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

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  • Theresia M Schnurr, The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark., Danmark
  • Hermina Jakupović, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark. hermina.jakupovic@sund.ku.dk., Danmark
  • Germán D Carrasquilla, The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark., Danmark
  • Lars Ängquist, The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark., Danmark
  • Niels Grarup, The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark.
  • ,
  • Thorkild I A Sørensen, The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark., Department of Public Health, Section of Epidemiology, Faculty of Health and Social Sciences, University of Copenhagen, Copenhagen, Denmark., Danmark
  • Anne Tjønneland, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark., Department of Public Health, Section of Epidemiology, Faculty of Health and Social Sciences, University of Copenhagen, Copenhagen, Denmark., Danmark
  • Kim Overvad
  • Oluf Pedersen, The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark., Danmark
  • Torben Hansen, The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark., Danmark
  • Tuomas O Kilpeläinen, The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark., Danmark

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 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.

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.

OriginalsprogEngelsk
TidsskriftDiabetologia
Vol/bind63
Nummer7
Sider (fra-til)1324-1332
ISSN0012-186X
DOI
StatusUdgivet - 2020

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