Journal Article

Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study

Groop, Leif C., Agnoli, Claudia, Sánchez, María-José, Forouhi, Nita G., Clarke, Geraldine M., Morris, Andrew P., Scott, Robert A., Barroso, Inês, Franks, Paul W., Langenberg, Claudia, Pedersen, Oluf, Quirós, J. Ramón, Schulze, Matthias B., Rolandsson, Olov, Barricarte, Aurelio, Clavel-Chapelon, Françoise, Nilsson, Peter M., Key, Timothy J., Overvad, Kim, Palli, Domenico, van der Schouw, Yvonne T., Deloukas, Panos, Khaw, Kay Tee, van der A, Daphne L., Riboli, Elio, Spijkerman, Annemieke M. W., Tumino, Rosario, Kröger, Janine, Navarro, Carmen, Wareham, Nicholas J., Kerrison, Nicola D., McCarthy, Mark I., Tormo, Maria-Jose, Hansen, Torben, Palla, Luigi, Wheeler, Eleanor, Sacerdote, Carlotta, Sharp, Stephen J., Lajous, Martin, Duell, Eric J., Boeing, Heiner, Kaaks, Rudolf, Froguel, Philippe, Fagherazzi, Guy, Panico, Salvatore, Arriola, Larraitz, Slimani, Nadia

2014

Overview

Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction  = 1.20×10-4). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction  = 1.50×10-3) and waist circumference (p for interaction  = 7.49×10-9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alleles / Biology and Life Sciences / Body Mass Index / Clinical Medicine / Cohort Studies / Diabetes / Diabetes Mellitus, Type 2 - diet therapy / Diabetes Mellitus, Type 2 - genetics / Diet, Mediterranean / Endocrinology and Diabetes / Endokrinologi och diabetes / Epigenetic inheritance / Female / Genetic aspects / Genetic Predisposition to Disease / Genetic research / Health aspects / Health risk assessment / Humans / Klinisk medicin / Life Style / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Medicine and Health Sciences / Middle Aged / Motor Activity / Obesity / Polymorphism, Single Nucleotide - genetics / Proportional Hazards Models / Risk Factors / Studies / Type 2 diabetes / Waist Circumference - genetics / Weight control