报道。
本课题选取唐山市工人医院2型糖尿病患者为研究对象，分析其PAD的患病情况和非遗传性危险因素，探讨9p21上冠心病易感位点rs10757274和rs10757278和糖尿病人群PAD的关系以及这两个位点与环境因素的交互作用对糖尿病人群PAD发生的影响，以期为糖尿病患者PAD的早期预防、治疗和改善预后提供客观依据。
第一部分唐山市汉族人群糖尿病下肢血管病变的发生率和非遗传性危险因素的分析
目的：观察唐山市2型糖尿病患者下肢血管病变的患病情况和非遗传危险因素。
方法：采取整群抽样的方法，从唐山市3所三级甲等综合性医院中随机抽样，唐山市工人医院作为调查医院。本研究共入选年龄≥45岁汉族2型糖尿病就诊患者1389例，在研究人群中PAD人数为250例，非PAD人数为1139例。研究对象均被仔细登记一般情况和临床资料，测量身高、体重、血压和踝肱指数（ABI），并检测生化指标。两组间比较采用t检验、秩和检验或卡方检验，危险因素分析使用Logistic回归分析。所有的统计学分析应用SPSS16.0完成。
结果：所选糖尿病患者中PAD者为250人，PAD的患病率为18.0%（95%CI：16.0%-20.0%）。年龄、收缩压（SBP）、糖尿病病程、甘油三酯（TG）、高密度脂蛋白（HDL-C）、糖化血红蛋白（HbA1c）、吸烟、高血压、冠心病和脑梗死在PAD患者与非PAD患者中差异有统计学意义（p＜0.05）；性别、体重指数（BMI）、舒张压（DBP）、总胆固醇（TC）和低密度脂蛋白（LDL-C）在PAD患者与非PAD患者之间差异无统计学意义（p＞0.05）。糖尿病患者PAD患病率随着年龄增加而增加，卡方趋势性检验表明有统计学意义（χ~2
趋势=128.423，p＜0.01），多变量logistic回归分析显示（变量包含性别、年龄、BMI、吸烟、血脂、HbA1c、糖尿病病程、高血压、冠心病和脑梗死，下同。），年龄是糖尿病患者PAD患病的独立风险因素(OR=1.084；95%CI：1.065-1.104；p＜0.01)。男性与女性糖尿病患者比较，PAD患病率差异无统计学意义（χ~2=0.412，p=0.521），多变量logistic回归分析显示性别与糖尿病患者PAD患病风险无关（OR=1.428；95%CI：0.926-2.203；p=0.080)。糖尿病患者中BMI≥25者与BMI＜25者比较，PAD的患病率差异无统计学意义（χ~2=0.190，p=0.663），多变量logistic回归分析显示高BMI与糖尿病患者PAD患病风险无关（OR=1.063；95%CI：0.779-1.450；p=0.701）。吸烟与不吸烟者之间PAD患病率差别有统计学意义（χ~2=8.048，p=0.005），多变量logistic回归分析显示吸烟是糖尿病患者PAD患病的独立危险因素（OR=1.831；95%CI：1.232-2.721；p=0.003）。多变量logistic回归分析显示低HDL-C和高HbA1c与糖尿病患者PAD患病风险相关（HDL-C：OR=1.419，95%CI：1.021-1.971，p=0.037；HbA1c：OR=1.495，95%CI：1.034-2.161，p=0.033）；糖尿病患者PAD患病率随着糖尿病病程的增加而增加，卡方趋势性检验有统计学意义（χ~2趋势=32.249，p＜0.01），多变量logistic回归分析显示糖尿病病程≥15年者PAD患病风险是＜5年者2倍多，（95%CI：1.365-2.981，p＜0.01）。糖尿病患者中高血压人群与非高血压人群比较，PAD患病率差异有统计学意义（χ~2=13.813，p＜0.01），多变量logistic回归分析显示高血压是PAD的独立因素（OR=1.559；95%CI：1.140-2.133，p=0.005）；糖尿病患者合并冠心病、脑梗死者与非合并者比较，PAD患病率差别有统计学意义（p＜0.01），多变量logistic回归分析显示冠心病和脑梗死均是糖尿病患者PAD发生的独立危险因素（冠心病：OR=2.060，95%CI：1.479-2.868，p＜0.01；脑梗死：OR=1.962，95%CI：1.385-2.780，p＜0.01）。
小结：本次调查中唐山市年龄≥45岁的糖尿病患者PAD的患病率为18.0%（95%CI：16.0%-20.0%）。年龄、吸烟、低HDL-C、高HbA1c、糖尿病病程、高血压、冠心病和脑梗死是PAD发生的危险因素。
第二部分9p21上位点多态性与糖尿病下肢血管病变的关联研究
目的：探讨9p21上位点多态性与糖尿病下肢血管病变的关系。
方法：本研究选取的糖尿病人群年龄≥45岁。所有糖尿病人群均随机选自唐山市工人医院内分泌二科就诊的2型糖尿病患者，其中PAD患者250例，年龄匹配的非PAD患者为252例。提取外周血DNA，应用飞行质谱(MALDI–TOF–MS)的技术完成样品位点rs10757274和rs10757278单核苷酸多态性（SNP）的基因分型。
两组间比较采用t检验、秩和检验或卡方检验，危险因素分析使用Logistic回归分析。所有的统计学分析应用SPSS16.0完成。应用haploview4.0评估基因位点的哈迪-温伯格平衡（Hardy–Weinberg equilibrium，HWE）。
结果：
（1）糖尿病人群中PAD组和非PAD组rs10757274和rs10757278基因型分布均符合Hardy–Weinberg平衡（p＞0.05）。
（2）在糖尿病人群中，这两个位点的等位基因和基因型频率在PAD组和非PAD组之间均存在着显著的统计学差异（p＜0.05）。
（3）在糖尿病人群中，应用累加基因模型（additive model）进行分析，调整性别、年龄、吸烟、高血压、血脂异常、HbA1c和糖尿病病程后，rs10757274是PAD患病的独立风险因素（OR=1.537，95%CI：1.169-2.020，p＜0.01）。进一步应用多变量logistic回归分析调整其他因素后显示，rs10757274的AG基因型使糖尿病人群PAD的患病风险提高了约1.6倍（95%CI：1.002-2.414，p＜0.05），GG基因型则使其提高了约2.4倍（95%CI：1.359-4.086，p＜0.01）。同样，应用additive model进行分析，调整上述因素后，rs10757278也是PAD患病的独立风险因素（OR=1.493，95%CI：1.140-1.955，p＜0.01），进一步多因素显示，其GG基因型使糖尿病人群PAD的患病风险提高了约2.2倍（95%CI：1.304-3.855，p＜0.01）。
（4）在排除大血管病变的敏感性分析中，应用additive model进行分析，在多变量logistic回归分析中调整性别、年龄、吸烟、高血压、血脂异常、HbA1c和糖尿病病程等因素后显示，rs10757274仍与PAD患病的独立相关（OR=1.476，95%CI：1.057-2.061，p＜0.05。进一步应用多变量logistic回归分析调整其他因素后显示，其GG基因型使糖尿病人群PAD的患病风险提高了约2.2倍（95%CI：1.127-4.289，p＜0.05）。同样，应用additive model进行分析，调整上述因素后，rs10757278也仍与PAD患病的风险独立相关（OR=1.437，95%CI：1.034-1.997；p＜0.05）。进一步多因素分析显示，其GG基因型使糖尿病人群PAD的患病风险提高了约2.1倍（95%CI：1.084-4.020，p＜0.05）。
小结：9p21上rs10757274和rs10757278基因多态性与糖尿病人群PAD的患病风险相关。
第三部分糖尿病下肢血管病变中9p21位点多态性与其他因素的交互作用研究
目的：探讨糖尿病患者中对于PAD影响9p21上rs10757274和rs10757278位点多态性与环境因素之间是否存在交互作用。
方法：所选糖尿病人群同第二部分。应用logistic回归模型计算OR值和95%CI。所有数据分析采用SPSS16.0统计软件进行。
结果：以下OR值均为多因素logistic回归分析所得，包括的因素为年龄、性别、吸烟、血脂异常、高血压、HbA1c和糖尿病病程（不包括变量本身，年龄除外），其中年龄为连续变量。
（1）年龄与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在年龄＜65岁的糖尿病患者中，rs10757274与PAD患病风险相关（OR=2.840，95%CI：1.579-5.109，p＜0.05）；在年龄≥65岁的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与年龄＜65岁之间不存在交互作用（p=0.090）。同样rs10757274的AG和GG基因型与年龄＜65岁之间不存在交互作用（p均＞0.05）。
应用additive model分析，在年龄＜65岁的糖尿病患者中，rs10757278与PAD患病风险相关（OR=2.371，95%CI：1.334-4.213，p＜0.05），在年龄≥65岁的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与年龄＜65岁之间不存在交互作用（p=0.241）。同样，rs10757278的GG基因型与年龄＜65岁之间不存在交互作用（p=0.266）。
（2）性别与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在男性糖尿病患者中，rs10757274与PAD患病风险相关（OR=1.770，95%CI：1.159-2.701，p＜0.05），在女性糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与性别之间不存在交互作用（p=0.388）。同样，rs10757274的GG基因型与性别之间不存在交互作用（p=0.382）。
应用additive model分析，在男性糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.665，95%CI：1.096-2.528，p＜0.05），在女性糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与性别之间不存在交互作用（p=0.521）。同样，rs10757278的GG基因型与性别之间不存在交互作用（p=0.458）。
