Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study.

Journal Article; Research Support, Non-U.S. Gov't;BACKGROUND 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. METHODS AND FINDINGS 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. CONCLUSIONS 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.Funding: No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following agencies: PWF: Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, Swedish Heart-Lung Foundation; PD: Work was supported by the Wellcome Trust; LCG: Swedish Research Council; MJT: Health Research Fund (FIS) of the Spanish Ministry of Health; Murcia Regional Government (Nu 6236); LA: EJD: The Spanish Ministry of Health – ISCII RETICC RD06/0020; RK: German Cancer Aid, German Ministry of Research (BMBF); TJK: Cancer Research UK; KTK: Medical Research Council UK, Cancer Research UK; APM: Wellcome Trust grant numbers WT098017 and WT090532; CN: Health Research Fund (FIS) of the Spanish Ministry of Health; Murcia Regional Government (Nu 6236); PMN: Swedish Research Council; KO: Danish Cancer Society; SP: Compagnia di San Paolo; JRQ: Asturias Regional Government; OR: The Va¨sterboten County Council; AMWS and DLvdA: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands; RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government; YTvdS: Verification of diabetes cases was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht; IB: Wellcome Trust grant 098051 and United Kingdom NIHR Cambridge Biomedical Research Centre; MIM: InterAct, Wellcome Trust (083270/Z/07/Z), MRC (G0601261); ER: Imperial College Biomedical Research Centre.Ye