Human Genetic Variation in F3 and Its Impact on Tissue Factor-Dependent Disease

Abstract

Tissue factor (TF) is the primary initiator of blood coagulation in humans. As improper intravascular TF expression and procoagulant activity underlie numerous thrombotic disorders, there has been longstanding interest in the contribution of heritable genetic variation in F3, the gene encoding TF, to human disease. This review seeks to comprehensively and critically synthesize small case-control studies focused on candidate single nucleotide polymorphisms (SNPs), as well as modern genome-wide association studies (GWAS) seeking to discover novel associations between variants and clinical phenotypes. Where possible, correlative laboratory studies, expression quantitative trait loci, and protein quantitative trait loci are evaluated to glean potential mechanistic insights. Most disease associations implicated in historical case-control studies have proven difficult to replicate in large GWAS. Nevertheless, SNPs linked to F3, such as rs2022030, are associated with increased F3 mRNA expression, monocyte TF expression after endotoxin exposure, and circulating levels of the prothrombotic biomarker D-dimer, consistent with the central role of TF in the initiation of blood coagulation.

Figure 1.. Summary and chromosomal location of reported F3 SNP associations.

Visual representation of pertinent human SNPs on chromosome 1 mapping in or near F3 that have been associated with: Thrombotic or hemostatic clinical traits in case-control studies (blue), D-dimer levels in genome-wide association studies (GWAS, burgundy), circulating tissue factor protein levels identified as protein quantitative trait loci (pQTL, gold), and F3 mRNA expression levels identified as expression or splicing quantitative trait loci (e/sQTL, purple). Note that most potential associations have not been independently replicated or established as causal. Chromosome positions reflect genome build GRCh38.p14. For clarity, the orientation of F3 in the upper panel reflects the direction of F3 transcription on the antisense strand, which differs from the orientation of the gene depicted in the chromosomal view (lower panel).