Journal Article

Exploring the Effects of Methylenetetrahydrofolate Reductase Gene Variants <i>C677T</i> and <i>A1298C</i> on the Risk of Orofacial Clefts in 261 Norwegian Case-Parent Triads

Astanand Jugessur, Allen J. Wilcox, Rolv T. Lie, Jeffrey C. Murray, Jack A. Taylor, Arve Ulvik, Christian A. Drevon, Hallvard A. Vindenes and Frank E. Åbyholm

in American Journal of Epidemiology

Published on behalf of Johns Hopkins Bloomberg School of Public Health

Volume 157, issue 12, pages 1083-1091
Published in print June 2003 | ISSN: 0002-9262
Published online June 2003 | e-ISSN: 1476-6256 | DOI: http://dx.doi.org/10.1093/aje/kwg097
Exploring the Effects of Methylenetetrahydrofolate Reductase Gene Variants C677T and A1298C on the Risk of Orofacial Clefts in 261 Norwegian Case-Parent Triads

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Folic acid and the methylenetetrahydrofolate reductase (MTHFR) gene have both been implicated in the etiology of orofacial clefts. The authors selected 261 case-parent triads (173 cases with cleft lip with or without cleft palate (CL/P) and 88 cases with cleft palate only (CPO)) from a Norwegian population-based study of orofacial clefts (May 1996–1998). A case-parent triad design was used to examine whether MTHFR variants C677T and A1298C, and their haplotypes, are risk factors for orofacial clefts. Among CL/P cases, the child’s genotype at C677T or A1298C did not influence the risk. However, children of mothers carrying the C677T variant allele had a lower risk of CL/P. For CPO, children carrying the C677T variant allele had about a twofold increased risk, whereas the mother’s genotypes did not contribute to the risk. The haplotype-based transmission/disequilibrium test showed that except for 677T/1298A (p = 0.06), none of the other haplotypes showed evidence of excess transmission to the offspring. The authors also explored interaction of C677T with maternal use of folic acid among children with CPO. Surprisingly, the risk associated with the child’s carrying either CT or TT was higher (fourfold) when the mother used folic acid. These findings suggest a possible role of MTHFR and folic acid in the causation of orofacial clefts, but the strength and direction of these effects remain to be clarified.

Keywords: abnormalities; cleft lip; cleft palate; folic acid; genes; genetic predisposition to disease; haplotypes; vitamins; Abbreviations: CI, confidence interval; CL/P, cleft lip with or without cleft palate; CPO, cleft palate only; MTHFR, methylenetetrahydrofolate reductase; PCR, polymerase chain reaction.

Journal Article.  6435 words.  Illustrated.

Subjects: Public Health and Epidemiology

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