Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach

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  • Patel, J.
    • Other Affiliation: University of Arkansas for Medical Sciences
  • Bircan, E.
    • Other Affiliation: University of Arkansas for Medical Sciences
  • Tang, X.
    • Other Affiliation: University of Arkansas for Medical Sciences
  • Orloff, M.
    • Other Affiliation: University of Arkansas for Medical Sciences
  • Hobbs, C.A.
    • Other Affiliation: Rady Children’s Institute for Genomic Medicine
  • Browne, M.L.
    • Other Affiliation: University at Albany
  • Botto, L.D.
    • Other Affiliation: University of Utah
  • Finnell, R.H.
    • Other Affiliation: Baylor College of Medicine
  • Jenkins, M.M.
    • Other Affiliation: Centers for Disease Control and Prevention
  • Olshan, A.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Romitti, P.A.
    • Other Affiliation: University of Iowa
  • Shaw, G.M.
    • Other Affiliation: Stanford University
  • Werler, M.M.
    • Other Affiliation: Boston University
  • Li, J.
    • Other Affiliation: University of Arkansas for Medical Sciences
  • Nembhard, W.N.
    • Other Affiliation: University of Arkansas for Medical Sciences
  • the National Birth Defects Prevention Study
Abstract
  • Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.
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  • Article
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  • In Copyright
License
  • CC0 1.0 Universal
Journal title
  • PLoS Genetics
Journal volume
  • 17
Journal issue
  • 3
Language
  • English
Version
  • Publisher
Funder
  • National Center for Advancing Translational Sciences, NCATS: U54TR001629
  • 09-001, 13-003, 18-001
  • Centers for Disease Control and Prevention, CDC: 02081, 96043
  • National Institutes of Health, NIH: U01DD001039, U01DD001229
  • National Center on Birth Defects and Developmental Disabilities, NCBDDD: U01DD001226, U01DD001227, U01DD001285
  • National Institute of Child Health and Human Development, NICHD: R01HD039054
  • Arkansas Biosciences Institute, ABI: 037062
  • Translational Research Institute, University of Arkansas for Medical Sciences, TRI, UAMS: 1U54TR001629-01A1
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD
ISSN
  • 1553-7390
Publisher
  • Public Library of Science

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