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Association of coagulation‐related and inflammation‐related genes and factor VIIc levels with stroke: the Cardiovascular Health Study
Author(s) -
ZAKAI N. A.,
LANGE L.,
LONGSTRETH W. T.,
O’MEARA E. S.,
KELLEY J. L.,
FORNAGE M.,
NIKERSON D.,
CUSHMAN M.,
REINER A. P.
Publication year - 2011
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2010.04149.x
Subject(s) - stroke (engine) , medicine , single nucleotide polymorphism , hazard ratio , cohort , confidence interval , risk factor , haplotype , rotterdam study , allele , genotype , genetics , biology , gene , mechanical engineering , engineering
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.