Abstract

Objective: Fetal malnutrition may predispose to type 2 diabetes (T2D) through gene programming and developmental changes. Previous studies showed that these effects may be modulated by genetic variation. Genome Wide Association studies discovered and replicated a number of T2D associated genes. We investigated the effects of such well-studied polymorphisms and their interactions with fetal malnutrition on T2D risk and related phenotypes in the Dutch Famine Birth Cohort.

Research Design and Methods: The CDKAL1-rs7754840, CDKN2AB-rs10811661, HHEX-rs1111875, IGF2BP2-rs4402960, KCNJ11-rs5219, SLC30A8-rs13266634 and TCF7L2-rs7903146 polymorphisms were genotyped in 772 participants of the Dutch Famine Birth Cohort Study (n=328 exposed, n=444 unexposed). Logistic and linear regression models served to analyze their interactions with prenatal exposure to famine on T2D, Impaired Glucose Tolerance (IGT) and Area Under the Curves (AUCs) of glucose and insulin during Oral Glucose Tolerance Testing (OGTT).

Results: In the total population, the TCF7L2 and IGF2BP2 variants most strongly associated with increased risk for T2D/IGT and increased AUC glucose, while the CDKAL1 polymorphism associated with decreased AUC insulin. The IGF2BP2 polymorphism showed an interaction with prenatal exposure to famine on AUC glucose. (β=−9.2, 95% CI –16.2;−2.1; p=0.009)

Conclusions: The IGF2BP2 variant showed a nominal interaction with exposure to famine in utero, decreasing OGTT AUCs for glucose. This may provide a clue that modulation of the consequences of fetal environment depends on an individual's genetic background.