Paternally Transmitted Haplotypes of the Imprinted Insulin Gene are Associated with Size for Gestational Age
Small for gestational age newborns are at significantly increased risk of death and morbidity. Adults born small for gestational age are at significantly increased risk of cardiovascular disease, stroke, type 2 diabetes, and pregnancy-related hypertension and diabetes.
Purpose: This study reports the results of analyses of the association between single nucleotide polymorphisms (SNPs) in the insulin gene and size for gestational age. The insulin gene is imprinted, in that the allele transmitted by the father is the predominant allele expressed during fetal development.
Methods: 210 healthy African-American mother-newborn pairs were recruited in a cross-sectional design. Six SNPs in the insulin-IGF2 gene cluster were genotyped in both mothers and newborns. Haplotypes were computationally inferred. The parental origin of each haplotype could be inferred unambiguously for >70% of the newborns. Analyses of the association between parental origin of each haplotype and size for gestational age used both unambiguous transmissions and proper weighting of ambiguous transmissions.
Results: Among mothers, no SNP or haplotype exhibited significant association with size for gestational age. Among newborns, three SNPs in high linkage disequilibrium with each other and with the 5’ insulin VNTR allele size classes exhibited significant (p <= 0.01) association with size for gestational age, both as individual genotypes and as combined haplotypes. No difference in size for gestational age was observed among haplotypes transmitted by the mother. However, a significant (p = 0.003) difference was observed according to the haplotype transmitted by the father.
Conclusions: Fetal genetic polymorphisms in the insulin gene are associated with variation in size for gestational age individually and as inferred haplotypes. This association is due to the haplotype transmitted by the father. This observation is entirely consistent with the pattern of imprinting of the insulin gene.