Genetic polymorphisms associated with carotid artery intima-media thickness and coronary artery calcification in women of the Kronos Early Estrogen Prevention Study

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.