HHEX-IDE polymorphism is associated with low birth weight in offspring with a family history of type 1 diabetes

Context: The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion also reduce birth weight, and an association of low birth weight and the type 2 diabetes risk alleles at the HHEX-IDE and CDKAL1 loci were recently reported. Objective: Here, we examined the relationship between type 2 diabetes risk alleles and birth weight in a diabetic environment presented in children of mothers with type 1 diabetes. Research Design and Methods: Birth weight and genotyping of single nucleotide polymorphisms (SNPs) at the CDKAL1, HHEX-IDE, and SLC30A8 loci was obtained and analyzed in 729 singleton full-term children of mothers with type 1 diabetes born in Germany. Results: The fetal risk alleles of HHEX-IDE SNP rs5015480 and SNP rs10882102 were associated with reduced birth weight: 81g (95%confidence interval, 20-140 g; P=0.009) and 85g (95% confidence interval, 25-145 g; P = 0.005) lower birth weight per risk allele, respectively. The association remained significant after adjusting for maternal pregnancy-glycosylated hemoglobin. Fetal genotypes at the CDKAL1 and SLC30A8 loci were not associated with birth weight in this cohort. Conclusions: The association of low birth weight and type 2 diabetes risk alleles of the HHEX-IDE locus is confirmed in children of mothers with type 1 diabetes.