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. 2014 May 20;11(5):e1001647.
doi: 10.1371/journal.pmed.1001647. eCollection 2014 May.

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

Claudia Langenberg  1 , Stephen J Sharp  1 , Paul W Franks  2 , Robert A Scott  1 , Panos Deloukas  3 , Nita G Forouhi  1 , Philippe Froguel  4 , Leif C Groop  5 , Torben Hansen  6 , Luigi Palla  1 , Oluf Pedersen  7 , Matthias B Schulze  8 , Maria-Jose Tormo  9 , Eleanor Wheeler  3 , Claudia Agnoli  10 , Larraitz Arriola  11 , Aurelio Barricarte  12 , Heiner Boeing  8 , Geraldine M Clarke  13 , Françoise Clavel-Chapelon  14 , Eric J Duell  15 , Guy Fagherazzi  14 , Rudolf Kaaks  16 , Nicola D Kerrison  1 , Timothy J Key  17 , Kay Tee Khaw  18 , Janine Kröger  8 , Martin Lajous  19 , Andrew P Morris  13 , Carmen Navarro  20 , Peter M Nilsson  21 , Kim Overvad  22 , Domenico Palli  23 , Salvatore Panico  24 , J Ramón Quirós  25 , Olov Rolandsson  26 , Carlotta Sacerdote  27 , María-José Sánchez  28 , Nadia Slimani  29 , Annemieke M W Spijkerman  30 , Rosario Tumino  31 , Daphne L van der A  30 , Yvonne T van der Schouw  32 , Inês Barroso  33 , Mark I McCarthy  34 , Elio Riboli  35 , Nicholas J Wareham  1
Affiliations

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

Claudia Langenberg et al. PLoS Med. .

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.

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Conflict of interest statement

IB and her spouse own stock in the companies GlaxoSmithKline (GSK) and Incyte (INCY). LCG and MIM are members of the Editorial Board of PLOS Medicine.

Figures

Figure 1
Figure 1. Hazard ratios for type 2 diabetes per standard deviation (4.4 alleles) increase in the imputed, unweighted genetic risk score by country and overall: the InterAct study.
Figure 2
Figure 2. Hazard ratios for type 2 diabetes per standard deviation (4.4 alleles) increase in the imputed, unweighted genetic risk score within strata defined by sex, diabetes family history, body mass index, waist circumference, age, physical activity, and Mediterranean diet score: the InterAct study.
Prentice-weighted Cox regression models are adjusted for age, sex, and centre. F, female; M, male; Med., Mediterranean.
Figure 3
Figure 3. Hazard ratios for type 2 diabetes per standard deviation (4.4 alleles) increase in the imputed, unweighted genetic risk score within strata defined by sex, diabetes family history, body mass index, waist circumference, age, physical activity, and Mediterranean diet score: the InterAct study.
Prentice-weighted Cox regression models are adjusted for age, sex, centre, and BMI. F, female; M, male; Med., Mediterranean.
Figure 4
Figure 4. Cumulative incidence of type 2 diabetes (percent) by quartiles of the imputed, unweighted genetic risk score and strata of body mass index, waist circumference, physical activity, and Mediterranean diet score: the InterAct study.
(A) BMI (red: <25 kg/m2; blue: 25 to <30 kg/m2; black: ≥30 kg/m2), (B) WC (red: <94 cm in men and <80 cm in women; blue: 94 to <102 cm in men and 80 to <88 cm in women; black: ≥102 cm in men and ≥88 cm in women), (C) physical activity (red: active; blue: moderately active; green: moderately inactive; black: inactive), and (D) Mediterranean diet score (red: 11–18; blue: 7–10; black: 0–6).
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