Theresia M. Schnurr, Thorkild I. A. Sørensen,Tuomas O. Kilpeläinen & Hermina Jakupović & Anne Tjønneland & Germán D. Carrasquilla & Kim Overvad & Lars Ängquist & Oluf Pedersen & Niels Grarup & Torben Hansen -Springer-Verlag GmbH Germany, part of Springer Nature 2020
Aims/hypothesis We aimed to investigate whether the impact of obesity and unfavourable lifestyle on type 2 diabetes risk is accentuated by genetic predisposition.
Methods We examined the joint association of genetic predisposition, obesity and unfavourable lifestyle with incident type 2 diabetes using a case-cohort study nested within the Diet, Cancer and Health cohort in Denmark. The study sample included 4729 individuals who developed type 2 diabetes during a median 14.7 years of follow-up, and a randomly selected cohort sample of 5402 individuals. Genetic predisposition was quantified using a genetic risk score (GRS) comprising 193 known type 2 diabetesassociated loci (excluding known BMI loci) and stratified into low (quintile 1), intermediate and high (quintile 5) genetic risk groups. Lifestyle was assessed by a lifestyle score composed of smoking, alcohol consumption, physical activity and diet. We used Prentice-weighted Cox proportional-hazards models to test the associations of the GRS, obesity and lifestyle score with incident type 2 diabetes, as well as the interactions of the GRS with obesity and unfavourable lifestyle in relation to incident type 2diabetes.
Results Obesity (BMI ≥ 30 kg/m2) and unfavourable lifestyle were associated with higher risk for incident type 2 diabetes regardless of genetic predisposition (p > 0.05 for GRS–obesity and GRS–lifestyle interaction). The effect of obesity on type 2
diabetes risk (HR 5.81 [95%CI 5.16, 6.55]) was high, whereas the effects of high genetic risk (HR 2.00 [95%CI 1.76, 2.27]) and unfavourable lifestyle (HR 1.18 [95% CI 1.06, 1.30]) were relatively modest. Even among individuals with low GRS and favourable lifestyle, obesity was associated with a >8-fold risk of type 2 diabetes compared with normal-weight individuals in the same GRS and lifestyle stratum.
Conclusions/interpretation Having normal body weight is crucial in the prevention of type 2 diabetes, regardless of genetic predisposition.
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