（3）吸烟与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在不吸烟的糖尿病患者中，rs10757274与PAD患病风险相关（OR=1.710，95%CI：1.203-2.433，p＜0.05），在吸烟的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与吸烟之间不存在交互作用（p=0.378）。同样，rs10757274的GG基因型与吸烟之间不存在交互作用(p=0.353)。
应用additive model分析，在不吸烟的糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.724，95%CI：1.214-2.447，p＜0.05）；在吸烟的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与吸烟之间不存在交互作用（p=0.231）。同样，rs10757278的GG基因型与吸烟之间不存在交互作用（p=0.236）。
（4）血脂异常与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在血脂正常的糖尿病患者中，rs10757274与PAD患病风险相关（OR=2.140，95%CI：1.103-4.154，p＜0.05），在血脂异常的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与血脂异常之间不存在交互作用（p=0.099）。同样，rs10757274的AG和GG基因型与血脂异常之间不存在交互作用（p均＞0.05)。
应用additive model分析，在血脂正常的糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.964，95%CI：1.091-3.537，p＜0.05），在血脂异常的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与血脂异常之间不存在交互作用（p=0.236）。
（5）高血压与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model及该位点的AG和GG基因型进行分析发现，rs10757274及其AG和GG基因型与高血压之间均不存在交互作用。
应用additive model分析，在血压正常的糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.668，95%CI：1.093-2.545，p＜0.05），在血压异常的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与高血压之间不存在交互作用（p=0.634）。同样，rs10757278的GG基因型与高血压之间不存在交互作用（p=0.642）。
（6）高HbA1c与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在HbA1c正常的糖尿病患者中，rs10757274与PAD患病风险无关，在高HbA1c的糖尿病患者中，该位点与PAD患病风险相关（OR=1.501，95%CI：1.103-2.042，p＜0.05），然而这个位点与高HbA1c之间不存在交互作用（p=0.942）。同样，rs10757274的GG基因型与高HbA1c之间不存在交互作用（p=0.948）。
应用additive model分析，在HbA1c正常的糖尿病患者中，rs10757278与PAD患病风险无关，在高HbA1c的糖尿病患者中，该位点与PAD患病风险相关（OR=1.457，95%CI：1.076-1.973，p＜0.05），然而这个位点与高HbA1c之间不存在交互作用（p=0.899）。同样，rs10757278的GG基因型与高HbA1c之间不存在交互作用（p=0.907）。
（7）糖尿病病程与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在糖尿病病程＜15年的患者中，rs10757274与PAD患病风险相关（OR=1.584，95%CI：1.136-2.209，p＜0.05），在糖尿病病程≥15年的患者中，该位点与PAD患病风险无关，然而这个位点与糖尿病病程＜15年之间不存在交互作用（p=0.870）。同样，rs10757274的AG和GG基因型与糖尿病病程＜15年之间均不存在交互作用（p均＞0.05）。
应用additive model分析，在糖尿病病程＜15年的糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.528，95%CI：1.095-2.123，p＜0.05），在糖尿病病程≥15年的患者中，该位点与PAD患病风险无关，然而这个位点与糖尿病病程＜15年之间不存在交互作用（p=0.857）。同样，rs10757278的GG基因型与糖尿病病程＜15年之间不存在交互作用（p=0.749）。
小结：在对糖尿病患者PAD的影响中，9p21上rs10757274和rs10757278多态性与年龄、性别、吸烟、血脂异常、高血压、HbA1c和糖尿病病程等之间不存在交互作用。
Peripheral arterial disease (PAD) is a kind of complicated chronic disease,caused by multiple genetic and environmental factors, with high risk ofcardiovascular events, cardiovascular mortality, and all-cause mortality. Therisk of PAD was increased in the patients with type2diabetes mellitus, with amagnified risk of early-onset and faster progression compared with that in thepopulation without diabetes. At present, due to lack of remarkably clinicalsymptom in the PAD patients with diabetes, the PAD patients with diabetes areunderdiagnosed.
In the patients with diabetes, a lot of non-inherited factors (such as age,smoking, dyslipidaemia, hypertension, high glucose and diabetes duration)played an important role in the prevalence of PAD. Epidemiological studiesshowed the prevalence of PAD was different in different ethical populationwith diabetes, suggesting the inherited factors played the important role in theprevalence of PAD in the diabetes.
Presently, numerous genome-wide studies have shown that variants onchromosome9p21are closely associated with increased risk of atheroscleroticdiseases including coronary artery disease (CAD), myocardial infarction andstroke, with two representative single nucleotide polymorphisms (SNPs)rs10757274and rs10757278on9p21linked particularly with CAD. Moreover,both loci are also significantly associated with ischaemic stroke. PAD is acommon form of atherosclerotic disease that has a similar aetiology andpathogenesis to CAD and ischaemic stroke. According to our knowledge, onlyfew studies investigated the association of9p21with PAD. However, no studyexplored the association of9p21with PAD in diabetics.
Therefore, the present study recruited the participates with Type2 diabetes from Tangshan Gongren hospital investigated the prevalence andnon-inherited factors of PAD in the patients with diabetes in Tangshan, andexplored the association of the polymorphisms on9p21with PAD and theinteraction of9p21and non-inherited factors on PAD in diabetics, whichcould provided evidence for prevention, therapy and improving of prognosisof PAD with diabetes.
