Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions

Abstract

Intrauterine growth in non-diabetic pregnancies is reported to be influenced by type 1 diabetes susceptibility genes. In particular, the high-risk HLA DR4_DQB1*0302 haplotype is associated with increased birthweight. The aim of this study was to determine whether HLA DR4 was associated with increased birthweight in a maternal diabetes environment and whether effects persisted during early childhood. Birthweight and gestational age were obtained in singleton births from mothers with type 1 diabetes (n = 1161) or whose fathers or siblings have type 1 diabetes (n = 872). Weight and height at ages 2 and 5 years were obtained from paediatric records. Data were adjusted for (gestational) age and sex and expressed as percentiles of German reference data. HLA DR typing was obtained for all children and 1090 children also had insulin gene (INS) variable number of tandem repeats (VNTR) typing. Maternal type 1 diabetes was associated with increased birthweight, gestational age and birthweight percentiles (all p < 0.0001). In children of mothers with type 1 diabetes, birthweight percentile was further related to maternal HbA(1c) during pregnancy (r = 0.26; p < 0.0001) and was independently increased if children had HLA DR4 alleles (76th vs 64th percentile; p < 0.0001). HLA DR4 was not associated with birthweight in children of non-diabetic mothers. Birthweight was not associated with INS VNTR genotypes. High birthweight, but not HLA DR4 was associated with increased weight and BMI at ages 2 and 5 years (p < 0.0001). Our findings are consistent with the hypothesis that a diabetic intrauterine environment interacts with gene(s) marked by the type 1 diabetes susceptibility HLA DR4 alleles to increase fetal growth.