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Association of birth weight with polymorphisms in the IGF2, H19, and IGF2R genes.

ABSTRACT: There is a substantial genetic component for birth weight variation. We tested 18 single nucleotide polymorphisms (SNPs) in the IGF2, H19, and IGF2R genes for associations with birth weight variation in 342 mother-newborn pairs (birth weight 2.1-4.7 kg at term) and 527 parent-newborn trios (birth weight 2.1-5.1 kg) across three localities. SNPs in the IGF2R (rs8191754; maternal genotype), IGF2 (rs3741205; newborn genotype), and 5' region of the H19 (rs2067051, rs2251375, and rs4929984) genes were associated with birth weight. Detailed analyses to distinguish direct maternal, direct newborn, and parent of origin effects for the most strongly associated H19 SNP (rs4929984) determined that the association of maternal genotype with newborn birth weight was due to parent of origin effects not direct maternal effects. That SNP is located near the CTCF binding sites that influence expression of the maternally imprinted IGF2 and paternally imprinted H19 locus, and there are statistically significant and independent opposite effects of the same rs4929984 allele, depending on the parent from which it was inherited.

SUBMITTER: Adkins RM

PROVIDER: S-EPMC3063315 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Association of birth weight with polymorphisms in the IGF2, H19, and IGF2R genes.

Adkins Ronald M RM Somes Grant G Morrison John C JC Hill James B JB Watson Erin M EM Magann Everett F EF Krushkal Julia J

Pediatric research 20101101 5

There is a substantial genetic component for birth weight variation. We tested 18 single nucleotide polymorphisms (SNPs) in the IGF2, H19, and IGF2R genes for associations with birth weight variation in 342 mother-newborn pairs (birth weight 2.1-4.7 kg at term) and 527 parent-newborn trios (birth weight 2.1-5.1 kg) across three localities. SNPs in the IGF2R (rs8191754; maternal genotype), IGF2 (rs3741205; newborn genotype), and 5' region of the H19 (rs2067051, rs2251375, and rs4929984) genes wer ...[more]

PMID: 20639793

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Project description:Imprinted genes play important roles in placental differentiation, growth and function, with profound effects on fetal development. In humans, H19 and IGF2 are imprinted, but imprinting of IGF2R remains controversial. The H19 non-coding RNA is a negative regulator of placental growth and altered placental imprinting of H19-IGF2 has been associated with pregnancy complications such as preeclampsia, which have been attributed to abnormal first trimester placentation. This suggests that changes in imprinting during the first trimester may precede aberrant placental morphogenesis. To better understand imprinting in the human placenta during early gestation, we quantified allele-specific expression for H19, IGF2 and IGF2R in first trimester (6-12 weeks gestation) and term placentae (37-42 weeks gestation) using pyrosequencing. Expression of IGF2R was biallelic, with a mean expression ratio of 49:51 (SD = 0.07), making transient imprinting unlikely. Expression from the repressed H19 alleles ranged from 1-25% and was higher (P<0.001) in first trimester (13.5 ± 8.2%) compared to term (3.4 ± 2.1%) placentae. Surprisingly, despite the known co-regulation of H19 and IGF2, little variation in expression of the repressed IGF2 alleles was observed (2.7 ± 2.0%). To identify regulatory regions that may be responsible for variation in H19 allelic expression, we quantified DNA methylation in the H19-IGF2 imprinting control region and H19 transcription start site (TSS). Unexpectedly, we found positive correlations (P<0.01) between DNA methylation levels and expression of the repressed H19 allele at 5 CpG's 2000 bp upstream of the H19 TSS. Additionally, DNA methylation was significantly higher (P<0.05) in first trimester compared with term placentae at 5 CpG's 39-523 bp upstream of the TSS, but was not correlated with H19 repressed allele expression. Our data suggest that variation in H19 imprinting may contribute to early programming of placental phenotype and illustrate the need for quantitative and robust methodologies to further elucidate the role of imprinted genes in normal and pathological placental development.

