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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

  • Sherly X. Li
  • Fumiaki Imamura
  • Zheng Ye
  • Matthias B Schulze
  • Jusheng Zheng
  • Eva Ardanaz
  • Larraitz Arriola
  • Heiner Boeing
  • Courtney Dow
  • Guy Fagherazzi
  • Paul W. Franks
  • Antonio Agudo
  • Sara Grioni
  • Rudolf Kaaks
  • Verena A. Katzke
  • Timothy J Key
  • Kay Tee Khaw
  • Francesca Romana Mancini
  • Carmen Navarro
  • Peter M. Nilsson
  • 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
Publishing year: 2017-07-01
Language: English
Pages: 263-275
Publication/Series: American Journal of Clinical Nutrition
Volume: 106
Issue: 1
Document type: Journal article review
Publisher: American Society for Clinical Nutrition

Abstract english

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.


  • Medical Genetics
  • Diabetes
  • Diet
  • Effect modification
  • Gene
  • Interaction
  • Macronutrient
  • Replication
  • Systematic review


  • Genetic and Molecular Epidemiology
  • Internal Medicine
  • ISSN: 0002-9165
Paul Franks
E-mail: paul [dot] franks [at] med [dot] lu [dot] se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49



Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00