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

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.