Part-1Prevalence and non-inherited risk factors of peripheral arterialdisease in Han patients with type2diabetes in Tangshan
Objective：To investigated the prevalence and non-inherited risk factorsof peripheral arterial disease in the patients with type2diabetes mellitus inTangshan.Methods：Tangshan Gongren hospital were randomly chosed from threethird-grade class-A hospital by cluster sampling. This study included1389Han patients with type2diabetes aged≥45years (250patients with PAD and1139patients without PAD). For all study participants, data regardingdemographic characteristics and medical history were collected byquestionnaire interview or review of medical records. The height, body weightand ankle-brachial index (ABI) were measured. Serum total cholesterol (TC),triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C) levels, and glycosylated hemoglobin (HbA1c)were determined. Comparisons of parameters were tested by Student’s t-test,Mann-Whitney U-test or chi-square test. Logistic regression analysis was doneto estimate odds ratios (ORs) and their corresponding95%confidenceintervals. Statistical analyses were performed using SPSS16.0.
Results: In this study the prevalence of PAD was18.0%(95%CI，16.0%-20.0%) in the diabetic patients (250PAD patients) in Tangshan. Therewere significant differences in age, systolic blood pressure (SBP), diabetesduration, TG, HDL-C, HbA1c, smoking, hypertension, CAD and cerebralinfarction (CI) between the PAD patients and non-PAD patients (p＜0.05).There were no significant differences in sex, body mass index (BMI), diastolicblood pressure (DBP), TC and LDL-C between the PAD patients and non-PAD patients (p＞0.05). The trend for the increase of the prevalence ofPAD according to age was statistically significant in diabetics (χ~2
趋势=128.423,p＜0.01). Age was the independent risk factor of PAD (OR,1.084;95%CI,1.065-1.104; p＜0.01) by multivariate logistic regression analysis (Thevariates included sex, age, BMI, smoking status, lipemia, HbA1c, diabetesduration, hypertension, CAD and CI, with the same to the following.). Therewere no significant difference in prevalence of PAD between male and female(χ~2=0.412, p=0.521), and the sex was not associated with PAD in diabetics（OR=1.428；95%CI:0.926-2.203；p=0.080), using multivariate logisticregression analysis. There were no significant difference in prevalence of PADbetween the diabetics with BMI≥25and those with BMI＜25(χ~2=0.190,p=0.663), and the BMI was not associated with PAD in diabetics (OR=1.063；95%CI:0.779-1.450；p=0.701), using multivariate logistic regression analysis.There were significant difference in prevalence of PAD between smokers andnon-smokers in diabetics (χ~2=8.048, p=0.005), and the smoking wassignificantly associated with the increased risk of PAD in diabetics (OR=1.831;95%CI:1.232-2.721; p=0.003), using multivariate logistic regression analysis.Low HDL-C and high HbA1c level were the independent risk factors for PADin diabetics (OR=1.419,95%CI:1.021-1.971, p=0.037; OR=1.495,95%CI:1.034-2.161, p=0.033; respectively), using multivariate logistic regressionanalysis. The trend for the increase of the prevalence of PAD according todiabetes duration was statistically significant in diabetics (χ~2趋势=32.249, p＜0.01). The diabetes duration≥15years were the independent risk factors forPAD (OR=2.017,95%CI:1.365-2.981, p＜0.01) using multivariate logisticregression analysis, compared with the diabetes duration＜15years. Therewere significant difference in prevalence of PAD between the diabetics withhypertension and those without hypertension (χ~2=13.813, p＜0.01), and thehypertension was significantly associated with the increased risk of PAD(OR=1.559；95%CI:1.140-2.133; p=0.005), using multivariate logisticregression analysis. There were significant difference in prevalence of PADbetween the diabetics with CAD or CI and those without CAD or CI (p＜0.01), and the CAD and CI were significantly associated with the increased risk ofPAD in diabetics (OR=2.060，95%CI:1.479-2.868，p＜0.01；OR=1.962，95%CI:1.385-2.780，p＜0.01；respectively), using multivariate logisticregression analysis.
Conclusion： In this study, the prevalence of PAD was18%(95CI,16%-20%) in the diabetics aged≥45years in Tangshan. The age,smoking, low HDL-C, high HbAIc, diabetes duration, hypertension, CAD andCI were significantly associated with the increased risk of PAD.
Part-2The association of the polymorphisms on9p21with peripheralarterial disease in the patients with type2diabetes
Objective：To explore the association of the polymorphisms on9p21with peripheral arterial disease in the patients with type2diabetes mellitus.
Methods：The study randomly recruited the participates with diabetesaged≥45years (250cases and252age-matched controls), who were attendingthe Second Department of Endocrinology in Tangshan Gongren hospital.Genomic DNA was isolated using a QIAamp DNA mini kit. Genotyping ofrs10757274and rs10757278was performed by matrix-assisted laserdesorption/ionization time-of-flight mass spectrometry (MALDI–TOF–MS).
Comparisons of parameters were tested by Student’s t-test,Mann-Whitney U-test or chi-square test. Logistic regression analysis was doneto estimate odds ratios (ORs) and their corresponding95%confidenceintervals. Statistical analyses were performed using SPSS16.0. TheHardy–Weinberg equilibrium for rs10757274and rs10757278was analyzedusing Haploview, version4.0.
Results:
(1) Both rs10757274and rs10757278were in Hardy–Weinbergequilibrium in both groups in the population with diabetes mellitus (p＞0.05).
(2) There were significant differences in genotype distribution ofrs10757274and rs10757278between the PAD patients and non-PAD patientsin the diabetics (p＜0.05).
(3) Rs10757274was the independent risk factors for PAD in diabetics in additive model (OR=1.537,95%CI:1.169-2.020, p＜0.01) after adjustmentfor sex, age, smoking, hypertension, dyslipidaemia, HbA1c and diabetesduration. Moreover, the AG genotype of rs10757274increased1.6folds riskof PAD (95%CI:1.002-2.414, p＜0.05) and GG genotype of this locusincreased2.4folds risk of PAD (95%CI:1.359-4.086, p＜0.01). Similarly,rs10757278was also the independent risk factors for PAD in diabetics inadditive model after adjustment for other factors (OR=1.493，95%CI：1.140-1.955，p＜0.01). Moreover, GG genotype of this locus increased2.2folds risk of PAD (95%CI:1.304-3.855, p＜0.01).
(4) Rs10757274was still the independent risk factors for PAD indiabetics in additive model, further excluding the patients with macrovasculardiseases with adjustment for the traditional factors (OR=1.476,95%CI:1.057-2.061, p＜0.05). Moreover, GG genotype of this locus increased2.2folds risk of PAD (95%CI：1.127-4.289，p＜0.05).Similarly, rs10757278werestill the independent risk factors for PAD in diabetics in additive model afteradjustment for other factors (OR=1.437,95%CI:1.034-1.997; p＜0.05).Moreover, GG genotype of this locus increased2.1folds risk of PAD (95%CI：1.084-4.020，p＜0.05).
Conclusion: Rs10757274and rs10757278on9p21were significantlyassociated with the increased risk of PAD in diabetics.
Part-3The interaction of the polymorphisms on9p21and environmentalfactors on peripheral arterial disease in the patients with diabetes
Objective：To explore the interaction of rs10757274and rs10757278andenvironmental factors on peripheral arterial disease in the patients withdiabetes mellitus.
