The EPIC-Norfolk Study
Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study.
PLoS Medicine 2013 ; 11: e1001647.
Langenberg C, Sharp SJ, Franks PW, Scott RA, Deloukas P, Forouhi NG, Froguel P, Groop LC, Hansen T, Palla L, Pedersen O, Schulze MB, Tormo MJ, Wheeler E, Agnoli C, Arriola L, Barricarte A, Boeing H, Clarke GM, Clavel-Chapelon F, Duell EJ, Fagherazzi G, Kaaks R, Kerrison ND, Key TJ, Khaw KT, Kröger J, Lajous M, Morris AP, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quirós JR, Rolandsson O, Sacerdote C, Sánchez MJ, Slimani N, Spijkerman AM, Tumino R, van der A DL, van der Schouw YT, Barroso I, McCarthy MI, Riboli E, and Wareham NJ
DOI : 10.1371/journal.pmed.1001647
PubMed ID : 24845081
PMCID : PMC4028183
URL : https://pubmed.ncbi.nlm.nih.gov/24845081/
Abstract
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.