Development of a Rapid and Inexpensive Assay for Detecting a Surrogate Genetic Polymorphism of HLA-B*58:01: A Partially Predictive but Useful Biomarker for Allopurinol-related Stevens-Johnson Syndrome/toxic Epidermal Necrolysis in Japanese
Development of a Rapid and Inexpensive Assay for Detecting a Surrogate Genetic Polymorphism of HLA-B*58:01: A Partially Predictive but Useful Biomarker for Allopurinol-related Stevens-Johnson Syndrome/toxic Epidermal Necrolysis in Japanese
复制标题
DOI：
10.2133/dmpk.dmpk-11-nt-120
复制
发表时间：
2012-08-25
影响因子：
2.1
通讯作者：
Saito, Yoshiro
中科院分区：
文献类型：
--
作者：
Maekawa, Keiko;Nishikawa, Jun;Saito, Yoshiro
别嘌呤醇诱导的Stevens-Johnson综合征（SJS）/中毒性表皮坏死松解症（TEN）与包括日本人在内的各种人群中的HLA-B*58：01密切相关。我们证明，在日本别嘌呤醇相关SJS/TEN患者的既往研究中，6号染色体HLA区域周围的几个单核苷酸多态性（SNP）与HLA-B*58：01密切相关。它们非常强的连锁性表明，这些SNP可用作替代生物标志物，以发现HLA-B*58：01携带者，以避免这些严重的不良反应。在本研究中，为了加快应用这种药物基因组学信息在临床情况下正确使用别嘌呤醇，我们开发了一种聚合酶链反应限制性片段长度多态性银屑病易感性1候选者1中rs 9263726基因分型的PCR-RFLP分析（PSORS 1C 1）基因与HLA-B*58：01处于绝对连锁不平衡（r（2）= 1，D' = 1）。利用FokI限制性内切酶建立的PCR-RFLP检测方法能够稳健地检测rs 9263726的GG、GA和AA三种不同基因型，从而发现HLA-B*58：01携带者。这种稳健且廉价的检测方法可用于预筛选HLA-B*58：01受试者，HLA-B*58：01是别嘌呤醇诱导的SJS/TEN的遗传高危因素。
Allopurinol-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is strongly associated with HLA-B*58:01 in various populations including Japanese. We demonstrated that several single nucleotide polymorphisms (SNPs) around the HLA region on chromosome 6 were strongly linked with HLA-B*58:01 in a previous study using Japanese allopurinol-related SJS/TEN patients. Their very strong linkage suggests that these SNPs could be used as surrogate biomarkers to find carriers of HLA-B*58:01 to avoid these serious adverse effects. In the present study, to expedite the application of this pharmacogenomic information to the proper usage of allopurinol in a clinical situation, we developed a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay for the genotyping of rs9263726 in the psoriasis susceptibility 1 candidate 1 (PSORS1C1) gene, which is in absolute linkage disequilibrium (r(2) = 1, D' = 1) with HLA-B*58:01. The developed PCR-RFLP assay using Fokl restriction enzyme was able to detect three different genotypes, GG, GA, and AA of rs9263726 robustly, and thus to find HLA-B*58:01 carriers. This robust and inexpensive assay would be useful for pre-screening the subjects with HLA-B*58:01, a genetically high risk factor for allopurinol-induced SJS/TEN.