Department of Medical Genetics, University of Calgary, Calgary, AB, Canada.
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
Pharmacogenomics J. 2022 May;22(3):173-179. doi: 10.1038/s41397-022-00271-x. Epub 2022 Apr 23.
One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p < 0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.
一个限制氯氮平在精神分裂症治疗中应用的问题是罕见但潜在致命的心肌炎风险。我们之前的全基因组关联研究和人类白细胞抗原分析确定了与氯氮平诱导性心肌炎相关的假定基因座。然而，细胞色素 P450 基因、拷贝数变异和罕见有害变异的 DNA 变异的贡献尚未被研究。我们使用 25 例氯氮平诱导性心肌炎病例和 25 例人口统计学匹配的氯氮平耐受对照的全基因组测序数据，探索了这些未被探索的 DNA 变异类别。我们根据罕见变异基因负担分析确定了 15 个基因（MLLT6、CADPS、TACC2、L3MBTL4、NPY、SLC25A21、PARVB、GPR179、ACAD9、NOL8、C5orf33、FAM127A、AFDN、SLC6A11、PXDN）与氯氮平诱导性心肌炎有名义上的关联（p<0.05）。在这些基因中，有 13 个在人类心肌组织中表达。尽管需要对这些发现进行独立的复制，但我们的研究提供了初步的证据，表明罕见遗传变异可能在氯氮平诱导性心肌炎易感性中起作用。
