Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Antimicrob Agents Chemother. 2019 Jul 25;63(8). doi: 10.1128/AAC.02692-18. Print 2019 Aug.
Antituberculosis drug-induced liver injury (ATDILI) is a common side effect leading to tuberculosis (TB) treatment disruption. The mechanism of the disease remains poorly understood. We conducted a genomewide association study (GWAS) to investigate all possible genetic factors of ATDILI in Thai patients. This study was carried out in Thai TB patients, including 79 ATDILI cases and 239 tolerant controls from our network hospitals in Thailand. Nearly 1 million single-nucleotide polymorphisms (SNPs) were genotyped across the whole genome using an Illumina OmniExpress Exome BeadChip array. In the discovery stage, we identified strong association signals on chromosome 8 originating from the -acetyltransferase () region. The A allele of rs1495741, the top SNP in the intergenic region of and (14 kb from ), was significantly associated with ATDILI (recessive model, odds ratio of 6.01 [95% confidence interval, 3.42 to 10.57]; = 6.86E-11). This particular SNP was reported as a tag SNP for inferred phenotypes. The AA, AG, and GG genotypes represented slow acetylators, intermediate acetylators, and fast acetylators, respectively. The tag SNP genotypes demonstrated a concordance rate of 94.98% with acetylator phenotypes. This GWAS shows that is the most important risk factor for ATDILI in the Thai population.
抗结核药物性肝损伤（ATDILI）是导致结核病（TB）治疗中断的常见副作用。该疾病的发病机制仍不清楚。我们进行了全基因组关联研究（GWAS），以研究泰国患者中可能导致 ATDILI 的所有遗传因素。这项研究在泰国的结核病患者中进行，包括 79 例 ATDILI 病例和 239 例来自我们在泰国网络医院的耐受对照。使用 Illumina OmniExpress Exome BeadChip 阵列在全基因组范围内对近 100 万个单核苷酸多态性（SNP）进行了基因分型。在发现阶段，我们在 8 号染色体上发现了源自乙酰基转移酶（）区域的强烈关联信号。rs1495741 的 A 等位基因，位于 和 （14 kb 来自）基因间区域的顶级 SNP，与 ATDILI 显著相关（隐性模型，比值比为 6.01 [95%置信区间，3.42 至 10.57]；= 6.86E-11）。该特定 SNP 被报道为推断表型的 标签 SNP。AA、AG 和 GG 基因型分别代表慢乙酰化者、中间乙酰化者和快乙酰化者。标签 SNP 基因型与 乙酰化表型的符合率为 94.98%。这项 GWAS 表明，在泰国人群中，是 ATDILI 的最重要危险因素。
