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Associations between polymorphisms within the thymidylate synthase gene and spina bifida
Kelly A Volcik1, Gary M Shaw, Huiping Zhu
1Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030, USA.
Birth Defects Research. Part A, Clinical and Molecular Teratology
|January 28, 2004
Summary
Thymidylate synthase (TS) gene polymorphisms, particularly in untranslated regions, are linked to increased spina bifida (SB) risk in non-Hispanic white newborns. These findings highlight the role of folate metabolism gene variations in SB etiology.
Area of Science:
- Genetics
- Developmental Biology
- Public Health
Background:
- Thymidylate synthase (TS) gene polymorphisms may influence enzyme activity, affecting folate and homocysteine levels.
- Reduced risk of spina bifida (SB) is associated with folate metabolism, suggesting a link to TS gene variations.
Purpose of the Study:
- To investigate the association between thymidylate synthase (TS) gene polymorphisms and the risk of spina bifida (SB).
Main Methods:
- Genomic DNA was analyzed from newborn blood spots of SB cases and controls.
- Frequencies of two TS gene polymorphisms (promoter enhancer region TSER and 3'UTR deletion) were determined using PCR and RFLP.
- Sequencing of all seven TS gene exons was performed to identify coding region variations.
Main Results:
- The TSER 2/2 homozygous genotype showed a slightly increased risk for SB (OR=1.4).
- In non-Hispanic whites, the TSER 2/2 genotype increased SB risk 4-fold (OR=4.0), and the 3'UTR +/+ genotype increased risk 3-fold (OR=3.6).
- Combined TSER,3'UTR (2/2,+/+) genotype showed over 4-fold increased SB risk in non-Hispanic whites (OR=4.7).
Conclusions:
- This study is the first to link TS gene polymorphisms to SB risk.
- Polymorphisms in untranslated regions of the TS gene significantly increase SB risk (4-fold or more) in non-Hispanic whites.
- No increased risk was observed in Hispanic whites, African-Americans, or Asian-Americans.