Haplotype and genotype effects of the F7 gene on circulating factor VII, coagulation activation markers and incident coronary heart disease in UK men

Abstract

Background: Evidence for the associations of single nucleotide polymorphisms (SNPs) in the F7 gene and factor (F)VII levels and with risk of coronary heart disease (CHD) is inconsistent. We examined whether F7 tagging SNPs (tSNPs) and haplotypes were associated with FVII levels, coagulation activation markers (CAMs) and CHD risk in two cohorts of UK men.

Methods: Genotypes for eight SNPs and baseline levels of FVIIc, FVIIag and CAMs (including FVIIa) were determined in 2773 healthy men from the Second Northwick Park Heart Study (NPHS-II). A second cohort, Whitehall II study (WH-II, n = 4055), was used for replication analysis of FVIIc levels and CHD risk.

Results: In NPHS-II the minor alleles of three SNPs (rs555212, rs762635 and rs510317; haplotype H2) were associated with higher levels of FVIIag, FVIIc and FVIIa, whereas the minor allele for two SNPs (I/D323 and rs6046; haplotype H5) was associated with lower levels. Adjusted for classic risk factors, H2 carriers had a CHD hazard ratio of 1.34 [95% confidence interval (CI): 1.12-1.59; independent of FVIIc], whereas H5 carriers had a CHD risk of 1.29 (95% CI: 1.01-1.56; not independent of FVIIc) and significantly lower CAMs. Effects of haplotypes on FVIIc levels were replicated in WH-II, as was the association of H5 with higher CHD risk [pooled-estimate odds ratio (OR) 1.16 (1.00-1.36), P = 0.05], but surprisingly, H2 exhibited a reduced risk for CHD.

Conclusion: tSNPs in the F7 gene strongly influence FVII levels. The haplotype associated with low FVIIc level, with particularly reduced functional activity, was consistently associated with increased risk for CHD, whereas the haplotype associated with high FVIIc level was not.

Figure 1

Pair-wise linkage disequilibrium structure represent as a D′ (different color intensities) and r² values (numbers) in 7 SNPs. The rs numbers and the relative physical distance between the SNPs are shown above (exons are the larger rectangular boxes). The color gradient indicates relative level of LD from black complete to white no LD.

Figure 2

The association between FVIIc levels and haplotypes H2/H5, in NPHS-II.

Figure 3

Association between haplotype H2, H5 and CHD in NPHS-II and WH-II studies. HR, hazard ratio in NPHS-II study; OR, odds ratio in WH-II study. Adjusted for age, clinic, BMI, diabetes, total cholesterol, smoking, and systolic blood pressure, Lower panel shows pooled OR for both NPHS-II and WH-II.