title: Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts.
abstract: Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case-control and offspring-parent triad designs into a "hybrid design" to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first-trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (1996-2001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well-established risk exposures.
authors.affiliation: Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway. oivind.skare@medisin.uio.no
authors.forename: Oivind
authors.initials: O
authors.lastname: Skare
authors.forename: Astanand
authors.initials: A
authors.lastname: Jugessur
authors.forename: Rolv Terje
authors.initials: RT
authors.lastname: Lie
authors.forename: Allen James
authors.initials: AJ
authors.lastname: Wilcox
authors.forename: Jeffrey Clark
authors.initials: JC
authors.lastname: Murray
authors.forename: Astrid
authors.initials: A
authors.lastname: Lunde
authors.forename: Truc Trung
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Håkon Kristian
authors.initials: HK
authors.lastname: Gjessing
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D003069:Coffee; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D059647:Gene-Environment Interaction; D006801:Humans; D018811:Maternal Exposure; D011247:Pregnancy; D012107:Research Design; D012907:Smoking / Q000235:genetics; D014801:Vitamin A / Q000235:genetics
chemical_list: D003069:Coffee; D014801:Vitamin A; D005492:Folic Acid