Single- and Multimarker Genome-Wide Scans Evidence Novel Genetic Risk Modifiers for Venous Thromboembolism

Abstract

Previous genome-wide association studies (GWASs) have established several susceptibility genes for venous thromboembolism (VTE) and suggested many others. However, a large proportion of the genetic variance in VTE remains unexplained. Here, we report genome-wide single- and multimarker as well as gene-level associations with VTE in 964 cases and 899 healthy controls of European ancestry. We report 19 loci at the genome-wide level of association (p ≤ 5 × 10−8). Our results add to the strong support for the association of genetic variants in F5, NME7, ABO, and FGA with VTE, and identify several loci that have not been previously associated with VTE. Altogether, our novel findings suggest that 20 susceptibility genes for VTE were newly discovered by our study. These genes may impact the production and prothrombotic functions of platelets, endothelial cells, and white and red blood cells. Moreover, the majority of these genes have been previously associated with cardiovascular diseases and/or risk factors for VTE. Future studies are warranted to validate our findings and to investigate the shared genetic architecture with susceptibility factors for other cardiovascular diseases impacting VTE risk.

Recommendations from the ICM-VTE: General

“…Many previously known VTE loci are associated with the coagulation cascade. Herrera-Riveor et al, identified 20 susceptibility genes for VTE that do not participate directly in the coagulation cascade and proposed increased VTE risk was due to possible effect on platelet formation or function, cardiovascular development, and repair, and/or inflammation 33 . Ideally, in the future, genetic profiles could be established for surgical patients to assess the risk for developing a VTE.…”

“…There is a continued effort to identify loci associated with VTE through genome-wide association studies (GWAS), which compare the DNA of large cohorts of patients with VTE to control subjects. In three recent GWAS, 14, 22, and 20 susceptibility genes for VTE have been discovered, respectively 33-35 . Previously identified and novel single nucleotide polymorphisms (SNPs) identified in these three studies can be found in Table I.…”

“…Other loci such as non-O blood (ABO), fibrinogen gamma (FGC) and hyperhomocystenemia (MTHFR) have since been associated with increased VTE risk. Many more loci associated with increased VTE risk continue to be discovered through genome-wide association [31][32][33][34][35] .…”

Heterozygous Nme7 Mutation Affects Glucose Tolerance in Male Rats

“…Nme1 was shown to regulate glucose-stimulated insulin secretion in an in vitro experiment [ 23 ]. Over ten distinct SNPs in NME7 were found to be associated with blood pressure [ 24 ] and electrocardiographic traits [ 25 ], or venous thromboembolism [ 26 , 27 ] in several genome-wide association studies. We have previously demonstrated an association of NME7 gene variants with insulin secretion and lipid spectrum changes in two independent Caucasian populations [ 8 ].…”

COVID-19 host genetics and ABO blood group susceptibility

“…The extent to which the observed ABO blood group effects also apply to novel SARS-CoV Tables Table 1. Genome-wide significant (P<5×10 Genomes populations [64]) with rs687289 (see below). rs687289 COVID-19 severity [14]; rs687289 is associated with blood protein levels [69], monocyte count [70,71], venous thromboembolism [72,73], fibroblast growth factor 23 levels [74], and coagulations factor VIII and von Willebrand factor plasma levels [75][76][77] (studies unrelated to COVID-19 or SARS-CoV-2).…”