Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, MA, USA.
Nat Commun. 2019 May 13;10(1):2128. doi: 10.1038/s41467-019-10110-6.
Drug resistance diagnostics that rely on the detection of resistance-related mutations could expedite patient care and TB eradication. We perform minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole-genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We evaluate genome-wide associations between mutations in MTB genes or non-coding regions and resistance, followed by validation in an independent data set of 792 patient isolates. We confirm associations at 13 non-canonical loci, with two involving non-coding regions. Promoter mutations are measured to have smaller average effects on resistance than gene body mutations. We estimate the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. This study highlights the complexity of the genomic mechanisms associated with the MTB resistance phenotype, including the relatively large number of potentially causal loci, and emphasizes the contribution of the non-coding portion of the genome.
耐药性诊断依赖于耐药相关突变的检测，可以加速患者治疗和结核病的消除。我们对 1452 株临床结核分枝杆菌（MTB）分离株进行了 12 种抗结核药物的最低抑菌浓度检测，并进行了 Illumina 全基因组测序。我们评估了 MTB 基因或非编码区域突变与耐药性之间的全基因组关联，然后在 792 例患者分离株的独立数据集进行验证。我们确认了 13 个非典型基因座上的关联，其中两个涉及非编码区域。启动子突变对耐药性的平均影响小于基因体突变。我们估计 11 种抗结核药物的耐药表型的遗传力，并发现已知耐药基因的贡献低于预期。本研究强调了与 MTB 耐药表型相关的基因组机制的复杂性，包括潜在的因果基因座数量相对较多，以及基因组非编码部分的贡献。
