Interaction between prenatal growth and high-risk genotypes in the development of type 2 diabetes

Aims/hypothesis: early environmental factors and genetic variants have been reported to be involved in the pathogenesis of type 2 diabetes. The aim of this study was to investigate whether there is an interaction between birthweight and common variants in the TCF7L2, HHEX, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B and JAZF1 genes in the risk of developing type 2 diabetes. Methods: a total of 2,003 participants from the Helsinki Birth Cohort Study, 311 of whom were diagnosed with type 2 diabetes by an OGTT, were genotyped for the specified variants. Indices for insulin sensitivity and secretion were calculated. Results: low birthweight was associated with type 2 diabetes (p?=?0.008) and impaired insulin secretion (p?=?0.04). Of the tested variants, the risk variant in HHEX showed a trend towards a low birthweight (p?=?0.09) and the risk variant in the CDKN2A/2B locus was associated with high birthweight (p?=?0.01). The TCF7L2 risk allele was associated with increased risk of type 2 diabetes. Pooling across all nine genes, each risk allele increased the risk of type 2 diabetes by 11%. Risk variants in the HHEX, CDKN2A/2B and JAZF1 genes interacted with birthweight, so that the risk of type 2 diabetes was highest in those with lower birthweight (p???0.05). The interaction was also present in the pooled data. Conclusions/interpretation: low birthweight might affect the strength of the association of some common variants (HHEX, CDKN2A/2B and JAZF1) with type 2 diabetes. These findings need to be replicated in independent cohort