title: Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT).
abstract: The etiology of nonsyndromic oral clefts (cleft lip, cleft palate, or cleft lip and palate) is still controversial, but is considered to involve both genetic and environmental factors. One of suspected environmental factors is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) found in tobacco, herbicides, contaminated soil, and food. TCDD administered during organogenesis in mice causes a high incidence of CP in fetuses. There is ample evidence that aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), and cytochrome P450 1A1 (CYP1A1) are involved in TCDD metabolism. We assessed whether there is any association in the Japanese population of nonsyndromic oral clefts with single nucleotide polymorphisms (SNPs) in the AHR, ARNT, and CYP1A1 genes using transmission disequilibrium test (TDT) and case-control study. We identified and investigated three SNPs in ARNT; 567G/C (V189V), IVS12-19T/G, and 2117C/T (P706L). Two amino acid substitutions, R554L in AHR and I462V in CYP1A1, were also investigated. In the TDT, the C allele of ARNT 567G/C was preferentially transmitted to patients (P = 0.033). When a haplotype consisting of 567G/C and IVS12-19T/G in ARNT was considered, the preferential transmission of the CT (567C-IVS12-19T) haplotype was observed (P = 0.0012). In a case-control study, a significant association of IVS12-19T/G in ARNT was observed (P = 0.021). The SNPs studied in AHR and CYP1A1 were not associated with the disease. Our results suggest that ARNT is involved in the development of nonsyndromic oral clefts in the Japanese population.
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kayano
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kanno
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
mesh_terms: D000328:Adult; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002648:Child; D002971:Cleft Lip / Q000235:genetics* / Q000503:physiopathology*; D002972:Cleft Palate / Q000235:genetics* / Q000503:physiopathology*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004785:Environmental Pollutants / Q000506:poisoning*; D005260:Female; D006239:Haplotypes; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000506:poisoning*; D016133:Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C497396:ARNT protein, human; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019363:Cytochrome P-450 CYP1A1