Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but poses a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD defined by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC), 610 women participating in the Kronos Early Estrogen Prevention Study (KEEPS), a clinical trial of MHT to prevent progression of CVD, were genotyped for 13,229 single nucleotide polymorphisms (SNPs) within 764 genes from anticoagulant, procoagulant, fibrinolytic, or innate immunity pathways. According to linear regression, proportion of European ancestry correlated negatively, but age at enrollment and pulse pressure correlated positively with CIMT. Adjusting for these variables, two SNPs, one on chromosome 2 for MAP4K4 gene (rs2236935, β = 0.037, P value = 2.36 × 10(-06)) and one on chromosome 5 for IL5 gene (rs739318, β = 0.051, P value = 5.02 × 10(-05)), associated positively with CIMT; two SNPs on chromosome 17 for CCL5 (rs4796119, β = -0.043, P value = 3.59 × 10(-05); rs2291299, β = -0.032, P value = 5.59 × 10(-05)) correlated negatively with CIMT; only rs2236935 remained significant after correcting for multiple testing. Using logistic regression, when we adjusted for waist circumference, two SNPs (rs11465886, IRAK2, chromosome 3, OR = 3.91, P value = 1.10 × 10(-04); and rs17751769, SERPINA1, chromosome 14, OR = 1.96, P value = 2.42 × 10(-04)) associated positively with a CAC score of >0 Agatston unit; one SNP (rs630014, ABO, OR = 0.51, P value = 2.51 × 10(-04)) associated negatively; none remained significant after correcting for multiple testing. Whether these SNPs associate with CIMT and CAC in women randomized to MHT remains to be determined.

译文

更年期激素治疗 (MHT) 可能会限制心血管疾病 (CVD) 的进展,但会带来血栓形成的风险。为了测试与颈动脉内膜中层厚度 (CIMT) 和冠状动脉钙化 (CAC) 定义的亚临床CVD相关的靶向候选基因变异,610参加Kronos早期雌激素预防研究 (KEEPS) 的妇女,MHT预防CVD进展的临床试验,在抗凝剂,促凝剂,纤溶或先天免疫途径的764基因内对13,229单核苷酸多态性 (snp) 进行基因分型。根据线性回归,欧洲血统的比例呈负相关,但入学年龄和脉压与CIMT呈正相关。调整这些变量,两个snp,一个在2号染色体上的MAP4K4基因 (rs2236935,β = 0.037,p值 = 2.36 × 10(-06)),一个在5号染色体上的IL5基因 (rs739318,β = 0.051,p值 = 5.02 × 10(-05)),与CIMT呈正相关; CCL5 17号染色体上的两个snp (rs4796119,β = -0.043,p值 = 3.59 × 10(-05); rs2291299,β = -0.032,p值 = 5.59 × 10(-05)) 与CIMT呈负相关; 校正多重测试后,只有rs2236935仍然显著。使用逻辑回归,当我们调整腰围时,两个snp (rs11465886,IRAK2,3号染色体,OR = 3.91,p值 = 1.10 × 10(-04); 和rs17751769,SERPINA1,14号染色体,OR = 1.96,p值 = 2.42 × 10(-04)) 与> 0 Agatston单位的CAC评分呈正相关; 1个SNP (rs630014,ABO,OR = 0.51,p值 = 2.51 × 10(-04)) 呈负相关; 校正多重测试后无显著。这些snp是否与CIMT和CAC相关,在随机分配到MHT的女性中仍有待确定。

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