Genome-Wide Search for Nonadditive Allele Effects Identifies as Involved in the Variability of Factor V Activity.

Background: Factor V (FV) is a key molecular player in the coagulation cascade. FV plasma levels have been associated with several human diseases, including thrombosis, bleeding, and diabetic complications. So far, 2 genes have been robustly found through genome-wide association analyses to contribute to the inter-individual variability of plasma FV levels: structural F5 gene and PLXDC2.

Methods And Results: The authors used the underestimated Brown-Forsythe methodology implemented in the QuickTest software to search for non-additive genetic effects that could contribute to the inter-individual variability of FV plasma activity. QUICKTEST was applied to 4 independent genome-wide association studies studies (LURIC [Ludwigshafen RIsk and Cardiovascular Health Study], MARTHA [Marseille Thrombosis Association], MEGA [Multiple Environmental and Genetic Assessment], and RETROVE [Riesgo de Enfermedad Tromboembolica Venosa]) totaling 4505 participants of European ancestry with measured FV plasma levels. Results obtained in the 4 cohorts were meta-analyzed using a fixed-effect model. Additional analyses involved exploring haplotype and gene×gene interactions in downstream investigations. A genome-wide significant signal at the locus on chr8q21.3 with lead variant rs75463553 with no evidence for heterogeneity across cohorts was observed (=0.518). Although rs75463553 did not show an association with mean FV levels (=0.49), it demonstrated a robust significant (=3.38x10) association with the variance of FV plasma levels. Further analyses confirmed the reported association of with neutrophil biology and revealed that rs75463553 likely interacts with two loci, and , known for their involvement in smoking biology.

Conclusions: This comprehensive approach identifies the role of as a novel molecular player in the genetic regulation of FV, shedding light on the contribution of neutrophils to FV biology.