基于全基因组关联研究的抗结核药物不良反应风险预测模型的建立

The success of using N-acetyltransferase 2 (NAT2) genotype to adjust the dosage of anti-tuberculosis drugs (ATD) to reduce the incidence of ATD-induced hepatitis (ATDH) and to improve the efficacy of anti-tuberculosis therapy indicates that genetic variation plays an important role in the individualized diagnosis and treatment of tuberculosis. However, as the positive predictive value of NAT2 genotypes for ATDH is only about 30%, we hypothesized that there are other variants in the genome that affect ATDH. In this proposal, we aim to study adverse reactions induced by ATD. This will be the first study of adverse reactions of ATD using the latest Chinese genome-wide association study (GWAS) chip. This chip detects about 700,000 genetic variants, including functional variants from different databases and all drug metabolism related genetic loci that have been reported. We will use of screening with GWAS, verification with multicenter population study, confirmation with prospective cohort study, and functional verification to obtain the genetic susceptibility loci associated with adverse reactions of ATD. Combined with clinical parameters, we will establish prediction models of adverse reactions of ATD based on the whole genome. This study will not only help to clarify the genetic etiology and pathogenesis of ATD caused by interactions of gene-gene and gene-clinical parameters, but also accords with the strategy of “translational medicine” and “precision medicine”.

以N-乙酰基转移酶2（NAT2）基因型调整抗结核药（ATD）剂量以减少抗结核药物肝损害（ATDH）发生率、提高结核疗效获得成功，表明基因变异在结核病个体化诊治中具有重要地位。但在ATDH预测中，NAT2基因型阳性预测值仅约30％，我们推测基因组中尚有其它影响ATDH的位点。本研究以ATD致不良反应为研究对象，首次使用最新中国人群药物不良反应芯片进行全基因关联研究（GWAS），该芯片检测70万个遗传变异位点，含多种数据库功能性位点，及已报道的所有药物代谢遗传学相关位点。通过候选易感基因初筛、多中心人群验证、前瞻性队列研究、功能验证等多阶段的研究，获得与ATD不良反应相关的遗传易感位点；结合临床参数，建立基于全基因组学的ATD不良反应风险预测模型。该研究不仅有助于阐明基因-基因之间、基因-临床参数之间相互作用导致ATD不良反应的遗传病因与病理机制，同时也符合“转化医学”及“精准医学”的战略。

结核病疫情严重，仍是重大疾病，抗结核药物不良反应除了导致各系统功能障碍还会导致抗结核药物中断、方案改变、结核病的复发、耐药、甚至死亡。通过基因 SNPs 的关联研究，可发现与 ADRs 发生相关的基因型，对选择或设计新的预防及治疗干预措施、减少药物不良反应、提高抗结核治疗效果具有重要意义。本研究对完成了282例样本（81例肝功能损害；90例药物过敏反应；110例对照）的GWAS分析，损害组与对照组GWAS分析发现3个位点的P值小于9.26×10-6 （rs77355199、rs6518253及rs73082118），药物过敏组与对照组GWAS分析5个SNP位点（rs117076155、rs12797664、rs78934484、rs150232843及rs190527210）P值小于9.26×10-8。通过GWAS分析能够找到药物不良反应组与正常组之间存在显著差异的SNP位点，筛选到了抗结核药物不良反应的易感基因。可能为结核病患者的精准治疗提供新的理论基础。