Variability of the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene

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.

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“…1. The schematic structure of the human ARNT gene [Scheel et al, 2002]. Genetic variations are indicated by arrows.…”

Section: Sequencingmentioning

confidence: 99%

“…We amplified exons 1-22 and a 1 kb promoter region of ARNT using previously identified primers by standard PCR [Scheel et al, 2002]. The amplified products were purified (Qiagen K.K, Tokyo, Japan) and directly sequenced with ABI genetic analyzer 310 (Applied Biosystems, Foster City, CA).…”

Section: Dna Analysismentioning

confidence: 99%

Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT)

Kayano

Suzuki

Kanno

et al. 2004

American J of Med Genetics Pt A

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“…It was found that mice with the Arnt gene disrupted specifically in T cells were resistant to TCDD-induced thymic involution, a response observed in normal mice exposed to the inducer (Tomita et al, 2003). Although several polymorphisms of human Arnt gene have been cited in the literature, their functional impact on human CYP1A induction has not been established (Anttila et al, 2000;Cao and Hegele, 2000;Watanabe et al, 2001;Scheel et al, 2002). As for the regulatory proteins for CYP3A induction, there are only a few reports on the polymorphisms of RXR (Hegele and Cao, 2001), but their influence on CYP3A and CYP2B induction is unclear.…”

Section: Downloaded Frommentioning

confidence: 99%

Metabolism-Based Drug-Drug Interactions: What Determines Individual Variability in Cytochrome P450 Induction?

Tang¹,

Lin²,

Lu³

2005

Drug Metab Dispos

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ABSTRACT:Individual variability in cytochrome P450 (P450) induction comprises an important component contributing to the difficulties in assessing and predicting metabolism-based drug-drug interactions in humans. In this article, we outline the major factors responsible for the individual variability in P450 induction, including variable transporter activity and metabolism of inducers in vivo, genetic variations of P450 genes and their regulatory regions, genetic variations of receptors and regulatory proteins required for induction, and different physiological and environmental elements. With a better understanding of the major determinants in P450 induction and a profile of the phenotypes of these determinants in each individual, it is believed that the individual variability in induction-mediated drug-drug interactions can be adequately evaluated.

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“…To date, two informative polymorphisms, Arg554Lys at exon 10 of AHR and Pro185Ala at exon 6 of AHRR, have been identified in the Japanese population, whereas no useful polymorphism has been detected for ARNT in the Japanese population, including the Asp511Asn and Asp517Glu at exon 16 that have been identified in non-Japanese populations [13][14][15]. In this context, Fujita et al [14] have reported that the frequencies of the Pro allele and the Pro/Pro genotype of AHRR Pro185Ala polymorphism are significantly higher in 59 boys with severe MP (<-2.5 SD) than in 80 control males, whereas the prevalence of AHR Arg554Lys polymorphism is similar between the two groups of males.…”

mentioning

confidence: 99%

Association of Micropenis with Pro185Ala Polymorphism of the Gene for Aryl Hydrocarbon Receptor Repressor Involved in Dioxin Signaling

Soneda¹,

Fukami²,

Fujimoto

et al. 2005

Endocr J

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Abstract. The prevalence of undermasculinized external genitalia has increased in several countries including Japan, and this phenomenon has primarily been ascribed to the deleterious effects of environmental endocrine disruptors such as dioxins. To examine a possible role of the genetic susceptibility to dioxins in the development of micropenis (MP), we studied the Arg554Lys polymorphism of the gene for aryl hydrocarbon receptor (AHR) and the Pro185Ala polymorphism of the gene for aryl hydrocarbon receptor repressor (AHRR), in 73 boys with MP (34 boys with mild MP from -2.1 to -2.5 SD and 39 boys with severe MP below -2.5 SD) and 80 control males (50 boys and 30 fertile adult males). The allele and genotype frequencies of the AHR polymorphism were comparable between the two groups of males, but those of the AHRR polymorphism were significantly different, with the Pro allele and the Pro/Pro genotype being more frequent in boys with MP than in control males (P-value: 0.0029 for the allele frequency and 0.011 for the genotype frequency). In addition, both polymorphisms were comparable in the allele and genotype frequencies between boys with mild MP and those with severe MP and between control boys and control fertile adult males. The results suggest that the AHRR Pro185Ala polymorphism may constitute a susceptibility locus for the development of MP in response to dioxins.

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Variability of the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene

Cited by 19 publications

References 29 publications

Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT)

Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT)

Metabolism-Based Drug-Drug Interactions: What Determines Individual Variability in Cytochrome P450 Induction?

Association of Micropenis with Pro185Ala Polymorphism of the Gene for Aryl Hydrocarbon Receptor Repressor Involved in Dioxin Signaling

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