title: Polymorphisms in DNA repair genes as risk factors for spina bifida and orofacial clefts.
abstract: Repairing DNA damage is critical during embryogenesis because development involves sensitive periods of cell proliferation, and abnormal cell growth or death can result in malformations. Knockout mouse experiments have demonstrated that disruption of DNA repair genes results in embryolethality and structural defects. Studies using mid-organogenesis rat embryos showed that DNA repair genes were variably expressed. It is hypothesized that polymorphisms that alter the functionality of DNA repair enzymes may modify the risk of malformations. We conducted a case-control analysis to investigate the relationship between DNA repair gene polymorphisms and the risk of spina bifida and oral clefts. Newborn screening blood spot DNA was obtained for 250 cases (125 spina bifida, 125 oral clefts) identified by the California Birth Defects Monitoring Program, and 350 non-malformation controls identified from birth records. Six single nucleotide polymorphisms of five DNA repair genes representing three distinct repair pathways were interrogated including: XRCC1 (Arg399Gln), APE1 (Asp148Glu), XRCC3 (Thr241Met), hOGG1(Ser326Cys), XPD (Asp312Asn, Lys751Gln). Elevated or decreased odds ratios (OR, adjusted for race/ethnicity) for spina bifida were found for genotypes containing at least one copy of the variant allele for XPD [751Gln, OR = 1.62; 95% confidence interval (CI) = 1.05-2.50] and APE 148 (OR = 0.58; CI = 0.37-0.90). A decreased risk of oral clefts was found for XRCC3 (OR = 0.62; CI = 0.39-0.99) and hOGG1 (326 Cys/Cys, OR = 0.22; CI = 0.06-0.78). This study suggested that polymorphisms of DNA repair genes, representing different major repair pathways, may affect risk of two major birth defects. Future, larger studies, examining additional repair genes, birth defects, and interaction with exposures are recommended.
authors.affiliation: Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina 27599, USA. andy_olshan@unc.edu
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Olshan
authors.forename: G M
authors.initials: GM
authors.lastname: Shaw
authors.forename: R C
authors.initials: RC
authors.lastname: Millikan
authors.forename: C
authors.initials: C
authors.lastname: Laurent
authors.forename: R H
authors.initials: RH
authors.lastname: Finnell
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002971:Cleft Lip / Q000175:diagnosis / Q000235:genetics; D002972:Cleft Palate / Q000175:diagnosis / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005787:Gene Frequency; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D015810:Linkage Disequilibrium; D009056:Mouth Abnormalities / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D015997:Neonatal Screening; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012307:Risk Factors; D016135:Spinal Dysraphism / Q000175:diagnosis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; C110901:X-ray repair cross complementing protein 3; C000619371:XRCC1 protein, human; C000619352:Xrcc1 protein, mouse; C000619372:Xrcc1 protein, rat; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C497292:ERCC2 protein, human