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

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.

Update on Clubfoot: Etiology and Treatment

“…A recent study points toward a polygenic threshold model for clubfoot inheritance where multiple genes and environmental factors will be found to play a role [42]. Variants in genes responsible for a variety of environmental factors have been associated with an increase risk of clubfoot [31,39,44,59]. In addition, using a candidate gene approach, other genetic variants have been associated with clubfoot including variants in homeodomain transcription factors HOXD12 and HOXD13 [72], and several apoptotic genes including the caspase genes [32].…”

“…In a study of over 3000 patients, Honein et al reported an association of smoking with clubfoot, with an adjusted odds ratio of clubfoot of 1.34 for smoking only, 6.52 for family history only, and 20.30 for combined exposure to smoking and family history [33]. Variants in genes responsible for the metabolism of tobacco [31], seasonal viral infections [44], elevated maternal homocysteine [39], and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms [59] have also been associated with an increased risk of clubfoot.…”

Interaction Between Genetics and Environment in the Development of Clubfoot

“…Sharp et al studied the use of folic acid supplements in early pregnancy, observing that this seemed to reduce the risk of CTEV [26].…”

“…This led onto studies into the genetics of folic acid metabolism, with a case parent triad genetic study finding a significant decrease in the incidence of CTEV in mothers with increasing numbers of T alleles for the MTHFR gene [26].…”

Genome-wide association study identifies new disease loci for isolated clubfoot

“…A role for common genetic variants in clubfoot susceptibility has been evaluated for candidate genes, including HOX homeodomain genes and caspase genes that both show modest association 5 6. Clubfoot has also been associated with maternal methylenetetrahydrofolate reductase gene ( MTHFR ) polymorphisms 7. However, clubfoot remains as one of a handful of common human birth defects for which an unbiased genome-wide association study has not yet been published.…”