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Thymidylate synthase polymorphisms and risks of human orofacial clefts
Gary M Shaw1, Wei Yang, Spencer Perloff
1Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. gmshaw@stanford.edu
Birth Defects Research. Part A, Clinical and Molecular Teratology
|February 14, 2013
Summary
Folic acid may reduce orofacial cleft risks, linked to TYMS gene variants and maternal folate intake. Homozygosity for the 28-bp VNTR variant increased cleft palate risk, especially with low folate. Further research is needed.
Area of Science:
- Genetics
- Nutritional Science
- Developmental Biology
Background:
- Folic acid supplementation in early pregnancy is associated with reduced risks of orofacial clefts, but underlying genetic and environmental mechanisms remain unclear.
- Thymidylate synthase (TYMS) is a critical folate-dependent enzyme in DNA synthesis, making its variants potential modulators of cleft risk.
- Investigating the interplay between TYMS gene variants and maternal folate intake is crucial for understanding cleft etiology.
Purpose of the Study:
- To investigate the association between two functional TYMS gene variants (28-bp VNTR and 1494del6) and the risk of cleft palate (CP) and cleft lip with/without CP (CLP).
- To examine potential effect measure modification between these TYMS variants and maternal folate intake on cleft risk.
Main Methods:
- A case-control study was conducted using data from deliveries between July 1999 and June 2003 in California.
- Case groups comprised infants with CLP or CP, while controls were randomly selected non-malformed liveborn infants.
- Maternal interviews collected data on vitamin use and dietary folate intake, with DNA analyzed from newborn bloodspots.
Main Results:
- The TYMS 1494del6 variant did not significantly influence CP or CLP risk.
- Homozygosity for the 28-bp VNTR variant was associated with an increased risk of CP (OR=1.8), particularly in Hispanic infants (OR=2.1).
- A significant interaction was observed between the 28-bp VNTR variant and combined folate intake, elevating CP risk (OR=10.0).
Conclusions:
- Findings suggest a potential role for the 28-bp VNTR variant and maternal folate status in CP development, aligning with biological plausibility.
- The observed associations, particularly the interaction effect, were based on limited sample sizes and require cautious interpretation.
- Replication of these findings in diverse populations is essential to confirm their validity and clinical relevance.
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