Langenberg, ClaudiaSharp, Stephen JFranks, Paul WScott, Robert ADeloukas, PanosForouhi, Nita GFroguel, PhilippeGroop, Leif CHansen, TorbenPalla, LuigiPedersen, OlufSchulze, Matthias BTormo, Maria-JoseWheeler, EleanorAgnoli, ClaudiaArriola, LarraitzBarricarte, AurelioBoeing, HeinerClarke, Geraldine MClavel-Chapelon, FrançoiseDuell, Eric JFagherazzi, GuyKaaks, RudolfKerrison, Nicola DKey, Timothy JKhaw, Kay TeeKröger, JanineLajous, MartinMorris, Andrew PNavarro, CarmenNilsson, Peter MOvervad, KimPalli, DomenicoPanico, SalvatoreQuirós, J RamónRolandsson, OlovSacerdote, CarlottaSanchez-Perez, Maria-JoseSlimani, NadiaSpijkerman, Annemieke M WTumino, Rosariovan der A, Daphne Lvan der Schouw, Yvonne TBarroso, InêsMcCarthy, Mark IRiboli, ElioWareham, Nicholas J2015-01-232015-01-232014-05-20Langenberg C, Sharp SJ, Franks PW, Scott RA, Deloukas P, Forouhi NG, et al. Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study. PLoS Med.. 2014 ; 11(5):e10016471549-1277http://hdl.handle.net/10668/1797Journal 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.enAlelosÍndice de Masa CorporalEstudios de CohortesDiabetes Mellitus Tipo 2Dieta MediterráneaFemeninoPredisposición Genética a la EnfermedadHumanosEstilo de VidaMasculinoMediana EdadActividad MotoraPolimorfismo de Nucleótido SimpleModelos de Riesgos ProporcionalesFactores de RiesgoCircunferencia de la CinturaMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::AllelesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Mass IndexMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort StudiesMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Nutrition Therapy::Diet Therapy::Diet, MediterraneanMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to DiseaseMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Psychology, Social::Life StyleMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle AgedMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Motor ActivityMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single NucleotideMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Proportional Hazards ModelsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk FactorsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Size::Waist Circumferenceresearch article24845081open access10.1371/journal.pmed.10016471549-1676PMC4028183