未接受降脂治疗的冠心病患者APOB基因多态性与危险因素的交互作用

Interaction between APOB gene polymorphism and risk factors in coronary heart disease patients without lipid-lowering treatment

目的 探讨未接受降脂治疗的冠心病患者APOB基因R532W位点多态性与冠心病发病风险的相关性,并分析该位点变异与冠心病危险因素在冠心病发病中的交互作用.方法 选取2006年1月至2013年1月于北京大学第三医院经冠状动脉造影证实1支或以上冠状动脉主要分支管腔狭窄≥50％,且临床诊断为冠心病的患者作为冠心病组（771例）,另选取同期与冠心病组患者年龄、性别匹配,冠状动脉造影或CT血管造影（CTA）未见冠状动脉主要分支管腔狭窄≥50％,且临床症状、心电图等检查除外冠心病者作为对照组（772例）.所有入选者均为中国北方汉族人群,既往均未接受任何降脂治疗.检测入选者的血脂指标.采用HumanExome BeadChip对入选者进行R532W基因分型测定.比较不同基因型患者间的血脂水平,并在显性（GA＋ AA比GG）、隐性（AA比GG＋GA）和加性（AA比GA比GG）遗传模型下分析该位点变异与冠心病发病风险的关系,探讨该位点与冠心病危险因素在冠心病发病中的交互作用.结果 （1） APOB基因R532W多态性与血脂水平的关系：在总体入选者中,AA基因型患者TC水平较GA基因型患者低（P＜0.05）,而AA与GG基因型,GA与GG基因型患者间TC水平差异则均无统计学意义,3种基因型的患者间其他血脂指标差异均无统计学意义.冠心病组3种基因型的患者间各血脂指标差异均无统计学意义.对照组中AA基因型患者TC水平较GA基因型低（P＜0.05）,而AA与GG基因型,GA与GG基因型患者间TC水平差异则均无统计学意义,3种基因型的患者间其他血脂指标差异均无统计学意义.（2）APOB基因R532W的等位基因和基因型频率分布的比较：R532W位点的GG、GA、AA 3种基因型在冠心病组患者中的频率分别为80.7％、18.2％和1.2％,在对照组患者中分别为74.6％、23.8％和1.6％,两组间频率分布差异有统计学意义（P＜0.05）.R532W最小等位基因频率为11.9％,且最小等位基因A的频率在冠心病组患者中低于对照组（10.2％比13.5％,P＜0.05）.（3）APOB基因R532W与冠心病发病风险的logistic回归分析结果：在显性遗传模型下（GA＋AA比GG）,A等位基因携带者较未携带者冠心病发病风险约低30％（OR=0.704,95％ CI0.553 ～0.869,P=0.004）;进一步校正性别、年龄、高血压、糖尿病和吸烟等混杂因素后,A等位基因携带者较未携带者冠心病发病风险低（OR=0.653,95％ CI 0.502 ～0.849,P=0.001）.而在隐性遗传模型下（AA比GG ＋GA）和加性遗传模型下（AA比GA比GG）,无论是否校正混杂因素,均未见R532W的多态性与冠心病发病风险相关（P＞0.05）.（4）APOB基因R532W与危险因素在冠心病发病中的交互作用：R532W位点变异与高血压、吸烟在冠心病发病中存在正相加交互作用,交互作用强度分别为1.453、1.077.而APOB基因R532W位点变异与糖尿病在冠心病发病中存在负相加交互作用,交互作用强度为0.553.结论 APOB基因R532W位点变异与中国北方汉族人群TC水平相关,其在一定程度上可降低未接受降脂治疗患者的冠心病发病风险,且与高血压、吸烟在冠心病发生中存在正相加交互作用,与糖尿病存在负相加交互作用.

Objective To investigate the association between APOB gene R532W polymorphism and the risk of coronary heart disease （CHD） in patients without lipid-lowering treatment and to analyze the interactions between the variation of R532W and different risk factors of CHD.Methods CHD and non-CHD were diagnosed according to coronary artery angiography （CAG） and/or coronary computed tomography angiogram （CTA） results,as well as clinical features.Blood samples from 771 CHD patients and 772 age-and sex-matched non-CHD controls,who never accepted any lipid-lowering treatments,were collected.R532W was genotyped by HumanExome BeadChip at BGI and strict quality control was made.Firstly,the association between R532W polymorphism and the risk of CHD in 3 genetic models （GA ＋ AA vs.GG,AA vs.GG ＋ GA,AA vs.GA vs.GG） after adjusting confounding factors was explored.Then,the interactions between the variation of this loci and risk factors related to CHD were investigated.Results （1） Total cholesterol （TC） levels were significantly lower in AA genotype than in GA genotype in the total cohort and non-CHD controls,but was similar among the 3 genotypes in CHD patients.（2） R532W GG,GA and AA distribution was 80.7％,18.2％ and 1.2％ in CHD patients,and 74.6％,23.8％ and 1.6％ in non-CHD controls （P ＜ 0.05）.（3） R532 polymorphism was related to the incidence of CHD in the dominant model,and A-allele carriers were related to about 35％ reduced risk of CHD （OR =0.653,95％ CI 0.502-0.849,P =0.001） after adjusting for confounding factors.（4） R532W polymorphism had positive interactions with hypertension （1.452） and smoke （1.077）,while negative interaction with diabetes （0.553） in the occurrence of CHD.Conclusions APOB gene R532W polymorphism is related to TC levels in Chinese north Han population.A-allele carries of R532W loci is linked with reduced risk of CHD in the absence of lipid-lowering treatment.R532W polymorphism has a positive additive interaction with hypertension and smoke,while a negative additive interaction with diabetes mellitus in the occurrence of CHD.