{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T02:59:23Z","timestamp":1789700363108,"version":"4.0.1"},"reference-count":85,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2010,12,1]],"date-time":"2010-12-01T00:00:00Z","timestamp":1291161600000},"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":[[2011,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Isolated clubfoot is a common orthopedic birth defect that affects approximately 135,000 newborns worldwide. It is characterized by ankle equinus, hindfoot varus, and forefoot adductus. Although numerous studies suggest a multifactorial etiology, the specific genetic and environmental components have yet to be delineated. Maternal smoking during pregnancy is the only common environmental factor consistently shown to increase the risk for clubfoot. Moreover, a positive family history of clubfoot, in conjunction with maternal smoking, increases the risk 20\u2010fold. These findings suggest that genetic variation in smoking metabolism (xenobiotic) genes may increase susceptibility to clubfoot. Based on this reasoning, we interrogated eight candidate genes from the xenobiotic metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Twenty\u2010two single\u2010nucleotide polymorphisms and two null alleles in these genes (<jats:italic>CYP1A1, CYP1A2, CYP1B1, CYP2A6, EPHX1, NAT2, GSTM1<\/jats:italic>, and <jats:italic>GSTT1<\/jats:italic>) were genotyped in a dataset composed of non\u2010Hispanic white and Hispanic multiplex and simplex families.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Only rs1048943\/<jats:italic>CYP1A1<\/jats:italic> had significantly altered transmission in the aggregate and multiplex non\u2010Hispanic white datasets (<jats:italic>p<\/jats:italic> = 0.003 and <jats:italic>p<\/jats:italic> = 0.009, respectively). Perturbation of <jats:italic>CYP1A1<\/jats:italic> can cause an increase in harmful, adduct\u2010forming metabolic intermediates. A significant interaction between <jats:italic>EPHX1<\/jats:italic> and <jats:italic>NAT2<\/jats:italic> was also found (<jats:italic>p<\/jats:italic> = 0.007). Importantly, for <jats:italic>CYP1A2<\/jats:italic>, significant maternal (<jats:italic>p<\/jats:italic> = 0.03; relative risk [RR] = 1.24; 95% confidence interval [CI], 1.04\u20131.44) and fetal (<jats:italic>p<\/jats:italic> = 0.01; RR = 1.33; 95% CI, 1.13\u20131.54) genotypic effects were identified, suggesting that both maternal and fetal genotypes can negatively impact limb development. No association was found between maternal smoking status and variation in xenobiotic metabolism genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>Together, these results suggest that xenobiotic metabolism genes are unlikely to play a major role in clubfoot; however, perturbation of this pathway may still play a contributory role. Birth Defects Research (Part A), 2011. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.20742","type":"journal-article","created":{"date-parts":[[2010,12,1]],"date-time":"2010-12-01T21:47:06Z","timestamp":1291240026000},"page":"20-28","source":"Crossref","is-referenced-by-count":18,"title":["Smoking, the xenobiotic pathway, and clubfoot"],"prefix":"10.1002","volume":"91","author":[{"given":"Amy","family":"Sommer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan H.","family":"Blanton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelyn","family":"Weymouth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. 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