Methods: The study population with diabetes was same to those in Part-2.Comparisons of parameters were tested by Student’s t-test, Mann-WhitneyU-test or chi-square test. Logistic regression analysis was done to estimateodds ratios (ORs) and their corresponding95%confidence intervals.Statistical analyses were performed using SPSS16.0.Results: The following OR were estimated by multivariate logistic regression analysis with adjusting for age (continuous variable), sex, smoking,dyslipidaemia, hypertension, HbA1c and diabetes duration, with excludingthe variate itself (not including the age).
(1)The interaction of age and the polymorphisms of rs10757274andrs10757278
In the diabetics aged＜65years, rs10757274was associated with theincreased risk of PAD in additive model (OR=2.840,95%CI:1.579-5.109, p＜0.05). In the diabetics aged≥65years, rs10757274was not associated withthe increased risk of PAD in additive model. No significant interactions werefound between the locus and age (p=0.090). Similarly, no significantinteractions were found between the AG and GG genotype of locus and age (pall＞0.05).
In the diabetics aged＜65years, rs10757278was associated with theincreased risk of PAD in additive model (OR=2.371，95%CI：1.334-4.213，p＜0.05); In the diabetics aged≥65years, rs10757278was not associated withthe increased risk of PAD in additive model. No significant interactions werefound between the locus and age (p=0.241). Similarly, no significantinteractions were found between the GG genotype of the locus and age(p=0.266).
(2)The interaction of sex and the polymorphisms of rs10757274andrs10757278
In the male diabetics, rs10757274was associated with the increased riskof PAD in additive model (OR=1.770，95%CI：1.159-2.701，p＜0.05). In thefemale diabetics, rs10757274was not associated with the increased risk ofPAD in additive model. No significant interactions were found between thelocus and sex (p=0.388). Similarly, no significant interactions were foundbetween the GG genotype of the locus and sex (p=0.382).
In the male diabetics, rs10757278was associated with the increased riskof PAD in additive model (OR=1.665，95%CI：1.096-2.528，p＜0.05). In thefemale diabetics, rs10757278was not associated with the increased risk ofPAD in additive model. No significant interactions were found between the locus and sex (p=0.521). Similarly, no significant interactions were foundbetween the GG genotype of the locus and sex (p=0.458).
(3)The interaction of smoking and the polymorphisms of rs10757274andrs10757278
In the non-smoker in diabetics, rs10757274was associated with theincreased risk of PAD in additive model (OR=1.710，95%CI：1.203-2.433，p＜0.05). In the smoker in diabetics, rs10757274was not associated with theincreased risk of PAD in additive model. No significant interactions werefound between the locus and smoking (p=0.378). Similarly, no significantinteractions were found between the GG genotype of the locus and smoking(p=0.353).
In the non-smoker in diabetics, rs10757278was associated with theincreased risk of PAD in additive model (OR=1.724，95%CI：1.214-2.447，p＜0.05). In the smoker in diabetics, rs10757278was not associated with theincreased risk of PAD in additive model. No significant interactions werefound between the locus and smoking (p=0.231). Similarly, no significantinteractions were found between the GG genotype of the locus and smoking(p=0.236).
(4)The interaction of dyslipidaemia and the polymorphisms ofrs10757274and rs10757278
In the diabetics without dyslipidaemia, rs10757274was associated withthe increased risk of PAD in additive model (OR=2.140，95%CI：1.103-4.154，p＜0.05). In the diabetics with dyslipidaemia, rs10757274was not associatedwith the increased risk of PAD in additive model. No significant interactionswere found between the locus and dyslipidaemia (p=0.099). Similarly, nosignificant interactions were found between the AG and GG genotype of thelocus and dyslipidaemia (p均＞0.05).
In the diabetics without dyslipidaemia, rs10757278were associated withthe increased risk of PAD in additive model (OR=1.964，95%CI：1.091-3.537，p＜0.05). In the diabetics with dyslipidaemia, rs10757278was not associatedwith the increased risk of PAD in additive model. No significant interactions were found between the locus and dyslipidaemia (p=0.236).
(5)The interaction of hypertension and the polymorphisms of rs10757274and rs10757278
No significant interactions were found between rs10757274(additivemodel) and hypertension. No significant interactions were found between theAG and GG genotype of this locus and hypertension yet.
In the diabetics with normal blood pressure, rs10757278was associatedwith the increased risk of PAD in additive model (OR=1.668，95%CI：1.093-2.545，p＜0.05). In the diabetics with hypertension, rs10757274was notassociated with the increased risk of PAD in additive model. No significantinteractions were found between the locus and hypertension (p=0.634).Similarly, no significant interactions were found between the GG genotype ofthe locus and hypertension (p=0.642).
(6)The interaction of HbA1c and the polymorphisms of rs10757274andrs10757278
In the diabetics with normal HbA1c level, rs10757274was not associatedwith the increased risk of PAD in additive model. In the diabetics with highHbA1c level, rs10757274was associated with the increased risk of PAD inadditive model (OR=1.501，95%CI：1.103-2.042，p＜0.05). No significantinteractions were found between the locus and high HbA1c level (p=0.942).Similarly, no significant interactions were found between the GG genotype ofthe locus and high HbA1c level (p=0.948).
In the diabetics with normal HbA1c level, rs10757278was not associatedwith the increased risk of PAD in additive model. In the diabetics with highHbA1c level, rs10757278was associated with the increased risk of PAD inadditive model (OR=1.457，95%CI：1.076-1.973，p＜0.05). No significantinteractions were found between the locus and high HbA1c level (p=0.899).Similarly, no significant interactions were found between the GG genotype ofthe locus and high HbA1c level (p=0.907).
(7)The interaction of diabetes duration and the polymorphisms ofrs10757274and rs10757278
In the diabetics with diabetes duration＜15years, rs10757274wasassociated with the increased risk of PAD in additive model (OR=1.584，95%CI：1.136-2.209，p＜0.05). In the diabetics with diabetes duration≥15years, rs10757274was not associated with the increased risk of PAD inadditive model. No significant interactions were found between the locus anddiabetes duration (p=0.870). Similarly, no significant interactions were foundbetween the AG and GG genotype of the locus and diabetes duration (p all＞0.05).
In the diabetics with diabetes duration＜15years, rs10757278wasassociated with the increased risk of PAD in additive model (OR=1.528，95%CI：1.095-2.123，p＜0.05). In the diabetics with diabetes duration≥15years, rs10757278was not associated with the increased risk of PAD inadditive model. No significant interactions were found between the locus anddiabetes duration (p=0.857). Similarly, no significant interactions were foundbetween the GG genotype of the locus and diabetes duration (p=0.749).
Conclusion： No significant interactions were found between thepolymorphisms of rs10757274and rs10757278and age, sex, smoking,dyslipidaemia, hypertension, HbA1c and diabetes duration for PAD in thediabetics.
