Pleiotropic effects of n-6 and n-3 fatty acid-related genetic variants on circulating hemostatic variables

Introduction: Data from epidemiological studies and clinical trials suggest an influence of dietary and circulating polyunsaturated fatty acids (PUFAs) on the hemostasis profile. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) related to plasma PUFAs levels. We aimed to investigate whether the SNPs related to plasma PUFAs levels were also associated with plasma levels of hemostatic variables.

Materials and methods: We tested the associations between 9 PUFA-related SNPs and 6 hemostatic variables in 9035 European Americans (EAs) and 2702 African Americans (AAs) in the Atherosclerosis Risk in Communities (ARIC) Study. We then conducted a replication study by looking-up our novel observed associations in three published GWAS for hemostatic factors in different EA populations.

Results: We observed a novel linoleic acid-related locus at the JMJD1C region associated with factor VII activity (FVIIc): rs10740118 and rs1935, Beta (p) = -1.31 (1 × 10^-3) and 1.37 (5 × 10^-4) in EAs, respectively, and - 1.24 (5 × 10^-4) and 1.28 (3 × 10^-4) in meta-analysis of EAs and AAs of ARIC. This novel association was replicated in two of three independent EA populations (p = 0.01 and 0.03 in meta-analyses). We confirmed previously reported associations at the docosapentaenoic acid-related GCKR locus with protein C and FVIIc and at JMJD1C with fibrinogen. Adjustment for plasma PUFAs did not abolish the associations between these loci and hemostatic variables.

Conclusions: Our study identified a novel association for FVIIc at JMJD1C, a histone demethylase that plays a role in DNA repair and possibly transcription regulation and RNA processing.