The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR), maternal use of folic acid supplements, and risk of isolated clubfoot: a case-parent triad analysis

Linda Sharp, Zofia Helena Miedzybrodzka, Amanda Hamilton Cardy, Julie Anne Inglis, Londale Madrigal, S. Barker, D. Chesney, Caroline Clark, N. Maffulli

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21 Citations (Scopus)

Abstract

Worldwide, 1-4 per 1,000 births are affected by clubfoot. Clubfoot etiology is unclear, but both genetic and environmental factors are thought to be involved. Low folate status in pregnant women has been implicated in several congenital malformations, and folate metabolism may be affected by polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR). Using a case-parent-triad design, the authors investigated whether the MTHFR C677T polymorphism, and maternal periconceptional folic acid supplement use, influenced risk of isolated clubfoot. Three hundred seventy-five United Kingdom case-parent triads were recruited in 1998-1999. Among the children, there was a significant trend of decreasing clubfoot risk with increasing number of T alleles: relative risk for CT vs. CC = 0.75, 95% confidence interval: 0.57, 0.97; relative risk for TT vs. CC = 0.57, 95% confidence interval: 0.35, 0.91; p trend = 0.006. This association was not modified by maternal folic acid use. Maternal MTHFR genotype did not influence clubfoot risk for the offspring overall, although a possible interaction with folic acid use was found. This is the first known report of a specific genetic polymorphism associated with clubfoot. The direction of the association is intriguing and suggests that DNA synthesis may be relevant in clubfoot development. However, clubfoot mechanisms are poorly understood, and the folate metabolism pathway is complex. Further research is needed to elucidate these relations.

Original languageEnglish
Pages (from-to)852-861
Number of pages9
JournalAmerican Journal of Epidemiology
Volume164
Issue number9
DOIs
Publication statusPublished - Nov 2006

Keywords

  • clubfoot
  • dietary supplements
  • folic acid
  • genes
  • 5,10-methylenetetrahydrofolate reductase (FADH2)
  • polymorphism, genetic
  • pregnancy
  • IDIOPATHIC TALIPES EQUINOVARUS
  • PLASMA HOMOCYSTEINE CONCENTRATIONS
  • LOG-LINEAR APPROACH
  • COLORECTAL-CANCER
  • FOLATE STATUS
  • CONGENITAL-ANOMALIES
  • COMMON MUTATION
  • DNA-DAMAGE
  • GENOTYPE
  • DISEASE

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