The impact of the combination of obesity and multiple prothrombotic genotypes on venous thromboembolism (VTE) risk remains unclear.
To investigate the joint effect of obesity and a genetic risk score (GRS) comprised of established prothrombotic single nucleotide polymorphisms (SNPs) on VTE risk using a population-based case-cohort.
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).
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 intervals [CI] 2.05-3.96) increased risk of overall VTE compared to those with BMI<25kg/m2 and 0-1 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.
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.

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