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


RESULTS
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.
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
Claudia
C
Langenberg
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
Stephen J
SJ
Sharp
Lund University, Malmö, Sweden; Umeå University, Umeå, Sweden.
Paul W
PW
Franks
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
Robert A
RA
Scott
The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Panos
P
Deloukas
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
Nita G
NG
Forouhi
Imperial College London, London, United Kingdom.
Philippe
P
Froguel
University Hospital Scania, Malmö, Sweden; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Leif C
LC
Groop
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Torben
T
Hansen
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
Luigi
L
Palla
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Science, University of Aarhus, Aarhus, Denmark; Institute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Oluf
O
Pedersen
German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
Matthias B
MB
Schulze
Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain; Consorcio de Investigación Biomédica de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Spain; Department of Health and Social Sciences, Universidad de Murcia, Spain.
Maria-Jose
MJ
Tormo
The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Eleanor
E
Wheeler
Epidemiology and Prevention Unit, Milan, Italy.
Claudia
C
Agnoli
Consorcio de Investigación Biomédica de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Spain; Public Health Division of Gipuzkoa, San Sebastian, Spain; Instituto de Investigación Sanitaria BioDonostia, Basque Government, San Sebastian, Spain.
Larraitz
L
Arriola
Consorcio de Investigación Biomédica de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Spain; Navarre Public Health Institute, Pamplona, Spain.
Aurelio
A
Barricarte
German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
Heiner
H
Boeing
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Geraldine M
GM
Clarke
Inserm, CESP U1018, Villejuif, France; Université Paris-Sud, UMRS 1018, Villejuif, France.
Françoise
F
Clavel-Chapelon
Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Barcelona, Spain.
Eric J
EJ
Duell
Inserm, CESP U1018, Villejuif, France; Université Paris-Sud, UMRS 1018, Villejuif, France.
Guy
G
Fagherazzi
German Cancer Research Center, Heidelberg, Germany.
Rudolf
R
Kaaks
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
Nicola D
ND
Kerrison
University of Oxford, Oxford, United Kingdom.
Timothy J
TJ
Key
University of Cambridge, Cambridge, United Kingdom.
Kay Tee
KT
Khaw
German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
Janine
J
Kröger
Inserm, CESP U1018, Villejuif, France; Center for Research on Population Health, National Institute of Public Health of Mexico, Cuernavaca, Mexico; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
Martin
M
Lajous
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Andrew P
AP
Morris
Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain; Consorcio de Investigación Biomédica de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Spain; Unit of Preventive Medicine and Public Health, School of Medicine, University of Murcia, Murcia, Spain.
Carmen
C
Navarro
Lund University, Malmö, Sweden.
Peter M
PM
Nilsson
Department of Public Health, Aarhus University, Aarhus, Denmark; Aalborg University Hospital, Aalborg, Denmark.
Kim
K
Overvad
Cancer Research and Prevention Institute, Florence, Italy.
Domenico
D
Palli
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
Salvatore
S
Panico
Public Health Directorate, Asturias, Spain.
J Ramón
JR
Quirós
Umeå University, Umeå, Sweden.
Olov
O
Rolandsson
Unit of Cancer Epidemiology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, University of Turin, Turin, Italy; Piedmont Reference Center for Epidemiology and Cancer Prevention, Torino, Italy; Human Genetics Foundation, Torino, Italy.
Carlotta
C
Sacerdote
Consorcio de Investigación Biomédica de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Spain; Andalusian School of Public Health, Granada, Spain.
María-José
MJ
Sánchez
International Agency for Research on Cancer, Lyon, France.
Nadia
N
Slimani
National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Annemieke M W
AM
Spijkerman
Azienda Sanitaria Provinciale di Ragusa, Ragusa, Italy; Aire Onlus, Ragusa, Italy.
Rosario
R
Tumino
National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Daphne L
DL
van der A
University Medical Center Utrecht, Utrecht, The Netherlands.
Yvonne T
YT
van der Schouw
The Wellcome Trust Sanger Institute, Cambridge, United Kingdom; University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom.
Inês
I
Barroso
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, United Kingdom; NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
Mark I
MI
McCarthy
School of Public Health, Imperial College London, London, United Kingdom.
Elio
E
Riboli
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
Nicholas J
NJ
Wareham
D000483:Alleles; D015992:Body Mass Index; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000235:genetics*; D038441:Diet, Mediterranean; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008019:Life Style; D008297:Male; D008875:Middle Aged; D009043:Motor Activity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016016:Proportional Hazards Models; D012307:Risk Factors; D055105:Waist Circumference / Q000235:genetics