Association of Birth Weight with Polymorphisms in the IGF2, H19 and IGF2R Genes

Adkins, Ronald M.; Somes, Grant W.; Morrison, John C.; Hill, Jamal; Watson, Erin; Magann, Everett F.; Krushkal, Julia

doi:10.1203/pdr.0b013e3181f1ca99

Cited by 43 publications

(46 citation statements)

References 42 publications

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“…Both IGF1 and IGF2 play a critical role in growth and have been linked to birth weight in genetic, epigenetic, and gene expression studies (Adkins et al, 2010;Heijmans et al, 2008;Koutsaki et al, 2011;McMinn et al, 2006;Ong et al, 2000;Straughen et al, 2015). Twin studies of IGF1 have found that intra-pair birth weight differences were significantly correlated with intra-pair IGF1 expression differences (Canpolat et al, 2011) and blood IGF1 concentrations (Westwood et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Changes in theIGF1RGene in Birth Weight Discordant Adult Monozygotic Twins

et al. 2015

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Low birth weight (LBW) can have an impact on health outcomes in later life, especially in relation to predisposition to metabolic disease. Several studies suggest that LBW resulting from restricted intrauterine growth leaves a footprint on DNA methylation in utero, and this influence likely persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg12562232, p = 2.62 × 10 −8 ), was significantly associated with birth weight discordance at a genome-wide false-discovery rate (FDR) of 0.05. We pursued replication in three additional independent datasets of birth weight discordant MZ pairs and observed the same direction of association, but the results were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect was particularly pronounced in older twins (randomeffects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent of genetic effects.

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Section: Discussionmentioning

confidence: 99%

DNA Methylation Changes in theIGF1RGene in Birth Weight Discordant Adult Monozygotic Twins

et al. 2015

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“…In previous work, we employed population genetic techniques to identify gene regions 1 The online version of this article contains supplemental material. exhibiting strong signatures of natural selection among Andeans and Tibetans from dense genome scan data (7,8).…”

Section: Study Participantsmentioning

confidence: 99%

“…Therefore, identifying the genetic and environmental factors contributing to IUGR is of particular interest for improving both perinatal and adult health. While recent studies have helped illuminate the role of maternal genetic variation on infant birth weight (1,21,60), much remains to be discovered with respect to the physiological pathways by which such genetic factors operate.…”

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confidence: 99%

“…Specifically, 40 genes or gene regions were identified by one or more tests of natural selection and confirmed in the two Andean genome scans, while 31 genes were identified in Tibetans (7,8) (Supplemental Table S1). 1 To test whether the previously identified selection-nominated candidate genes affect variation in phenotypes related to survival and reproduction at altitude (defined here as giving birth to a normal birth-weight offspring at high altitude), we performed a quantitative association study with 96 single nucleotide polymorphisms (SNPs) located in or near 16 selection-nominated candidate genes to identify genotype associations with birth weight in an independent sample of Andean or European women living at low or high altitude in Bolivia. Significant associations between birth weight and maternal SNPs were identified in or near two genes, namely, endothelin receptor type A (EDNRA) and the alpha-1 catalytic subunit of adenosine monophosphate-activated protein kinase (PRKAA1, also known as AMPK␣1).…”

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confidence: 99%

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MaternalPRKAA1andEDNRAgenotypes are associated with birth weight, andPRKAA1with uterine artery diameter and metabolic homeostasis at high altitude

Bigham

Julian

Wilson

et al. 2014

Physiological Genomics

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Bigham AW, Julian CG, Wilson MJ, Vargas E, Browne VA, Shriver MD, Moore LG. Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude. Physiol Genomics 46: 687-697, 2014. First published July 15, 2014; doi:10.1152/physiolgenomics.00063.2014.-Low birth weight and intrauterine growth restriction (IUGR) increase the risk of mortality and morbidity during the perinatal period as well as in adulthood. Environmental and genetic factors contribute to IUGR, but the influence of maternal genetic variation on birth weight is largely unknown. We implemented a gene-by-environment study wherein we utilized the growth restrictive effects of high altitude. Multigenerational highaltitude residents (Andeans) are protected from altitude-associated IUGR compared with recent migrants (Europeans). Using a combined cohort of low-and high-altitude European and Andean women, we tested 63 single nucleotide polymorphisms (SNPs) from 16 natural selection-nominated candidate gene regions for associations with infant birth weight. We identified significant SNP associations with birth weight near coding regions for two genes involved in oxygen sensing and vascular control, PRKAA1 and EDNRA, respectively. Next, we identified a significant association for the PRKAA1 SNP with an intermediate phenotype, uterine artery diameter, which has been shown to be related to Andean protection from altitude-associated reductions in fetal growth. To explore potential functional relationships for the effect of maternal SNP genotype on birth weight, we evaluated the relationship between maternal PRKAA1 SNP genotype and gene expression patterns in general and, in particular, of key pathways involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of IUGR. Our observations suggest that maternal genetic variation within genes that regulate oxygen sensing, metabolic homeostasis, and vascular control influence fetal growth and birth weight outcomes and hence Andean adaptation to high altitude.

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“…9 Indeed, the IGF2 and H19 loci have been thought to influence birth weight and growth, though results are conflicting. 10 Bouwland-Both et al 11 recently examined a prospective birth cohort of SGA children in The Netherlands and compared them to children who were AGA at term. The authors extracted DNA from umbilical cord white blood cells, examined DNA methylation, and observed that decreased DNA methylation of IGF2DMR was present among SGA children.…”

Section: Perinatal Programming 1167mentioning

confidence: 99%