Genetics of Venous Thrombosis: Insights from a New Genome Wide Association Study

Abstract

BackgroundVenous Thrombosis (VT) is a common multifactorial disease associated with a major public health burden. Genetics factors are known to contribute to the susceptibility of the disease but how many genes are involved and their contribution to VT risk still remain obscure. We aimed to identify genetic variants associated with VT risk.Methodology/Principal FindingsWe conducted a genome-wide association study (GWAS) based on 551,141 SNPs genotyped in 1,542 cases and 1,110 controls. Twelve SNPs reached the genome-wide significance level of 2.0×10−8 and encompassed four known VT-associated loci, ABO, F5, F11 and FGG. By means of haplotype analyses, we also provided novel arguments in favor of a role of HIVEP1, PROCR and STAB2, three loci recently hypothesized to participate in the susceptibility to VT. However, no novel VT-associated loci came out of our GWAS. Using a recently proposed statistical methodology, we also showed that common variants could explain about 35% of the genetic variance underlying VT susceptibility among which 3% could be attributable to the main identified VT loci. This analysis additionally suggested that the common variants left to be identified are not uniformly distributed across the genome and that chromosome 20, itself, could contribute to ∼7% of the total genetic variance.Conclusions/SignificanceThis study might also provide a valuable source of information to expand our understanding of biological mechanisms regulating quantitative biomarkers for VT.

Novel genetic predictors of venous thromboembolism risk in African Americans

“…Furthermore, a previous study has suggested that chromosome 20 may harbor common variants yet to be identified that could contribute ;7% of the total genetic variance underlying VTE susceptibility. 10 Our results help place these previous findings in the context of a specific gene and regulatory SNPs that affect the expression of this gene.…”

“…8,9 Genome-wide association studies (GWASs) in populations of EA have confirmed the 2 well-established risk variants, factor V Leiden (rs6025) and prothrombin G20210A (rs1799963), and have identified several singlenucleotide polymorphisms (SNPs) in the ABO blood group gene (ABO) as susceptibility loci. [10][11][12] However, these variants are found in higher frequencies among individuals of EA compared with AAs, particularly rs6025 and rs1799963 which are nearly absent in AAs. These studies suggest that genetic variation outside the well-established findings in EA populations may contribute to VTE risk in populations of African ancestry.…”

“…3,4,39,40 Nonetheless, AAs have a higher percentage of O blood type, which is in the opposite direction of what would be expected. 6,41 Several GWASs have identified polymorphisms in the ABO gene to be associated with risk of VTE among populations of EA [10][11][12] Although not at GWAS For personal use only. on May 12, 2018.…”

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

“…It has been observed in 2 case-control studies 23,24 but was not detected in recent genome-wide association studies (GWAS). [25][26][27][28][29] Preliminary works also suggested that the rs3136516-G allele could associate with increased risk of systemic lupus erythematous (SLE). 30 If confirmed, this association would add support for the role of thrombin generation into inflammatory diseases.…”

Genotipos frecuentemente asociados a trombofilias

“…Por otra parte, los estudios de asociación del genoma completo (Genome-Wide Association Study, GWAS) y otros estudios genéticos más recientes han puesto en evidencia una estrecha relación entre las alteraciones genéticas encontradas en algunos loci y la aparición de trombofilias; entre estas variaciones se encuentran las presentadas en los alelos A y B que codifican para el grupo sanguíneo ABO, las mutaciones en los genes que codifican para anticoagulantes naturales como antitrombina II y III (por ejemplo, antitrombina Cambridge II) o deficiencias en los mismos, el SNP C46T en el factor XII, variaciones en los niveles de la proteína C y la proteína S de la coagulación, las disfibrinogenemias y la homocisteinuria, entre otras (4,(16)(17)(18)(19)(20)(21)(22).…”