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

Langenberg C1, Sharp SJ1, Franks PW2, Scott RA1, Deloukas P3, Forouhi NG1, Froguel P4, Groop LC5, Hansen T6, Palla L1, Pedersen O7, Schulze MB8,Tormo MJ9, Wheeler E3, Agnoli C10, Arriola L11, Barricarte A12, Boeing H8, Clarke GM13, Clavel-Chapelon F14, Duell EJ15, Fagherazzi G14, Kaaks R16,Kerrison ND1, Key TJ17, Khaw KT18, Kröger J8, Lajous M19, Morris AP13, Navarro C20, Nilsson PM21, Overvad K22, Palli D23, Panico S24, Quirós JR25,Rolandsson O26, Sacerdote C27, Sánchez MJ28, Slimani N29, Spijkerman AM30, Tumino R31, van der A DL30, van der Schouw YT32, Barroso I33, McCarthy MI34, Riboli E35, Wareham NJ1.

Author information

Abstract

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. Please see later in the article for the Editors' Summary.