RESUMO
AIM: To construct a simple, low-cost typing method for the surrogate marker of HLA-A*31:01, a risk factor for carbamazepine (CBZ) related Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). MATERIALS & METHODS: DNAs from Japanese SJS/TEN patients were used for genotyping and developing the assay. RESULTS: HLA-A*31:01 was confirmed to be significantly associated with definite/probable cases of CBZ-related SJS/TEN (p = 0.0040). Three single nucleotide polymorphisms, rs1150738, rs3869066 and rs259945, were in absolute linkage disequilibrium with HLA-A*31:01 in 210 Japanese SJS/TEN patients. Robust genotyping of rs3869066 in ZNRD1-AS1 was developed using polymerase chain reaction-restriction fragment length polymorphism assays. CONCLUSION: Single nucleotide polymorphism genotyping is less time consuming and cheaper than conventional HLA typing, and would be useful for identifying Japanese patients at risk of CBZ-related SJS/TEN.
Assuntos
Povo Asiático/genética , Antígenos HLA-A/genética , Síndrome de Stevens-Johnson/genética , Anticonvulsivantes/efeitos adversos , Carbamazepina/efeitos adversos , DNA/genética , Frequência do Gene , Marcadores Genéticos , Genótipo , Humanos , Japão , Desequilíbrio de Ligação , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Síndrome de Stevens-Johnson/epidemiologia , Resultado do TratamentoRESUMO
Neonatal Fc receptor (FcRn) plays an important role in regulating IgG homeostasis in the body. Changes in FcRn expression levels or activity caused by genetic polymorphisms of FCGRT, which encodes FcRn, may lead to interindividual differences in pharmacokinetics of therapeutic antibodies. In this study, we sequenced the 5'-flanking region, all exons and their flanking regions of FCGRT from 126 Japanese subjects. Thirty-three genetic variations, including 17 novel ones, were found. Of these, two novel non-synonymous variations, 629G>A (R210Q) and 889T>A (S297T), were found as heterozygous variations. We next assessed the functional significance of the two novel non-synonymous variations by expressing wild-type and variant proteins in HeLa cells. Both variant proteins showed similar intracellular localization as well as antibody recycling efficiencies. These results suggested that at least no common functional polymorphic site with amino acid change was present in the FCGRT of our Japanese population.
Assuntos
Povo Asiático/genética , Antígenos de Histocompatibilidade Classe I/genética , Receptores Fc/genética , Variação Genética , Células HeLa , Humanos , Imunoglobulina G/imunologia , Japão , Polimorfismo GenéticoRESUMO
The vitamin D receptor (VDR) is a transcriptional factor responsive to 1alpha,25-dihydroxyvitamin D(3) and lithocholic acid, and induces expression of drug metabolizing enzymes CYP3A4, CYP2B6 and CYP2C9. In this study, the promoter regions, 14 exons (including 6 exon 1's) and their flanking introns of VDR were comprehensively screened for genetic variations in 107 Japanese subjects. Sixty-one genetic variations including 25 novel ones were found: 9 in the 5'-flanking region, 2 in the 5'-untranslated region (UTR), 7 in the coding exons (5 synonymous and 2 nonsynonymous variations), 12 in the 3'-UTR, 19 in the introns between the exon 1's, and 12 in introns 2 to 8. Of these, one novel nonsynonymous variation, 154A>G (Met52Val), was detected with an allele frequency of 0.005. The single nucleotide polymorphisms (SNPs) that increase VDR expression or activity, -29649G>A, 2T>C and 1592((*)308)C>A tagging linked variations in the 3'-UTR, were detected at 0.430, 0.636, and 0.318 allele frequencies, respectively. Another SNP, -26930A>G, with reduced VDR transcription was found at a 0.028 frequency. These findings would be useful for association studies on VDR variations in Japanese.