Abstract
BackgroundElevated levels of factor VIII (FVIII) and von Willebrand Factor (vWF) are well-established risk factors for cardiovascular diseases, in particular venous thrombosis. Although high, the heritability of these traits is poorly explained by the genetic factors known so far. The aim of this work was to identify novel single nucleotide polymorphisms (SNPs) that could influence the variability of these traits.MethodsThree independent genome-wide association studies for vWF plasma levels and FVIII activity were conducted and their results were combined into a meta-analysis totalling 1,624 subjects.ResultsNo single nucleotide polymorphism (SNP) reached the study-wide significance level of 1.12 × 10-7 that corresponds to the Bonferroni correction for the number of tested SNPs. Nevertheless, the recently discovered association of STXBP5, STX2, TC2N and CLEC4M genes with vWF levels and that of SCARA5 and STAB2 genes with FVIII levels were confirmed in this meta-analysis. Besides, among the fifteen novel SNPs showing promising association at p < 10-5 with either vWF or FVIII levels in the meta-analysis, one located in ACCN1 gene also showed weak association (P = 0.0056) with venous thrombosis in a sample of 1,946 cases and 1,228 controls.ConclusionsThis study has generated new knowledge on genomic regions deserving further investigations in the search for genetic factors influencing vWF and FVIII plasma levels, some potentially implicated in VT, as well as providing some supporting evidence of previously identified genes.
Highlights
Elevated levels of factor VIII (FVIII) and von Willebrand Factor are well-established risk factors for cardiovascular diseases, in particular venous thrombosis
The estimated heritability of FVIII and von Willebrand Factor (vWF) levels range between 40% and 60% [14,15] among which about 20% is attributable to the ABO locus
A total of 442,728 quality control (QC)-validated single nucleotide polymorphisms (SNPs) were common to the three genome wide association study (GWAS) and were tested through a meta-analysis for association with vWF and FVIII plasma levels
Summary
Elevated levels of factor VIII (FVIII) and von Willebrand Factor (vWF) are well-established risk factors for cardiovascular diseases, in particular venous thrombosis. These include single nucleotide polymorphisms (SNPs) at the BAI3 [9], LDLR [5,10], VWF [4] and ABO [11] genes, the latter being associated with other quantitative risk factors for CVD [12,13]. A genome wide association study (GWAS) within the CHARGE consortium [16] has recently identified five new genes, apart from their structural genes and ABO, consistently influencing vWF and/or FVIII plasma levels. These include CLEC4M, SCARA5, STX2, STXBP5 and TC2N, collectively explaining ~10% of the variability of each two traits. These observations suggest that there are additional genetic factors remaining to be identified and contributing to the hidden heritability of these quantitative traits
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