过氧化物酶体增殖物激活受体单核苷酸多态性基因-基因交互作用与非高密度脂蛋白胆固醇的关系

摘要

目的 探讨过氧化物酶体增殖物激活受体(PPARs) 10个SNPs与非高密度脂蛋白胆固醇(non-HDL-C)水平的关联及基因-基因的交互作用.方法 研究对象来自江苏省多代谢异常和代谢综合征综合防治研究队列人群.入组时间为1999年4月至2004年6月.2006年3月至2007年10月随访4 582名基线调查满5年的对象,共随访到4 083名.于2009年10月,对随访到的4 083名对象,在排除基线时患有心血管疾病、糖尿病、BMI＜ 18.5 kg/m2的基础上,从3 731名对象中,采用单纯随机抽样方法抽取其中的820名研究对象,对其基线血液标本进行PPARs/δ/γ10个SNP的基因多态性检测.运用logistic回归模型分析不同SNP与non-HDL-C的关联,并采用广义多因子降维法(GMDR)模型分析10个SNP的基因-基因交互作用.结果 820名研究对象中有男性270名,女性550名,年龄为(50.05±9.41)岁.单SNP关联分析显示,调整性别、年龄、吸烟、体力活动、高脂饮食和低纤饮食后,rs1800206-V等位基因和rs3856806-T等位基因与较高水平的non-HDL-C有关,rs 1800206-V等位基因携带者(LV+ VV基因型)non-HDL-C为(3.15±0.89) mg/L(F=15.01,P=0.002);rs3856806-T等位基因携带者(CT+TT基因型)non-HDL-C为(3.03±1.01) mg/L(F=9.87,P =0.005).GMDR模型分析显示,在调整同样的影响因素后,二阶、五阶、六阶和七阶交互作用模型均有统计学意义(P＜0.05),其中包括rs 1800206、rs3856806、rs135539、rs4253778、m2016520、rs1805192、rs709158的七阶模型交叉验证一致性为10/10,平均检验准确度为0.656 0,为最优模型.结论 rs1800206和rs3856806多态性与non-HDL-C水平升高有关联,并与rs135539、rs4253778、rs2016520、rs1805192、rs709158之间存在基因-基因交互作用.%Objective To examine the main effect of 10 Peroxisome proliferators-activated receptor (PPAR) SNP in contribution to non-HDL-C and study whether there is an interaction in the 10 SNPs.Methods Participants were recruited within the framework of the PMMJS (Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu province) cohort-population-survey,which was initiated from April 1999 to June 2004,and 5-year follow-up data from total 4 582 subjects were obtained between March 2006 and October 2007.A total of 4 083 participants received follow-up examination.After excluding subjects who had experienced stroke or exhibited cardiovascular disease,type 2 diabetes or a BMI ＜ 18.5 kg/m2,a total of 820 unrelated individual subjects were selected from 3 731 subjects on October of 2009.Blood samples which were collected at the baseline were subjected to PPARα,PPARδ and PPARγ 10 SNPs genotype analysis.Logistic regression model was used to examine the association between 10 SNPs in the PPARs and non-HDL-C.Interactions within the 10 SNP were explored by using the Generalized Multifactor Dimensionality Reduction (GMDR).Results A total of 820 participants (mean age was 50.05 ±9.41) were included in the study and 270 were males and 550 were females.Single-locus analysis showed that after adjusting gender,age,smoking,alcohol consumption,physical activity,high-fat diet and low-fiber diet factors,rs1800206-V and rs3856806-T were significantly associated with higher non-HDL-C levels.V allele (LV + VV genotype) carriers of rs1800206 have a average non-HDL-C levels on (3.15 ± 0.89) mg/L (F =15.01,P =0.002);T allele (CT + TT genotype) carriers of rs3856806 have a average non-HDL-C levels on (3.03 ± 1.01) mg/L(F =9.87,P =0.005).GMDR model analysis showed that after adjusting the same factors,two-locus model,five-locus model,six-locus model and seven-order interaction models were all statistically significant (P ＜ 0.05),and the seven-locus model (rs1800206,rs3856806,rs135539,rs4253778,rs2016520,rs1805192,rs709158) was the best model (P=0.001),the cross-validation consistency was 10/10 and testing accuracy was 0.656.Conclusion Rs1800206 and rs3856806 were significantly associated with non-HDL-C.And there was an gene-gene interaction among rs1800206,rs3856806,rs1800206,rs135539,rs4253778,rs2016520,rs1805192,rs3856806 and rs709158 which could influence the non-HDL-C levels.