Association between small for gestational age and paternally inherited 5′ insulin haplotypes

Abstract

To test the association between small for gestational age and polymorphisms in the insulin gene in newborns and their mothers, as well as the effect of the parental transmission of haplotypes. Pairs of healthy African-American full-term newborns (N=207) and mothers were recruited from Memphis TN and Jackson MS with birth weights ranging from 2210 to 4735 g. Six single nucleotide polymorphisms (SNPs) located in the insulin (INS) and insulin-like growth factor 2 (IGF2) genes were genotyped in mothers and newborns. Haplotypes composed of three SNPs in the 5' region of the INS-IGF2 locus were computationally inferred. Odds ratios for risk of small for gestational age (SGA) birth were calculated for individual SNPs and inferred haplotypes in the newborns and in the mothers using logistic regression. For 162 mother--newborn pairs the parental transmission of the haplotypes could be inferred, and the risks for SGA birth were calculated for the three common haplotypes in this sample. Three INS SNPs exhibited significant association with risk for SGA birth. The SNP alleles associated with increased risk for SGA were opposite in the maternal and newborn genomes, implying opposing influences on the rate of fetal growth. Consistent with these results, haplotypes composed of complementary nucleotide sequences (CAC at rs3842738, rs689 and rs3842748, respectively, in the newborn versus GTG in the mother) were significantly associated with risk for SGA birth. In analyses of haplotypes according to parental transmission, the same trend in risk for SGA was observed for both maternally and paternally transmitted haplotypes, although a significant difference in risk was observed only for paternally transmitted haplotypes. Polymorphisms near the 5' end of the INS-IGF2 locus are significantly associated with risk for SGA birth with a major effect due to the paternally transmitted haplotype, which is preferentially expressed due to imprinting.