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

Claudia Langenberg; Stephen J Sharp; Paul W Franks; Robert A Scott; Panos Deloukas; Nita G Forouhi; Philippe Froguel; Leif C Groop; Torben Hansen; Luigi Palla; Oluf Pedersen; Matthias B Schulze; Maria-Jose Tormo; Eleanor Wheeler; Claudia Agnoli; Larraitz Arriola; Aurelio Barricarte; Heiner Boeing; Geraldine M Clarke; Françoise Clavel-Chapelon; Eric J Duell; Guy Fagherazzi; Rudolf Kaaks; Nicola D Kerrison; Timothy J Key; Kay Tee Khaw; Janine Kröger; Martin Lajous; Andrew P Morris; Carmen Navarro; Peter M Nilsson; Kim Overvad; Domenico Palli; Salvatore Panico; J Ramón Quirós; Olov Rolandsson; Carlotta Sacerdote; María-José Sánchez; Nadia Slimani; Annemieke M W Spijkerman; Rosario Tumino; Daphne L van der A; Yvonne T van der Schouw; Inês Barroso; Mark I McCarthy; Elio Riboli; Nicholas J Wareham

doi:10.1371/journal.pmed.1001647

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

Claudia Langenberg, Stephen J Sharp, Paul W Franks, Robert A Scott, Panos Deloukas, Nita G Forouhi, Philippe Froguel, Leif C Groop, Torben Hansen, Luigi Palla, Oluf Pedersen, Matthias B Schulze, Maria-Jose Tormo, Eleanor Wheeler, Claudia Agnoli, Larraitz Arriola, Aurelio Barricarte, Heiner Boeing, Geraldine M Clarke, Françoise Clavel-ChapelonEric J Duell, Guy Fagherazzi, Rudolf Kaaks, Nicola D Kerrison, Timothy J Key, Kay Tee Khaw, Janine Kröger, Martin Lajous, Andrew P Morris, Carmen Navarro, Peter M Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, María-José Sánchez, Nadia Slimani, Annemieke M W Spijkerman, Rosario Tumino, Daphne L van der A, Yvonne T van der Schouw, Inês Barroso, Mark I McCarthy, Elio Riboli, Nicholas J Wareham

136 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	e1001647
Tidsskrift	P L o S Medicine (Print)
Vol/bind	11
Udgave nummer	5
Antal sider	14
ISSN	1549-1277
DOI	https://doi.org/10.1371/journal.pmed.1001647
Status	Udgivet - maj 2014

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10.1371/journal.pmed.1001647

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Langenberg, C., Sharp, S. J., Franks, P. W., Scott, R. A., Deloukas, P., Forouhi, N. G., Froguel, P., Groop, L. C., Hansen, T., Palla, L., Pedersen, O., Schulze, M. B., Tormo, M-J., Wheeler, E., Agnoli, C., Arriola, L., Barricarte, A., Boeing, H., Clarke, G. M., ... Wareham, N. J. (2014). Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study. P L o S Medicine (Print), 11(5), [e1001647]. https://doi.org/10.1371/journal.pmed.1001647

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, M-J, 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, M-J, Slimani, N, Spijkerman, AMW, Tumino, R, van der A, DL, van der Schouw, YT, Barroso, I, McCarthy, MI, Riboli, E & Wareham, NJ 2014, 'Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study', P L o S Medicine (Print), bind 11, nr. 5, e1001647. https://doi.org/10.1371/journal.pmed.1001647

@article{c93a1f4f6aea4aa38239728e3562e6e1,

title = "Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study",

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.",

keywords = "Alleles, Body Mass Index, Cohort Studies, Diabetes Mellitus, Type 2, Diet, Mediterranean, Female, Genetic Predisposition to Disease, Humans, Life Style, Male, Middle Aged, Motor Activity, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Waist Circumference",

author = "Claudia Langenberg and Sharp, {Stephen J} and Franks, {Paul W} and Scott, {Robert A} and Panos Deloukas and Forouhi, {Nita G} and Philippe Froguel and Groop, {Leif C} and Torben Hansen and Luigi Palla and Oluf Pedersen and Schulze, {Matthias B} and Maria-Jose Tormo and Eleanor Wheeler and Claudia Agnoli and Larraitz Arriola and Aurelio Barricarte and Heiner Boeing and Clarke, {Geraldine M} and Fran{\c c}oise Clavel-Chapelon and Duell, {Eric J} and Guy Fagherazzi and Rudolf Kaaks and Kerrison, {Nicola D} and Key, {Timothy J} and Khaw, {Kay Tee} and Janine Kr{\"o}ger and Martin Lajous and Morris, {Andrew P} and Carmen Navarro and Nilsson, {Peter M} and Kim Overvad and Domenico Palli and Salvatore Panico and Quir{\'o}s, {J Ram{\'o}n} and Olov Rolandsson and Carlotta Sacerdote and Mar{\'i}a-Jos{\'e} S{\'a}nchez and Nadia Slimani and Spijkerman, {Annemieke M W} and Rosario Tumino and {van der A}, {Daphne L} and {van der Schouw}, {Yvonne T} and In{\^e}s Barroso and McCarthy, {Mark I} and Elio Riboli and Wareham, {Nicholas J}",

year = "2014",

month = may,

doi = "10.1371/journal.pmed.1001647",

language = "English",

volume = "11",

journal = "P L o S Medicine (Online)",

issn = "1549-1277",

publisher = "Public Library of Science",

number = "5",

}

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 - 2014/5

Y1 - 2014/5

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

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

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

SN - 1549-1277

VL - 11

JO - P L o S Medicine (Online)

JF - P L o S Medicine (Online)

IS - 5

M1 - e1001647

ER -

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

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