TY - JOUR

T1 - Gene-lifestyle interaction and type 2 diabetes

T2 - the EPIC interact case-cohort study

AU - Langenberg, Claudia

AU - Sharp, Stephen J

AU - Franks, Paul W

AU - Scott, Robert A

AU - Deloukas, Panos

AU - Forouhi, Nita G

AU - Froguel, Philippe

AU - Groop, Leif C

AU - Hansen, Torben

AU - Palla, Luigi

AU - Pedersen, Oluf

AU - Schulze, Matthias B

AU - Tormo, Maria-Jose

AU - Wheeler, Eleanor

AU - Agnoli, Claudia

AU - Arriola, Larraitz

AU - Barricarte, Aurelio

AU - Boeing, Heiner

AU - Clarke, Geraldine M

AU - Clavel-Chapelon, Françoise

AU - Duell, Eric J

AU - Fagherazzi, Guy

AU - Kaaks, Rudolf

AU - Kerrison, Nicola D

AU - Key, Timothy J

AU - Khaw, Kay Tee

AU - Kröger, Janine

AU - Lajous, Martin

AU - Morris, Andrew P

AU - Navarro, Carmen

AU - Nilsson, Peter M

AU - Overvad, Kim

AU - Palli, Domenico

AU - Panico, Salvatore

AU - Quirós, J Ramón

AU - Rolandsson, Olov

AU - Sacerdote, Carlotta

AU - Sánchez, María-José

AU - Slimani, Nadia

AU - Spijkerman, Annemieke M W

AU - Tumino, Rosario

AU - van der A, Daphne L

AU - van der Schouw, Yvonne T

AU - Barroso, Inês

AU - McCarthy, Mark I

AU - Riboli, Elio

AU - Wareham, Nicholas J

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Alleles

KW - Body Mass Index

KW - Cohort Studies

KW - Diabetes Mellitus, Type 2

KW - Diet, Mediterranean

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Life Style

KW - Male

KW - Middle Aged

KW - Motor Activity

KW - Polymorphism, Single Nucleotide

KW - Proportional Hazards Models

KW - Risk Factors

KW - Waist Circumference

U2 - 10.1371/journal.pmed.1001647

DO - 10.1371/journal.pmed.1001647

M3 - Journal article

C2 - 24845081

VL - 11

JO - P L o S Medicine (Online)

JF - P L o S Medicine (Online)

SN - 1549-1277

IS - 5

M1 - e1001647

ER -