{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T20:51:18Z","timestamp":1761511878534},"reference-count":15,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2003,10,24]],"date-time":"2003-10-24T00:00:00Z","timestamp":1066953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2003,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Polymorphisms within the thymidylate synthase (TS) gene that influence enzyme activity may affect plasma folate levels and, indirectly, plasma homocysteine concentrations. We investigated whether TS polymorphisms contribute to spina bifida (SB) risk, given that a reduction in the risk of SB has been linked to folate metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Genomic DNA was extracted from newborn\u2010screening blood spots obtained from case infants with SB, and randomly selected, nonmalformed control infants. Genotype frequencies of two polymorphisms in the TS gene\u2014a 28\u2010bp tandem repeat in the promoter enhancer region (TSER) and a 6\u2010bp deletion in the 3\u2032UTR\u2014were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Additionally, all seven exons of the TS gene were sequenced to identify variations within the coding region of the gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We found that the TSER 2\/2 homozygous genotype was associated with a slightly increased risk for SB infants (odds ratio [OR] = 1.4 [0.8\u20132.4], <jats:italic>p<\/jats:italic> = 0.1). When the cohort was divided into separate ethnic groups, this risk increased by 4\u2010fold with the TSER 2\/2 homozygous genotype (OR = 4.0 [1.8\u20138.8], <jats:italic>p<\/jats:italic> = 0.001), and by 3\u2010fold with the 3\u2032UTR +\/+ homozygous genotype (OR = 3.6 [1.3\u201310.1], <jats:italic>p<\/jats:italic> = 0.02) in non\u2010Hispanic white cases. The combined TSER,3\u2032UTR (2\/2,+\/+) genotype showed a more than 4\u2010fold increased risk for SB within this specific ethnic group (OR = 4.7 [1.1\u201319.8], <jats:italic>p<\/jats:italic> = 0.04).<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>This study is the first to evaluate how TS polymorphisms contribute to the risk of SB. The current findings indicate that polymorphisms in the untranslated regions of the TS gene are associated with 4\u2010fold or more increased risks of SB in non\u2010Hispanic whites, but not in Hispanic whites, African\u2010Americans, or Asian\u2010Americans. Birth Defects Research (Part A), 2003. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.10029","type":"journal-article","created":{"date-parts":[[2003,11,12]],"date-time":"2003-11-12T14:55:09Z","timestamp":1068648909000},"page":"924-928","source":"Crossref","is-referenced-by-count":41,"title":["Associations between polymorphisms within the thymidylate synthase gene and spina bifida"],"prefix":"10.1002","volume":"67","author":[{"given":"Kelly A.","family":"Volcik","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary M.","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiping","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward J.","family":"Lammer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecile","family":"Laurent","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard H.","family":"Finnell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2003,10,24]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(95)00004-6"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3016.1991.tb00728.x"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1247\/csf.20.191"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/15.3.1259"},{"key":"e_1_2_6_6_1","first-page":"3249","article-title":"Polymorphic tandem repeats in the thymidylate synthase gene are associated with its protein expression in human gastrointestinal cancers","volume":"19","author":"Kawakami K","year":"1999","journal-title":"Anticancer Res"},{"key":"e_1_2_6_7_1","first-page":"4096","article-title":"Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression","volume":"7","author":"Kawakami K","year":"2001","journal-title":"Clin Cancer Res"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M204956200"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(02)00080-7"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1999.5833"},{"key":"e_1_2_6_11_1","first-page":"91","article-title":"Quality control of birth defect registry data: a case study","volume":"108","author":"Schulman J","year":"1993","journal-title":"Public Health Rep"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(90)93446-V"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a009555"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a122898"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-002-0779-2"},{"key":"e_1_2_6_16_1","first-page":"3361","article-title":"Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas","volume":"62","author":"Ulrich CM","year":"2002","journal-title":"Cancer Res"}],"container-title":["Birth Defects Research Part A: Clinical and Molecular Teratology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdra.10029","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdra.10029","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T22:52:31Z","timestamp":1700175151000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdra.10029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,10,24]]},"references-count":15,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2003,11]]}},"alternative-id":["10.1002\/bdra.10029"],"URL":"https:\/\/doi.org\/10.1002\/bdra.10029","archive":["Portico"],"relation":{},"ISSN":["1542-0752","1542-0760"],"issn-type":[{"value":"1542-0752","type":"print"},{"value":"1542-0760","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,10,24]]}}}