A family-based association study of congenital left-sided heart malformations and 5,10 methylenetetrahydrofolate reductase

Kim L. McBride, Susan Fernbach, Andres Menesses, Laura Molinari, Ellinor Quay, Ricardo Pignatelli, Jeffrey Towbin, John W. Belmont

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)825-830
Number of pages6
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume70
Issue number10
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

Fingerprint

Hypoplastic Left Heart Syndrome
Methylenetetrahydrofolate Reductase (NADPH2)
Aortic Coarctation
Congenital Heart Defects
Aortic Valve Stenosis
Genotype
Mothers
Infant Mortality
Heterozygote
Restriction Fragment Length Polymorphisms
Case-Control Studies
Odds Ratio

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Developmental Biology

Cite this

A family-based association study of congenital left-sided heart malformations and 5,10 methylenetetrahydrofolate reductase. / McBride, Kim L.; Fernbach, Susan; Menesses, Andres; Molinari, Laura; Quay, Ellinor; Pignatelli, Ricardo; Towbin, Jeffrey; Belmont, John W.

In: Birth Defects Research Part A - Clinical and Molecular Teratology, Vol. 70, No. 10, 01.10.2004, p. 825-830.

Research output: Contribution to journalArticle

McBride, Kim L. ; Fernbach, Susan ; Menesses, Andres ; Molinari, Laura ; Quay, Ellinor ; Pignatelli, Ricardo ; Towbin, Jeffrey ; Belmont, John W. / A family-based association study of congenital left-sided heart malformations and 5,10 methylenetetrahydrofolate reductase. In: Birth Defects Research Part A - Clinical and Molecular Teratology. 2004 ; Vol. 70, No. 10. pp. 825-830.
@article{ff8e166989e44e2a984b65280a647600,
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.",
author = "McBride, {Kim L.} and Susan Fernbach and Andres Menesses and Laura Molinari and Ellinor Quay and Ricardo Pignatelli and Jeffrey Towbin and Belmont, {John W.}",
year = "2004",
month = "10",
day = "1",
doi = "10.1002/bdra.20049",
language = "English (US)",
volume = "70",
pages = "825--830",
journal = "Teratology",
issn = "1542-0752",
publisher = "Wiley-Liss Inc.",
number = "10",

}

TY - JOUR

T1 - A family-based association study of congenital left-sided heart malformations and 5,10 methylenetetrahydrofolate reductase

AU - McBride, Kim L.

AU - Fernbach, Susan

AU - Menesses, Andres

AU - Molinari, Laura

AU - Quay, Ellinor

AU - Pignatelli, Ricardo

AU - Towbin, Jeffrey

AU - Belmont, John W.

PY - 2004/10/1

Y1 - 2004/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=8144226263&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=8144226263&partnerID=8YFLogxK

U2 - 10.1002/bdra.20049

DO - 10.1002/bdra.20049

M3 - Article

VL - 70

SP - 825

EP - 830

JO - Teratology

JF - Teratology

SN - 1542-0752

IS - 10

ER -