Project description:Genomic imprinting leads to parent-of-origin specific gene expression and is determined by epigenetic modification of genes. The paternally expressed gene insulin-like growth-factor 2 (IGF2) is located about ~100kb from the maternally expressed non-coding gene H19 on human chromosome 11, and both genes play major roles in embryonic and placental growth. Given adverse gestational environments can influence DNA methylation patterns in extra-embryonic tissues, we hypothesized that prenatal exposure to endocrine disrupting chemicals (EDCs) alters H19 and IGF2 methylation in placenta. Our study was restricted to a total of 196 women co-enrolled in the Predictors of Preeclampsia Study and the Harvard Epigenetic Birth Cohort. First trimester urine concentrations of 8 phenols and 11 phthalate metabolites were measured and used to characterize EDC exposure profiles. We assessed methylation of differentially methylated regions (DMRs) by pyrosequencing of H19, IGF2DMR0, and IGF2DMR2 and correlated values with phenol and phthalate metabolites. We also assessed overall expression and allele-specific expression of H19 and IGF2. We found several significant associations between DNA methylation and additive biomarker measurements. A significant decrease in H19 methylation was associated with high levels of the sum (?) of phthalate metabolites and metabolites of low molecular weight (LMW) phthalates. ?phthalate and LMW phthalate concentrations were inversely associated with IGF2DMR0 methylation values. Variation in methylation was not associated with changes in allele-specific expression. However increased deviation of allele-specific expression of H19 was associated with ?di(2-ethylhexyl) phthalate metabolites and high molecular weight phthalates. Neither methylation nor expression of these imprinted regions had a significant impact on birth length or birth weight. Overall, our study provides new insight into an epigenetic mechanism that occurs following EDC exposure.

Project description:BackgroundAssisted reproductive technology (ART) has been associated with low birth weight of fresh embryo transfer (FRESH) derived and increased birth weight of frozen embryo transfer (FET)-derived newborns. Owing to that, we focused on imprinted insulin-like growth factor 2 (IGF2)/H19 locus known to be important for normal growth. This locus is regulated by H19 imprinting control region (ICR) with seven binding sites for the methylation-sensitive zinc finger regulatory protein (CTCF). A polymorphism rs10732516 G/A in the sixth binding site for CTCF, associates with a genotype-specific trend to the DNA methylation. Due to this association, 62 couples with singleton pregnancies derived from FRESH (44 IVF/18 ICSI), 24 couples from FET (15 IVF/9 ICSI), and 157 couples with spontaneously conceived pregnancies as controls were recruited in Finland and Estonia for genotype-specific examination. DNA methylation levels at the H19 ICR, H19 DMR, and long interspersed nuclear elements in placental tissue were explored by MassARRAY EpiTYPER (n = 122). Allele-specific changes in the methylation level of H19 ICR in placental tissue (n = 26) and white blood cells (WBC, n = 8) were examined by bisulfite sequencing. Newborns' (n = 243) anthropometrics was analyzed by using international growth standards.ResultsA consistent trend of genotype-specific decreased methylation level was observed in paternal allele of rs10732516 paternal A/maternal G genotype, but not in paternal G/maternal A genotype, at H19 ICR in ART placentas. This hypomethylation was not detected in WBCs. Also genotype-specific differences in FRESH-derived newborns' birth weight and head circumference were observed (P = 0.04, P = 0.004, respectively): FRESH-derived newborns with G/G genotype were heavier (P = 0.04) and had larger head circumference (P = 0.002) compared to newborns with A/A genotype. Also, the placental weight and birth weight of controls, FRESH- and FET-derived newborns differed significantly in rs10732516 A/A genotype (P = 0.024, P = 0.006, respectively): the placentas and newborns of FET-derived pregnancies were heavier compared to FRESH-derived pregnancies (P = 0.02, P = 0.004, respectively).ConclusionsThe observed DNA methylation changes together with the phenotypic findings suggest that rs10732516 polymorphism associates with the effects of ART in a parent-of-origin manner. Therefore, this polymorphism should be considered when the effects of environmental factors on embryonic development are studied.

Dataset Information

Association of birth weight with polymorphisms in the IGF2, H19, and IGF2R genes.

Publications

Association of birth weight with polymorphisms in the IGF2, H19, and IGF2R genes.

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