Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
MRC Centre for Drug Safety Science, Wolfson Centre for Personalised Medicine, University of Liverpool, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners, Liverpool, UK.
Transl Psychiatry. 2020 Jan 27;10(1):37. doi: 10.1038/s41398-020-0722-0.
Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10), with odds ratios ranging 5.5-13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P = 1.21 × 10; OR = 6.36), located in the GNA15 gene, previously associated with heart failure. The HLA-C07:01 allele was identified as potentially predisposing to clozapine-induced myocarditis (OR = 2.89, 95% CI: 1.11-7.53), consistent with a previous report of association of the same allele with clozapine-induced agranulocytosis. Another seven HLA alleles, including HLA-B07:02 (OR = 0.25, 95% CI: 0.05-1.2) were found to be putatively protective. Long-read DNA sequencing provided increased resolution of HLA typing and validated the HLA associations. The PRS explained 66% of liability (P value = 9.7 × 10). Combining clinical and genetic factors together increased the proportion of variability accounted for (r 0.73, P = 9.8 × 10). However, due to the limited sample size, individual genetic associations were not statistically significant after correction for multiple testing. We report novel candidate genetic associations with clozapine-induced myocarditis, which may have potential clinical utility, but larger cohorts are required for replication.
氯氮平是治疗精神分裂症最有效的抗精神病药物，但它会引起危及生命的药物不良反应，包括心肌炎。本研究旨在确定与氯氮平耐受对照相比，患有氯氮平诱导心肌炎的精神分裂症患者是否具有遗传易感性。我们测量了不同类型的遗传变异，包括全基因组单核苷酸多态性（SNP）、改变蛋白表达的编码变异，以及人类白细胞抗原（HLA）基因的可变形式，以及 42 例病例和 67 例对照的传统临床危险因素。我们基于 96 个不同遗传位点的变异计算了多基因风险评分（PRS），以估计氯氮平诱导心肌炎的遗传易感性。我们的全基因组关联分析确定了四个提示心肌炎风险增加的 SNP（P < 1 × 10），比值比范围为 5.5-13.7。P 值最低的 SNP 是 rs74675399（chr19p13.3，P = 1.21 × 10；OR = 6.36），位于 GNA15 基因中，先前与心力衰竭有关。HLA-C07:01 等位基因被确定为可能易患氯氮平诱导的心肌炎（OR = 2.89，95%CI：1.11-7.53），与先前报道的相同等位基因与氯氮平诱导的粒细胞缺乏症有关。另外七个 HLA 等位基因，包括 HLA-B07:02（OR = 0.25，95%CI：0.05-1.2），被认为具有潜在的保护作用。长读 DNA 测序提高了 HLA 分型的分辨率，并验证了 HLA 相关性。PRS 解释了 66%的易感性（P 值= 9.7 × 10）。将临床和遗传因素结合起来可以增加可解释的变异性比例（r 0.73，P = 9.8 × 10）。然而，由于样本量有限，在进行多次检验校正后，个体遗传相关性没有统计学意义。我们报告了与氯氮平诱导心肌炎相关的新候选遗传相关性，这些相关性可能具有潜在的临床应用价值，但需要更大的队列进行复制。
