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

Abstract

Objective: 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. Subjects: Pairs of healthy African-American full-term newborns (N ¼ 207) and mothers were recruited from Memphis TN and Jackson MS with birth weights ranging from 2210 to 4735 g. Methods: 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 0 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. Results: 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. Conclusion: Polymorphisms near the 5 0 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.

Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation

“…The developing embryo, on the other hand, needs large quantities of deoxynucleotide triphosphate precursor pools that are required for error‐free DNA synthesis. There are other published studies reporting SNPs having opposing effects [Shi et al, ; Adkins et al, ]. For example, Adkins et al [Adkins et al, ] found that maternal haplotypes in the insulin and IGF2 had a significant association with small for gestational age (SGA) birth, in newborns however, the opposite haplotype conferred risk of SGA.…”

“…There are other published studies reporting SNPs having opposing effects [Shi et al, ; Adkins et al, ]. For example, Adkins et al [Adkins et al, ] found that maternal haplotypes in the insulin and IGF2 had a significant association with small for gestational age (SGA) birth, in newborns however, the opposite haplotype conferred risk of SGA. The authors conclude that these haplotypes have an opposing influence on the growth rate of the embryo.…”

Prenatal Famine and Genetic Variation Are Independently and Additively Associated with DNA Methylation at Regulatory Loci within IGF2/H19

“…For INS and IGF2 this resulted in a region stretching from rs11042594 to rs3842748 (NCBI 36 chr11:2,073,729-2,137,971) and for H19 in a region stretching from rs3741219 till rs3890907 (NCBI36 chr11:1,973,195-1,984,719). In addition, we selected 16 SNPs in these regions that have been associated with relevant phenotypes such as being born small for gestational age [54], [72], birth weight [73]–[75], body mass index [55], [56], [60], [76], [77], type two diabetes [60], postnatal growth [75] and IGF2 levels [74], [78] or with DNA methylation at IGF2 DMR or H19 DMR [8]. Twelve of these SNPs were also in the CEU HapMap set.…”

DNA methylation ofIGF2,GNASAS,INSIGFandLEPand being born small for gestational age

“…Using a cut-off of ≤1.3 SDS (the tenth percentile, N = 34 vs. N = 75)or ≤2SDS (frequently used by pediatric endocrinologists, N = 13 vs. N = 75) of the IGF2-INS region was found to influence the risk of being born SGA. 24 GNAS and LEP have both been found to be differentially expressed between placentas of IUGR and normal children. 25 Both the GNAS region and leptin are similarly involved in early growth and glucose metabolism as the IGF2-INS region.…”