Joint effects of atrial fibrillation and prothrombotic genotypes on the risk of ischemic stroke.

Background: Atrial fibrillation (AF) is a major risk factor for ischemic stroke. Whether prothrombotic single nucleotide polymorphisms (SNPs) impact stroke risk in AF is not well known.

Objectives: To investigate the joint effects of five prothrombotic SNPs and AF on ischemic stroke risk.

Methods: A sub-cohort (n=14,583) was randomly sampled from the Tromsø (1994-2012) and the Trøndelag Health (HUNT) (1995-2008) studies. DNA was genotyped for rs8176719 (ABO blood type), rs6025 (Factor V Leiden; FVL), rs1799963 (prothrombin G20210A), rs2066865 (fibrinogen-γ; FGG) and rs2036914 (Factor 11; F11). Hazard ratios (HR) with 95% confidence intervals (CI) for incident ischemic stroke were estimated by AF status for individual SNPs and by categories of a genetic risk score (GRS).

Results: 1091 participants developed AF during follow-up, of whom 169 (15.5%) subsequently had a stroke. Having ≥ 1 risk allele in prothrombin, FVL, F11 or FGG was not associated with excess stroke risk in AF. In the absence of AF, ≥ 1 risk allele(s) in ABO was not associated with stroke (HR 1.03, 95% CI 0.85-1.25), whereas those with AF and ≥ 1 risk allele(s) in ABO had a 1.4-fold increased stroke risk compared to those with AF and no risk allele (HR 1.42, 95% CI 0.99-2.04). There was no linear increase in stroke risk across categories of the GRS in participants either with or without AF.

Conclusions: Most prothrombotic SNPs were not associated with ischemic stroke risk, regardless of AF status. The ABO SNP was associated with ischemic stroke risk in those with AF only.