Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: Systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct

Research output: Contribution to journalReview article


Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. Objective: We aimed to identify existing evidence for genemacronutrient interactions and T2D and to examine the reported interactions in a large-scale study. Design: We systematically reviewed studies reporting genemacronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate countryspecific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Results: Thirteen observational studies met the eligibility criteria (n < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (v-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction < 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions. Am J Clin Nutr 2017;106:263-75.


  • Sherly X. Li
  • Fumiaki Imamura
  • Zheng Ye
  • Matthias B Schulze
  • Jusheng Zheng
  • Eva Ardanaz
  • Larraitz Arriola
  • Heiner Boeing
  • Courtney Dow
  • Guy Fagherazzi
  • Antonio Agudo
  • Sara Grioni
  • Rudolf Kaaks
  • Verena A. Katzke
  • Timothy J Key
  • Kay Tee Khaw
  • Francesca Romana Mancini
  • Carmen Navarro
  • N. Charlotte Onland-Moret
  • Kim Overvad
  • Domenico Palli
  • Salvatore Panico
  • J Ramón Quirós
  • Olov Rolandsson
  • Carlotta Sacerdote
  • María-José Sánchez
  • Nadia Slimani
  • Ivonne Sluijs
  • Annemieke M. W. Spijkerman
  • Anne Tjonneland
  • Rosario Tumino
  • Stephen J. Sharp
  • Elio Riboli
  • Claudia Langenberg
  • Robert A. Scott
  • Nita G. Forouhi
  • Nicholas J Wareham
External organisations
  • University of Cambridge
  • German Institute of Human Nutrition
  • German Center for Diabetes Research
  • Health Research Institute of Navarra (IDISNA)
  • Public Health Division of Gipuzkoa
  • Centre for Research in Epidemiology and Population Health (CESP)
  • University of Paris-Sud
  • Catalan Institute of Oncology
  • German Cancer Research Centre
  • University of Oxford
  • Murcia Regional Health Council
  • University of Murcia
  • University Medical Center Utrecht
  • Aarhus University
  • Aalborg University
  • Cancer Research and Prevention Institute (ISPO)
  • University of Naples Federico II
  • Umeå University
  • Citta' della Salute e della Scienza Hospital-University of Turin
  • Centre for Cancer Epidemiology and Prevention (CPO Piemonte)
  • Human Genetics Foundation (HuGeF)
  • Instituto de Investigación Biosanitaria de Granada (Granada.ibs)
  • International Agency for Research on Cancer, World Health Organization
  • National Institute for Public Health and the Environment (RIVM)
  • Danish Cancer Society Research Center
  • Imperial College London
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics


  • Diabetes, Diet, Effect modification, Gene, Interaction, Macronutrient, Replication, Systematic review
Original languageEnglish
Pages (from-to)263-275
Number of pages13
JournalAmerican Journal of Clinical Nutrition
Issue number1
Publication statusPublished - 2017 Jul 1
Publication categoryResearch