Genomewide Association Study Confirming the Association of NAT2 with Susceptibility to Antituberculosis Drug-Induced Liver Injury in Thai Patients
Genomewide Association Study Confirming the Association of NAT2 with Susceptibility to Antituberculosis Drug-Induced Liver Injury in Thai Patients
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DOI：
10.1128/aac.02692-18
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发表时间：
2019-08-01
影响因子：
4.9
通讯作者：
Tokunaga, Katsushi
中科院分区：
文献类型：
--
作者：
Suvichapanich, Supharat;Wattanapokayakit, Sukanya;Tokunaga, Katsushi
抗结核药物诱导的肝损伤（ATDILI）是导致结核病（TB）治疗中断的常见副作用。该病的发病机制仍然知之甚少。我们进行了一项全基因组关联研究（GWAS），以调查泰国患者ATDILI的所有可能的遗传因素。这项研究在泰国结核病患者中进行，包括来自我们泰国网络医院的79例ATDILI病例和239例耐受对照。使用Illumina Omni Express Exome BeadChip阵列对整个基因组中近100万个单核苷酸多态性（SNP）进行基因分型。在发现阶段，我们确定了来自N-乙酰转移酶（NAT 2）区域的8号染色体上的强关联信号。rs 1495741的A等位基因是NAT 2和P503基因间区域（距NAT 2 14 kb）的最高SNP，与ATDILI显著相关（隐性模型，优势比为6.01 [95%置信区间，3.42至10.57]; P = 6.86E-11）。该特定SNP被报告为NAT 2推断表型的标签SNP。AA、AG和GG基因型分别代表NAT 2慢乙酰化因子、中间乙酰化因子和快乙酰化因子。标签SNP基因型与NAT 2乙酰化表型的符合率为94.98%。该GWAS表明，NAT 2是泰国人群中ATDILI的最重要风险因素。
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 Omni Express Exome BeadChip array. In the discovery stage, we identified strong association signals on chromosome 8 originating from the N-acetyltransferase (NAT2) region. The A allele of rs1495741, the top SNP in the intergenic region of NAT2 and P503 (14 kb from NAT2), was significantly associated with ATDILI (recessive model, odds ratio of 6.01 [95% confidence interval, 3.42 to 10.57]; P = 6.86E-11). This particular SNP was reported as a tag SNP for NAT2 inferred phenotypes. The AA, AG, and GG genotypes represented NAT2 slow acetylators, intermediate acetylators, and fast acetylators, respectively. The tag SNP genotypes demonstrated a concordance rate of 94.98% with NAT2 acetylator phenotypes. This GWAS shows that NAT2 is the most important risk factor for ATDILI in the Thai population.