Association of coagulation‐related and inflammation‐related genes and factor VIIc levels with stroke: the Cardiovascular Health Study

Summary. Background: Thrombosis and inflammation are critical in stroke etiology, but associations of coagulation and inflammation gene variants with stroke, and particularly factor VII levels, are inconclusive. Objectives: To test the associations between 736 single‐nucleotide polymorphisms (SNPs) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events, in the 5888 participants aged ≥ 65 years of the observational Cardiovascular Health Study cohort. Patients/Methods: With 16 years of follow‐up, age‐adjusted and sex‐adjusted Cox models were used to estimate associations of SNPs and FVIIc levels with future stroke. Results: Eight hundred and fifteen strokes occurred in 5255 genotyped participants without baseline stroke (748 ischemic strokes; 586 among whites). Among whites, six SNPs were associated with stroke, with a nominal P‐value of < 0.01: rs6046 and rs3093261 (F7); rs4918851 and rs3781387 (HABP2); and rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with FVIIc levels (units of percentage activity): rs6046 (β = ? 18.5, P = 2.38 × 10^?83) and rs3093261 (β = 2.99, P = 3.93 × 10^?6). After adjustment for age, sex, race, and cardiovascular risk factors, the association of FVIIc quintiles (Q) with stroke were as follows (hazard ratio; 95% confidence interval): Q1, reference; Q2, 1.4, 1.1–1.9); Q3, 1.1, 0.8–1.5); Q4, 1.5, 1.1–2.0); and Q5, 1.6, 1.2–2.2). Associations between SNPs and stroke were independent of FVIIc levels. Conclusions:   Variations in FVII‐related genes and FVIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for FVII in stroke etiology.