Journal Article

Obesity, unfavourable lifestyle and genetic risk of type 2 diabetes: a case-cohort study

Ängquist Lars, Hansen, Torben, Kilpeläinen, Tuomas O, Jakupović Hermina, Pedersen Oluf, Tjønneland, Anne, Schnurr, Theresia M, Grarup Niels, Sørensen Thorkild I A, Overvad Kim, Carrasquilla, Germán D

2020

Overview

Aims/hypothesisWe aimed to investigate whether the impact of obesity and unfavourable lifestyle on type 2 diabetes risk is accentuated by genetic predisposition.MethodsWe 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 diabetes-associated 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 2 diabetes.ResultsObesity (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/interpretationHaving normal body weight is crucial in the prevention of type 2 diabetes, regardless of genetic predisposition.

• Publisher: Springer Nature B.V
• Subject: Body weight / Cohort analysis / Diabetes / Diabetes mellitus (non-insulin dependent) / Diet / Genetics / Health risk assessment / Lifestyles / Obesity / Physical activity / Risk groups