Investigation of gene–diet interactions in the incretin system and risk of type 2 diabetes: the EPIC-InterAct study

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Aims/hypothesis. The gut incretin hormones glucagon-like
peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide
(GIP) have a major role in the pathophysiology of type 2
diabetes. Specific genetic and dietary factors have been found
to influence the release and action of incretins. We examined
the effect of interactions between seven incretin-related genetic
variants in GIPR, KCNQ1, TCF7L2 and WFS1 and dietary
components (whey-containing dairy, cereal fibre, coffee and
olive oil) on the risk of type 2 diabetes in the European
Prospective Investigation into Cancer and Nutrition (EPIC)-
InterAct study.
Methods. The current case-cohort study included 8086 incident
type 2 diabetes cases and a representative subcohort of 11,035
participants (median follow-up: 12.5 years). Prentice-weighted
Cox proportional hazard regression models were used to investigate
the associations and interactions between the dietary factors
and genes in relation to the risk of type 2 diabetes.
Results. An interaction (p= 0.048) between TCF7L2 variants
and coffee intake was apparent, with an inverse association
between coffee and type 2 diabetes present among carriers of
the diabetes risk allele (T) in rs12255372 (GG: HR 0.99 [95%
CI 0.97, 1.02] per cup of coffee; GT: HR 0.96 [95% CI 0.93,
0.98]); and TT: HR 0.93 [95% CI 0.88, 0.98]). In addition, an
interaction (p=0.005) between an incretin-specific genetic risk
score and coffee was observed, again with a stronger inverse
association with coffee in carriers with more risk alleles (0–3
risk alleles: HR 0.99 [95% CI 0.94, 1.04]; 7–10 risk alleles: HR
0.95 [95% CI 0.90, 0.99]). None of these associations were
statistically significant after correction for multiple testing.
Conclusions/interpretation. Our large-scale case-cohort study
provides some evidence for a possible interaction of TCF7L2
variants and an incretin-specific genetic risk score with coffee
consumption in relation to the risk of type 2 diabetes. Further
large-scale studies and/or meta-analyses are needed to confirm
these interactions in other populations.
Original languageEnglish
Pages (from-to)2613-2621
Issue number12
Publication statusPublished - 2016


  • Coffee
  • Dairy
  • Gene–environment interaction
  • GIPR
  • Incretins
  • KCNQ1
  • Olive oil
  • TCF7L2
  • WFS1

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