title: Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation.
abstract: Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity.
authors.affiliation: Biostatistics Program, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Tang
authors.affiliation: Division of Birth Defects Research, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Cleves
authors.affiliation: Biostatistics Program, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Todd G
authors.initials: TG
authors.lastname: Nick
authors.affiliation: Biostatistics Program, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Birth Defects Research, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Stewart L
authors.initials: SL
authors.lastname: MacLeod
authors.affiliation: Department of Biostatistics, College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Erickson
authors.affiliation: Biostatistics Program, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University Medical School, Palo Alto, California.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Division of Birth Defects Research, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Mosley
authors.affiliation: Division of Birth Defects Research, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Hobbs
mesh_terms: D000328:Adult; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019587:Dietary Supplements / Q000009:adverse effects; D005260:Female; D005492:Folic Acid / Q000009:adverse effects; D015870:Gene Expression; D059647:Gene-Environment Interaction; D005721:Glutamate-Cysteine Ligase / Q000235:genetics* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D007223:Infant; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012307:Risk Factors; D000097584:DNA Methyltransferase 3B
chemical_list: D050940:Betaine-Homocysteine S-Methyltransferase; D004248:DNA (Cytosine-5-)-Methyltransferases; D005492:Folic Acid; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000097584:DNA Methyltransferase 3B; C494551:BHMT2 protein, human; C573423:MTHFR protein, human; C494548:BHMT protein, human
keywords: congenital heart defects; folic acid supplementation; genetic variants; hybrid design; maternal obesity; obstructive heart defects
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