Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate?

American journal of epidemiology
Q2
Apr 2003
Citations:180
Influential Citations:8
Observational Studies (Human)
81
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Enhanced Details

Methods
Case-control triad study conducted in the Netherlands (1998–2000). 179 CL(P) triads and 204 control triads (mother, father, and infant). Infants were nonsyndromic CL(P) cases (or control infants); all families were Dutch Caucasians; infants aged 9–18 months at study. Design included case-control comparison and transmission disequilibrium test (TDT). Genotyping for MTHFR C677T and A1298C in mother, father, and infant; data collected included periconceptional folic acid supplement use and dietary folate intake via questionnaires and a validated FFQ.
Intervention
Periconceptional folic acid supplementation: daily folic acid 400–500 µg started 4 weeks before conception and continued until 8 weeks after conception; taken either as a single folic acid tablet or as part of a multivitamin containing folic acid.
Results
MTHFR C677T and A1298C genotypes/haplotypes were not independently associated with CL(P) risk in case-control or transmission disequilibrium analyses. A gene–environment interaction was observed: maternal MTHFR 677TT genotype combined with nonuse of periconceptional folic acid supplements or low dietary folate intake markedly increased CL(P) risk. Specific estimates include: 677TT with no supplement OR 5.9 (95% CI 1.1–30.9); 677TT with low dietary folate OR 2.8 (95% CI 0.7–10.5); both factors present OR 10.0 (95% CI 1.3–79.1); and maternal 1298CC with no supplements and low folate intake OR 6.5 (95% CI 1.4–30.2). The detrimental effect of low periconceptional folate intake was strongest in mothers with 677TT or 1298CC. MTHFR A1298C alone showed no association. Conclusion: MTHFR C677T and A1298C are not independent risk factors for CL(P); however, low periconceptional folate intake increases risk, particularly in mothers with 677TT or 1298CC genotypes, suggesting that folic acid supplementation and adequate dietary folate may reduce CL(P) risk in genetically susceptible mothers.
Limitations
Retrospective self-report of folic acid supplement use may lead to exposure misclassification and attenuation of associations. Some triads were not completely genotyped, reducing statistical power. Possible selection bias due to recruitment methods and missing data. The study population was ethnically homogeneous (Dutch Caucasians), limiting generalizability. Dietary folate intake was assessed 14 months after birth and may not perfectly reflect periconception intake.

Abstract

Periconceptional folic acid supplementation may reduce the risk of cleft lip with or without cleft palate (CL(P)). Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene reduce availability of 5-methyltetrahydrofolate, the predominant ...