在糖尿病患者中，许多非遗传因素（如年龄、吸烟、血脂异常、高血压、高血糖和糖尿病病程）在PAD发生中扮演着重要角色。流行病学调查显示，不同种族的糖尿病人群PAD患病率明显不同，提示遗传因素在糖尿病人群PAD的发生中可能占有重要角色。
目前多数全基因组研究表明9号染色体短臂21号区域（9p21）基因变异与动脉粥样硬化疾病如冠心病、心肌梗死和脑中风密切相关。在这个风险序列中具有代表性的两个位点rs10757274和rs10757278的单核苷酸多态性（single nucleotide polymorphism，SNP）与冠心病的相关性尤其突出。同时这两个位点与缺血性脑中风的风险增加也显著相关。PAD作为一种普通的动脉粥样硬化病变与冠心病和缺血性脑中风分享着相似或相同的病因和发病机制。据我们目前所知，关于9p21上动脉粥样硬化病变易感位点与PAD相关性探讨甚少，无论如何，9p21与糖尿病人群PAD的关联研究尚未见文献报道。
本课题选取唐山市工人医院2型糖尿病患者为研究对象，分析其PAD的患病情况和非遗传性危险因素，探讨9p21上冠心病易感位点rs10757274和rs10757278和糖尿病人群PAD的关系以及这两个位点与环境因素的交互作用对糖尿病人群PAD发生的影响，以期为糖尿病患者PAD的早期预防、治疗和改善预后提供客观依据。
第一部分唐山市汉族人群糖尿病下肢血管病变的发生率和非遗传性危险因素的分析
目的：观察唐山市2型糖尿病患者下肢血管病变的患病情况和非遗传危险因素。
方法：采取整群抽样的方法，从唐山市3所三级甲等综合性医院中随机抽样，唐山市工人医院作为调查医院。本研究共入选年龄≥45岁汉族2型糖尿病就诊患者1389例，在研究人群中PAD人数为250例，非PAD人数为1139例。研究对象均被仔细登记一般情况和临床资料，测量身高、体重、血压和踝肱指数（ABI），并检测生化指标。两组间比较采用t检验、秩和检验或卡方检验，危险因素分析使用Logistic回归分析。所有的统计学分析应用SPSS16.0完成。
结果：所选糖尿病患者中PAD者为250人，PAD的患病率为18.0%（95%CI：16.0%-20.0%）。年龄、收缩压（SBP）、糖尿病病程、甘油三酯（TG）、高密度脂蛋白（HDL-C）、糖化血红蛋白（HbA1c）、吸烟、高血压、冠心病和脑梗死在PAD患者与非PAD患者中差异有统计学意义（p＜0.05）；性别、体重指数（BMI）、舒张压（DBP）、总胆固醇（TC）和低密度脂蛋白（LDL-C）在PAD患者与非PAD患者之间差异无统计学意义（p＞0.05）。糖尿病患者PAD患病率随着年龄增加而增加，卡方趋势性检验表明有统计学意义（χ~2
趋势=128.423，p＜0.01），多变量logistic回归分析显示（变量包含性别、年龄、BMI、吸烟、血脂、HbA1c、糖尿病病程、高血压、冠心病和脑梗死，下同。），年龄是糖尿病患者PAD患病的独立风险因素(OR=1.084；95%CI：1.065-1.104；p＜0.01)。男性与女性糖尿病患者比较，PAD患病率差异无统计学意义（χ~2=0.412，p=0.521），多变量logistic回归分析显示性别与糖尿病患者PAD患病风险无关（OR=1.428；95%CI：0.926-2.203；p=0.080)。糖尿病患者中BMI≥25者与BMI＜25者比较，PAD的患病率差异无统计学意义（χ~2=0.190，p=0.663），多变量logistic回归分析显示高BMI与糖尿病患者PAD患病风险无关（OR=1.063；95%CI：0.779-1.450；p=0.701）。吸烟与不吸烟者之间PAD患病率差别有统计学意义（χ~2=8.048，p=0.005），多变量logistic回归分析显示吸烟是糖尿病患者PAD患病的独立危险因素（OR=1.831；95%CI：1.232-2.721；p=0.003）。多变量logistic回归分析显示低HDL-C和高HbA1c与糖尿病患者PAD患病风险相关（HDL-C：OR=1.419，95%CI：1.021-1.971，p=0.037；HbA1c：OR=1.495，95%CI：1.034-2.161，p=0.033）；糖尿病患者PAD患病率随着糖尿病病程的增加而增加，卡方趋势性检验有统计学意义（χ~2趋势=32.249，p＜0.01），多变量logistic回归分析显示糖尿病病程≥15年者PAD患病风险是＜5年者2倍多，（95%CI：1.365-2.981，p＜0.01）。糖尿病患者中高血压人群与非高血压人群比较，PAD患病率差异有统计学意义（χ~2=13.813，p＜0.01），多变量logistic回归分析显示高血压是PAD的独立因素（OR=1.559；95%CI：1.140-2.133，p=0.005）；糖尿病患者合并冠心病、脑梗死者与非合并者比较，PAD患病率差别有统计学意义（p＜0.01），多变量logistic回归分析显示冠心病和脑梗死均是糖尿病患者PAD发生的独立危险因素（冠心病：OR=2.060，95%CI：1.479-2.868，p＜0.01；脑梗死：OR=1.962，95%CI：1.385-2.780，p＜0.01）。
小结：本次调查中唐山市年龄≥45岁的糖尿病患者PAD的患病率为18.0%（95%CI：16.0%-20.0%）。年龄、吸烟、低HDL-C、高HbA1c、糖尿病病程、高血压、冠心病和脑梗死是PAD发生的危险因素。
第二部分9p21上位点多态性与糖尿病下肢血管病变的关联研究
目的：探讨9p21上位点多态性与糖尿病下肢血管病变的关系。
方法：本研究选取的糖尿病人群年龄≥45岁。所有糖尿病人群均随机选自唐山市工人医院内分泌二科就诊的2型糖尿病患者，其中PAD患者250例，年龄匹配的非PAD患者为252例。提取外周血DNA，应用飞行质谱(MALDI–TOF–MS)的技术完成样品位点rs10757274和rs10757278单核苷酸多态性（SNP）的基因分型。
两组间比较采用t检验、秩和检验或卡方检验，危险因素分析使用Logistic回归分析。所有的统计学分析应用SPSS16.0完成。应用haploview4.0评估基因位点的哈迪-温伯格平衡（Hardy–Weinberg equilibrium，HWE）。
结果：
（1）糖尿病人群中PAD组和非PAD组rs10757274和rs10757278基因型分布均符合Hardy–Weinberg平衡（p＞0.05）。
（2）在糖尿病人群中，这两个位点的等位基因和基因型频率在PAD组和非PAD组之间均存在着显著的统计学差异（p＜0.05）。
（3）在糖尿病人群中，应用累加基因模型（additive model）进行分析，调整性别、年龄、吸烟、高血压、血脂异常、HbA1c和糖尿病病程后，rs10757274是PAD患病的独立风险因素（OR=1.537，95%CI：1.169-2.020，p＜0.01）。进一步应用多变量logistic回归分析调整其他因素后显示，rs10757274的AG基因型使糖尿病人群PAD的患病风险提高了约1.6倍（95%CI：1.002-2.414，p＜0.05），GG基因型则使其提高了约2.4倍（95%CI：1.359-4.086，p＜0.01）。同样，应用additive model进行分析，调整上述因素后，rs10757278也是PAD患病的独立风险因素（OR=1.493，95%CI：1.140-1.955，p＜0.01），进一步多因素显示，其GG基因型使糖尿病人群PAD的患病风险提高了约2.2倍（95%CI：1.304-3.855，p＜0.01）。
（4）在排除大血管病变的敏感性分析中，应用additive model进行分析，在多变量logistic回归分析中调整性别、年龄、吸烟、高血压、血脂异常、HbA1c和糖尿病病程等因素后显示，rs10757274仍与PAD患病的独立相关（OR=1.476，95%CI：1.057-2.061，p＜0.05。进一步应用多变量logistic回归分析调整其他因素后显示，其GG基因型使糖尿病人群PAD的患病风险提高了约2.2倍（95%CI：1.127-4.289，p＜0.05）。同样，应用additive model进行分析，调整上述因素后，rs10757278也仍与PAD患病的风险独立相关（OR=1.437，95%CI：1.034-1.997；p＜0.05）。进一步多因素分析显示，其GG基因型使糖尿病人群PAD的患病风险提高了约2.1倍（95%CI：1.084-4.020，p＜0.05）。
小结：9p21上rs10757274和rs10757278基因多态性与糖尿病人群PAD的患病风险相关。
第三部分糖尿病下肢血管病变中9p21位点多态性与其他因素的交互作用研究
目的：探讨糖尿病患者中对于PAD影响9p21上rs10757274和rs10757278位点多态性与环境因素之间是否存在交互作用。
方法：所选糖尿病人群同第二部分。应用logistic回归模型计算OR值和95%CI。所有数据分析采用SPSS16.0统计软件进行。
结果：以下OR值均为多因素logistic回归分析所得，包括的因素为年龄、性别、吸烟、血脂异常、高血压、HbA1c和糖尿病病程（不包括变量本身，年龄除外），其中年龄为连续变量。
（1）年龄与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在年龄＜65岁的糖尿病患者中，rs10757274与PAD患病风险相关（OR=2.840，95%CI：1.579-5.109，p＜0.05）；在年龄≥65岁的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与年龄＜65岁之间不存在交互作用（p=0.090）。同样rs10757274的AG和GG基因型与年龄＜65岁之间不存在交互作用（p均＞0.05）。
应用additive model分析，在年龄＜65岁的糖尿病患者中，rs10757278与PAD患病风险相关（OR=2.371，95%CI：1.334-4.213，p＜0.05），在年龄≥65岁的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与年龄＜65岁之间不存在交互作用（p=0.241）。同样，rs10757278的GG基因型与年龄＜65岁之间不存在交互作用（p=0.266）。
