title: A family-based association study of congenital left-sided heart malformations and 5,10 methylenetetrahydrofolate reductase.
abstract: BACKGROUND
  Aortic valve stenosis (AVS), coarctation of the aorta (CoA), and hypoplastic left heart syndrome (HLHS) are obstructive malformations of the left ventricular outflow tract that account for a significant proportion of infant mortality. Two previous small case-control studies suggested methylenetetrahydrofolate reductase (MTHFR) polymorphisms may be associated with this group of malformations.
  
  
  METHODS
  We used a family-based association design with inclusion criteria of nonsyndromic diagnosis of AVS, CoA, and HLHS, powered to detect an odds ratio for the heterozygote of <1.5. A total of 207 affected offspring-parent trios were genotyped by restriction fragment length polymorphisms at the two common polymorphic loci C677T and A1298C.
  
  
  RESULTS
  Error rate estimation based on replicate samples was 0.76%. Mendelian inconsistency at either polymorphism was noted in 10 trios, for a calculated undetected error rate of 1.95%. A total of 197 trios were analyzed using the transmission disequilibrium test. Significant association was not found between both the C677T or A1298C polymorphisms and presence of a heart defect, whether analyzed as a group, or by sex, ethnicity, or specific diagnosis. A log-linear analysis did not find increased relative risk based on the maternal genotype.
  
  
  CONCLUSIONS
  We were unable to replicate previous association studies and concluded that neither the affected nor the maternal MTHFR genotype, by itself, is a major risk factor for congenital left ventricular outflow tract malformations.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
authors.forename: Susan
authors.initials: S
authors.lastname: Fernbach
authors.forename: Andres
authors.initials: A
authors.lastname: Menesses
authors.forename: Laura
authors.initials: L
authors.lastname: Molinari
authors.forename: Ellinor
authors.initials: E
authors.lastname: Quay
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pignatelli
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
mesh_terms: D005190:Family; D006330:Heart Defects, Congenital / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000378:metabolism*; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2)