Joint Effect of Multiple Prothrombotic Genotypes and Mean Platelet Volume on the Risk of Incident Venous Thromboembolism

Abstract

Background - A high mean platelet volume (MPV), a marker of increased platelet reactivity, is a risk factor for venous thromboembolism (VTE). Whether established prothrombotic single nucleotide polymorphisms (SNPs) further increase the VTE risk in subjects with high MPV because of biological interaction remains unknown.<p>

<p>Aim - To investigate the joint effect of high MPV and prothrombotic genotypes, comprising a 5-SNP genetic risk score (GRS), on the risk of VTE in a population-based case–cohort.<p>

<p>Methods - Incident VTE cases (n = 653) and a subcohort (n = 1,774) were derived from the Tromsø Study (1994–2012). DNA was genotyped for rs8176719 (ABO), rs6025 (F5), rs1799963 (F2), rs2036914 (F11), and rs2066865 (FGG). Hazard ratios (HRs) for VTE with 95% confidence intervals (CIs) were estimated according to predefined MPV-strata (<8.5, 8.5–9.5, ≥9.5 fL) and number of risk alleles for each individual SNP and the GRS (0–1, 2–3, ≥4 risk alleles) in models adjusted for age, sex, body mass index, and platelet count.<p>

<p>Results - The combination of high MPV and risk alleles, either as individual SNPs or the GRS, had an additive effect on VTE risk. Compared with subjects with MPV <8.5 fL and 0–1 risk allele, those with high MPV (≥9.5 fL) and ≥4 risk alleles had HRs of 2.80 (95% CI: 1.77-4.43) for overall VTE and 4.60 (95% CI: 2.20–9.60) for unprovoked events, respectively, but there was no supra-additive effect on risk estimates.<p>

<p>Conclusion - The combination of high MPV and prothrombotic genotypes had an additive effect on VTE risk, suggesting there is no biological interaction between these risk factors in the pathogenesis of VTE.