（2）性别与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在男性糖尿病患者中，rs10757274与PAD患病风险相关（OR=1.770，95%CI：1.159-2.701，p＜0.05），在女性糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与性别之间不存在交互作用（p=0.388）。同样，rs10757274的GG基因型与性别之间不存在交互作用（p=0.382）。
应用additive model分析，在男性糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.665，95%CI：1.096-2.528，p＜0.05），在女性糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与性别之间不存在交互作用（p=0.521）。同样，rs10757278的GG基因型与性别之间不存在交互作用（p=0.458）。
（3）吸烟与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在不吸烟的糖尿病患者中，rs10757274与PAD患病风险相关（OR=1.710，95%CI：1.203-2.433，p＜0.05），在吸烟的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与吸烟之间不存在交互作用（p=0.378）。同样，rs10757274的GG基因型与吸烟之间不存在交互作用(p=0.353)。
应用additive model分析，在不吸烟的糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.724，95%CI：1.214-2.447，p＜0.05）；在吸烟的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与吸烟之间不存在交互作用（p=0.231）。同样，rs10757278的GG基因型与吸烟之间不存在交互作用（p=0.236）。
（4）血脂异常与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在血脂正常的糖尿病患者中，rs10757274与PAD患病风险相关（OR=2.140，95%CI：1.103-4.154，p＜0.05），在血脂异常的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与血脂异常之间不存在交互作用（p=0.099）。同样，rs10757274的AG和GG基因型与血脂异常之间不存在交互作用（p均＞0.05)。
应用additive model分析，在血脂正常的糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.964，95%CI：1.091-3.537，p＜0.05），在血脂异常的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与血脂异常之间不存在交互作用（p=0.236）。
（5）高血压与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model及该位点的AG和GG基因型进行分析发现，rs10757274及其AG和GG基因型与高血压之间均不存在交互作用。
应用additive model分析，在血压正常的糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.668，95%CI：1.093-2.545，p＜0.05），在血压异常的糖尿病患者中，该位点与PAD患病风险无关，然而这个位点与高血压之间不存在交互作用（p=0.634）。同样，rs10757278的GG基因型与高血压之间不存在交互作用（p=0.642）。
（6）高HbA1c与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在HbA1c正常的糖尿病患者中，rs10757274与PAD患病风险无关，在高HbA1c的糖尿病患者中，该位点与PAD患病风险相关（OR=1.501，95%CI：1.103-2.042，p＜0.05），然而这个位点与高HbA1c之间不存在交互作用（p=0.942）。同样，rs10757274的GG基因型与高HbA1c之间不存在交互作用（p=0.948）。
应用additive model分析，在HbA1c正常的糖尿病患者中，rs10757278与PAD患病风险无关，在高HbA1c的糖尿病患者中，该位点与PAD患病风险相关（OR=1.457，95%CI：1.076-1.973，p＜0.05），然而这个位点与高HbA1c之间不存在交互作用（p=0.899）。同样，rs10757278的GG基因型与高HbA1c之间不存在交互作用（p=0.907）。
（7）糖尿病病程与9p21上位点rs10757274与rs10757278多态性交互作用分析
应用additive model分析，在糖尿病病程＜15年的患者中，rs10757274与PAD患病风险相关（OR=1.584，95%CI：1.136-2.209，p＜0.05），在糖尿病病程≥15年的患者中，该位点与PAD患病风险无关，然而这个位点与糖尿病病程＜15年之间不存在交互作用（p=0.870）。同样，rs10757274的AG和GG基因型与糖尿病病程＜15年之间均不存在交互作用（p均＞0.05）。
应用additive model分析，在糖尿病病程＜15年的糖尿病患者中，rs10757278与PAD患病风险相关（OR=1.528，95%CI：1.095-2.123，p＜0.05），在糖尿病病程≥15年的患者中，该位点与PAD患病风险无关，然而这个位点与糖尿病病程＜15年之间不存在交互作用（p=0.857）。同样，rs10757278的GG基因型与糖尿病病程＜15年之间不存在交互作用（p=0.749）。
小结：在对糖尿病患者PAD的影响中，9p21上rs10757274和rs10757278多态性与年龄、性别、吸烟、血脂异常、高血压、HbA1c和糖尿病病程等之间不存在交互作用。
Peripheral arterial disease (PAD) is a kind of complicated chronic disease,caused by multiple genetic and environmental factors, with high risk ofcardiovascular events, cardiovascular mortality, and all-cause mortality. Therisk of PAD was increased in the patients with type2diabetes mellitus, with amagnified risk of early-onset and faster progression compared with that in thepopulation without diabetes. At present, due to lack of remarkably clinicalsymptom in the PAD patients with diabetes, the PAD patients with diabetes areunderdiagnosed.
In the patients with diabetes, a lot of non-inherited factors (such as age,smoking, dyslipidaemia, hypertension, high glucose and diabetes duration)played an important role in the prevalence of PAD. Epidemiological studiesshowed the prevalence of PAD was different in different ethical populationwith diabetes, suggesting the inherited factors played the important role in theprevalence of PAD in the diabetes.
Presently, numerous genome-wide studies have shown that variants onchromosome9p21are closely associated with increased risk of atheroscleroticdiseases including coronary artery disease (CAD), myocardial infarction andstroke, with two representative single nucleotide polymorphisms (SNPs)rs10757274and rs10757278on9p21linked particularly with CAD. Moreover,both loci are also significantly associated with ischaemic stroke. PAD is acommon form of atherosclerotic disease that has a similar aetiology andpathogenesis to CAD and ischaemic stroke. According to our knowledge, onlyfew studies investigated the association of9p21with PAD. However, no studyexplored the association of9p21with PAD in diabetics.
