Joint Effect of Multiple Prothrombotic Genotypes and Obesity on the Risk of Incident Venous Thromboembolism

Abstract Background The impact of the combination of obesity and multiple prothrombotic genotypes on venous thromboembolism (VTE) risk remains unclear. Objective To investigate the joint effect of obesity and a genetic risk score (GRS) composed of established prothrombotic single nucleotide polymorphisms (SNPs) on VTE risk using a population-based case–cohort. Methods Cases with incident VTE (n = 1,470) and a subcohort (n = 12,826) were derived from the Tromsø Study (1994–2012) and the Trøndelag Health Study (HUNT) (1995–2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914) SNPs. Age- and sex-adjusted hazard ratios (HRs) were estimated according to body mass index (BMI) categories and number of risk alleles for individual SNPs and the GRS (0–1, 2, 3, ≥4 alleles). Results The combination of obesity (BMI ≥ 30kg/m2) and risk alleles, either as individual SNPs or as a GRS, had an additive effect on VTE risk (i.e., no biological interaction). Obese subjects who were carriers of ≥4 risk alleles had a 2.85-fold (95% confidence interval [CI]: 2.05–3.96) increased risk of overall VTE compared with those with BMI <25 kg/m2 and 0 to 1 risk allele. However, in subgroups, the combination of obesity and ≥4 risk alleles was more pronounced for deep vein thrombosis (DVT) (HR: 3.20; 95% CI: 2.09–4.90) and unprovoked VTE (HR: 3.82; 95% CI: 2.25–6.47), suggesting a supra-additive effect. Conclusion Our findings indicate that the combination of obesity and GRS has an additive effect on the risk of overall VTE. However, it may have a supra-additive effect on the risk of DVT and unprovoked VTE.