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American Journal of Epidemiology Advance Access published online on August 25, 2006
American Journal of Epidemiology, doi:10.1093/aje/kwj285
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.
Received July 15, 2005
Accepted April 7, 2006

ORIGINAL CONTRIBUTIONS

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 1 *, Zosia Miedzybrodzka 2, Amanda H. Cardy 3, Julie Inglis 2, Londale Madrigal 2, Simon Barker 4, David Chesney 5, Caroline Clark 2, and Nicola Maffulli 6

1 National Cancer Registry Ireland, Cork, Ireland
2 Medical Genetics Group, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, Scotland
3 Department of Public Health, University of Aberdeen, Aberdeen, Scotland
4 Department of Orthopaedic Surgery, Aberdeen University School of Medicine, Aberdeen, Scotland
5 Department of Orthopaedic Surgery, Freeman Hospital, Newcastle upon Tyne, England
6 Department of Trauma and Orthopaedic Surgery, Keele University School of Medicine, Stoke on Trent, England

* To whom correspondence should be addressed.
Linda Sharp, E-mail: linda.sharp{at}ncri.ie


  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.

Keywords: clubfoot; dietary supplements; folic acid; genes; 5,10-methylenetetrahydrofolate reductase (FADH2); polymorphism, genetic; pregnancy.

The first two authors contributed equally to this work, which was performed at the University of Aberdeen.


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