Therefore, the present study recruited the participates with Type2 diabetes from Tangshan Gongren hospital investigated the prevalence andnon-inherited factors of PAD in the patients with diabetes in Tangshan, andexplored the association of the polymorphisms on9p21with PAD and theinteraction of9p21and non-inherited factors on PAD in diabetics, whichcould provided evidence for prevention, therapy and improving of prognosisof PAD with diabetes.
Part-1Prevalence and non-inherited risk factors of peripheral arterialdisease in Han patients with type2diabetes in Tangshan
Objective：To investigated the prevalence and non-inherited risk factorsof peripheral arterial disease in the patients with type2diabetes mellitus inTangshan.Methods：Tangshan Gongren hospital were randomly chosed from threethird-grade class-A hospital by cluster sampling. This study included1389Han patients with type2diabetes aged≥45years (250patients with PAD and1139patients without PAD). For all study participants, data regardingdemographic characteristics and medical history were collected byquestionnaire interview or review of medical records. The height, body weightand ankle-brachial index (ABI) were measured. Serum total cholesterol (TC),triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C) levels, and glycosylated hemoglobin (HbA1c)were determined. Comparisons of parameters were tested by Student’s t-test,Mann-Whitney U-test or chi-square test. Logistic regression analysis was doneto estimate odds ratios (ORs) and their corresponding95%confidenceintervals. Statistical analyses were performed using SPSS16.0.
Results: In this study the prevalence of PAD was18.0%(95%CI，16.0%-20.0%) in the diabetic patients (250PAD patients) in Tangshan. Therewere significant differences in age, systolic blood pressure (SBP), diabetesduration, TG, HDL-C, HbA1c, smoking, hypertension, CAD and cerebralinfarction (CI) between the PAD patients and non-PAD patients (p＜0.05).There were no significant differences in sex, body mass index (BMI), diastolicblood pressure (DBP), TC and LDL-C between the PAD patients and non-PAD patients (p＞0.05). The trend for the increase of the prevalence ofPAD according to age was statistically significant in diabetics (χ~2
趋势=128.423,p＜0.01). Age was the independent risk factor of PAD (OR,1.084;95%CI,1.065-1.104; p＜0.01) by multivariate logistic regression analysis (Thevariates included sex, age, BMI, smoking status, lipemia, HbA1c, diabetesduration, hypertension, CAD and CI, with the same to the following.). Therewere no significant difference in prevalence of PAD between male and female(χ~2=0.412, p=0.521), and the sex was not associated with PAD in diabetics（OR=1.428；95%CI:0.926-2.203；p=0.080), using multivariate logisticregression analysis. There were no significant difference in prevalence of PADbetween the diabetics with BMI≥25and those with BMI＜25(χ~2=0.190,p=0.663), and the BMI was not associated with PAD in diabetics (OR=1.063；95%CI:0.779-1.450；p=0.701), using multivariate logistic regression analysis.There were significant difference in prevalence of PAD between smokers andnon-smokers in diabetics (χ~2=8.048, p=0.005), and the smoking wassignificantly associated with the increased risk of PAD in diabetics (OR=1.831;95%CI:1.232-2.721; p=0.003), using multivariate logistic regression analysis.Low HDL-C and high HbA1c level were the independent risk factors for PADin diabetics (OR=1.419,95%CI:1.021-1.971, p=0.037; OR=1.495,95%CI:1.034-2.161, p=0.033; respectively), using multivariate logistic regressionanalysis. The trend for the increase of the prevalence of PAD according todiabetes duration was statistically significant in diabetics (χ~2趋势=32.249, p＜0.01). The diabetes duration≥15years were the independent risk factors forPAD (OR=2.017,95%CI:1.365-2.981, p＜0.01) using multivariate logisticregression analysis, compared with the diabetes duration＜15years. Therewere significant difference in prevalence of PAD between the diabetics withhypertension and those without hypertension (χ~2=13.813, p＜0.01), and thehypertension was significantly associated with the increased risk of PAD(OR=1.559；95%CI:1.140-2.133; p=0.005), using multivariate logisticregression analysis. There were significant difference in prevalence of PADbetween the diabetics with CAD or CI and those without CAD or CI (p＜0.01), and the CAD and CI were significantly associated with the increased risk ofPAD in diabetics (OR=2.060，95%CI:1.479-2.868，p＜0.01；OR=1.962，95%CI:1.385-2.780，p＜0.01；respectively), using multivariate logisticregression analysis.
Conclusion： In this study, the prevalence of PAD was18%(95CI,16%-20%) in the diabetics aged≥45years in Tangshan. The age,smoking, low HDL-C, high HbAIc, diabetes duration, hypertension, CAD andCI were significantly associated with the increased risk of PAD.
Part-2The association of the polymorphisms on9p21with peripheralarterial disease in the patients with type2diabetes
Objective：To explore the association of the polymorphisms on9p21with peripheral arterial disease in the patients with type2diabetes mellitus.
Methods：The study randomly recruited the participates with diabetesaged≥45years (250cases and252age-matched controls), who were attendingthe Second Department of Endocrinology in Tangshan Gongren hospital.Genomic DNA was isolated using a QIAamp DNA mini kit. Genotyping ofrs10757274and rs10757278was performed by matrix-assisted laserdesorption/ionization time-of-flight mass spectrometry (MALDI–TOF–MS).
Comparisons of parameters were tested by Student’s t-test,Mann-Whitney U-test or chi-square test. Logistic regression analysis was doneto estimate odds ratios (ORs) and their corresponding95%confidenceintervals. Statistical analyses were performed using SPSS16.0. TheHardy–Weinberg equilibrium for rs10757274and rs10757278was analyzedusing Haploview, version4.0.
Results:
(1) Both rs10757274and rs10757278were in Hardy–Weinbergequilibrium in both groups in the population with diabetes mellitus (p＞0.05).
(2) There were significant differences in genotype distribution ofrs10757274and rs10757278between the PAD patients and non-PAD patientsin the diabetics (p＜0.05).
(3) Rs10757274was the independent risk factors for PAD in diabetics in additive model (OR=1.537,95%CI:1.169-2.020, p＜0.01) after adjustmentfor sex, age, smoking, hypertension, dyslipidaemia, HbA1c and diabetesduration. Moreover, the AG genotype of rs10757274increased1.6folds riskof PAD (95%CI:1.002-2.414, p＜0.05) and GG genotype of this locusincreased2.4folds risk of PAD (95%CI:1.359-4.086, p＜0.01). Similarly,rs10757278was also the independent risk factors for PAD in diabetics inadditive model after adjustment for other factors (OR=1.493，95%CI：1.140-1.955，p＜0.01). Moreover, GG genotype of this locus increased2.2folds risk of PAD (95%CI:1.304-3.855, p＜0.01).
(4) Rs10757274was still the independent risk factors for PAD indiabetics in additive model, further excluding the patients with macrovasculardiseases with adjustment for the traditional factors (OR=1.476,95%CI:1.057-2.061, p＜0.05). Moreover, GG genotype of this locus increased2.2folds risk of PAD (95%CI：1.127-4.289，p＜0.05).Similarly, rs10757278werestill the independent risk factors for PAD in diabetics in additive model afteradjustment for other factors (OR=1.437,95%CI:1.034-1.997; p＜0.05).Moreover, GG genotype of this locus increased2.1folds risk of PAD (95%CI：1.084-4.020，p＜0.05).
Conclusion: Rs10757274and rs10757278on9p21were significantlyassociated with the increased risk of PAD in diabetics.
Part-3The interaction of the polymorphisms on9p21and environmentalfactors on peripheral arterial disease in the patients with diabetes
Objective：To explore the interaction of rs10757274and rs10757278andenvironmental factors on peripheral arterial disease in the patients withdiabetes mellitus.
Methods: The study population with diabetes was same to those in Part-2.Comparisons of parameters were tested by Student’s t-test, Mann-WhitneyU-test or chi-square test. Logistic regression analysis was done to estimateodds ratios (ORs) and their corresponding95%confidence intervals.Statistical analyses were performed using SPSS16.0.Results: The following OR were estimated by multivariate logistic regression analysis with adjusting for age (continuous variable), sex, smoking,dyslipidaemia, hypertension, HbA1c and diabetes duration, with excludingthe variate itself (not including the age).
(1)The interaction of age and the polymorphisms of rs10757274andrs10757278
In the diabetics aged＜65years, rs10757274was associated with theincreased risk of PAD in additive model (OR=2.840,95%CI:1.579-5.109, p＜0.05). In the diabetics aged≥65years, rs10757274was not associated withthe increased risk of PAD in additive model. No significant interactions werefound between the locus and age (p=0.090). Similarly, no significantinteractions were found between the AG and GG genotype of locus and age (pall＞0.05).
In the diabetics aged＜65years, rs10757278was associated with theincreased risk of PAD in additive model (OR=2.371，95%CI：1.334-4.213，p＜0.05); In the diabetics aged≥65years, rs10757278was not associated withthe increased risk of PAD in additive model. No significant interactions werefound between the locus and age (p=0.241). Similarly, no significantinteractions were found between the GG genotype of the locus and age(p=0.266).
(2)The interaction of sex and the polymorphisms of rs10757274andrs10757278
In the male diabetics, rs10757274was associated with the increased riskof PAD in additive model (OR=1.770，95%CI：1.159-2.701，p＜0.05). In thefemale diabetics, rs10757274was not associated with the increased risk ofPAD in additive model. No significant interactions were found between thelocus and sex (p=0.388). Similarly, no significant interactions were foundbetween the GG genotype of the locus and sex (p=0.382).
In the male diabetics, rs10757278was associated with the increased riskof PAD in additive model (OR=1.665，95%CI：1.096-2.528，p＜0.05). In thefemale diabetics, rs10757278was not associated with the increased risk ofPAD in additive model. No significant interactions were found between the locus and sex (p=0.521). Similarly, no significant interactions were foundbetween the GG genotype of the locus and sex (p=0.458).
(3)The interaction of smoking and the polymorphisms of rs10757274andrs10757278
In the non-smoker in diabetics, rs10757274was associated with theincreased risk of PAD in additive model (OR=1.710，95%CI：1.203-2.433，p＜0.05). In the smoker in diabetics, rs10757274was not associated with theincreased risk of PAD in additive model. No significant interactions werefound between the locus and smoking (p=0.378). Similarly, no significantinteractions were found between the GG genotype of the locus and smoking(p=0.353).
In the non-smoker in diabetics, rs10757278was associated with theincreased risk of PAD in additive model (OR=1.724，95%CI：1.214-2.447，p＜0.05). In the smoker in diabetics, rs10757278was not associated with theincreased risk of PAD in additive model. No significant interactions werefound between the locus and smoking (p=0.231). Similarly, no significantinteractions were found between the GG genotype of the locus and smoking(p=0.236).
(4)The interaction of dyslipidaemia and the polymorphisms ofrs10757274and rs10757278
In the diabetics without dyslipidaemia, rs10757274was associated withthe increased risk of PAD in additive model (OR=2.140，95%CI：1.103-4.154，p＜0.05). In the diabetics with dyslipidaemia, rs10757274was not associatedwith the increased risk of PAD in additive model. No significant interactionswere found between the locus and dyslipidaemia (p=0.099). Similarly, nosignificant interactions were found between the AG and GG genotype of thelocus and dyslipidaemia (p均＞0.05).
In the diabetics without dyslipidaemia, rs10757278were associated withthe increased risk of PAD in additive model (OR=1.964，95%CI：1.091-3.537，p＜0.05). In the diabetics with dyslipidaemia, rs10757278was not associatedwith the increased risk of PAD in additive model. No significant interactions were found between the locus and dyslipidaemia (p=0.236).
(5)The interaction of hypertension and the polymorphisms of rs10757274and rs10757278
No significant interactions were found between rs10757274(additivemodel) and hypertension. No significant interactions were found between theAG and GG genotype of this locus and hypertension yet.
In the diabetics with normal blood pressure, rs10757278was associatedwith the increased risk of PAD in additive model (OR=1.668，95%CI：1.093-2.545，p＜0.05). In the diabetics with hypertension, rs10757274was notassociated with the increased risk of PAD in additive model. No significantinteractions were found between the locus and hypertension (p=0.634).Similarly, no significant interactions were found between the GG genotype ofthe locus and hypertension (p=0.642).
(6)The interaction of HbA1c and the polymorphisms of rs10757274andrs10757278
In the diabetics with normal HbA1c level, rs10757274was not associatedwith the increased risk of PAD in additive model. In the diabetics with highHbA1c level, rs10757274was associated with the increased risk of PAD inadditive model (OR=1.501，95%CI：1.103-2.042，p＜0.05). No significantinteractions were found between the locus and high HbA1c level (p=0.942).Similarly, no significant interactions were found between the GG genotype ofthe locus and high HbA1c level (p=0.948).
In the diabetics with normal HbA1c level, rs10757278was not associatedwith the increased risk of PAD in additive model. In the diabetics with highHbA1c level, rs10757278was associated with the increased risk of PAD inadditive model (OR=1.457，95%CI：1.076-1.973，p＜0.05). No significantinteractions were found between the locus and high HbA1c level (p=0.899).Similarly, no significant interactions were found between the GG genotype ofthe locus and high HbA1c level (p=0.907).
(7)The interaction of diabetes duration and the polymorphisms ofrs10757274and rs10757278
In the diabetics with diabetes duration＜15years, rs10757274wasassociated with the increased risk of PAD in additive model (OR=1.584，95%CI：1.136-2.209，p＜0.05). In the diabetics with diabetes duration≥15years, rs10757274was not associated with the increased risk of PAD inadditive model. No significant interactions were found between the locus anddiabetes duration (p=0.870). Similarly, no significant interactions were foundbetween the AG and GG genotype of the locus and diabetes duration (p all＞0.05).
In the diabetics with diabetes duration＜15years, rs10757278wasassociated with the increased risk of PAD in additive model (OR=1.528，95%CI：1.095-2.123，p＜0.05). In the diabetics with diabetes duration≥15years, rs10757278was not associated with the increased risk of PAD inadditive model. No significant interactions were found between the locus anddiabetes duration (p=0.857). Similarly, no significant interactions were foundbetween the GG genotype of the locus and diabetes duration (p=0.749).
Conclusion： No significant interactions were found between thepolymorphisms of rs10757274and rs10757278and age, sex, smoking,dyslipidaemia, hypertension, HbA1c and diabetes duration for PAD in thediabetics.
引文
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