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标题：Reply to Zhu et al.: Implications of CHRNB1 and ERBB2 in the pathobiology of myasthenia gravis
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作者：Ruth Chia ; Sara Saez-Atienzar ; Daniel B. Drachman 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：36
DOI：10.1073/pnas.2209096119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：We commend the work performed by Zhu et al. providing additional insights into the pathogenesis of myasthenia gravis ( 1). In essence, they applied Mendelian randomization to genome-wide data that we recently made public for a large cohort of patients diagnosed with the neuromuscular disorder ( 2). This powerful approach identified genetic variants increasing the risk of developing myasthenia gravis by influencing gene expression. Their most exciting observations centered on CHRNB1 and ERBB2, two loci we discovered in our genomic and transcriptomic analyses ( 2). Their data corroborated our conclusions in that they found rs4151121 to influence the expression of CHRNB1 in skeletal muscle. ERBB2 was also implicated in their search, though the lead variant and tissue involved differed between the two studies. We had identified rs2102928 in skeletal muscle as the candidate variant affecting ERBB2 expression, whereas rs1565922 in peripheral nerves was implicated in this current analysis. These findings are not mutually exclusive and point to this myasthenia gravis–related gene operating across multiple tissues. Regardless of these subtle differences, the two studies hint at CHRNB1 and ERBB2 playing a prominent role in the pathobiology of myasthenia gravis. Given that ERBB2 can modulate the expression of acetylcholine receptor subunits ( 3, 4), future studies should explore how the expression of these genes in nerves and skeletal muscle mediate the disease process. Our findings also have clinical implications as patients carrying the risk allele could have persistently lower expression of acetylcholine receptors, which may explain why some patients fail to enter remission ( 4). These observations suggest that new therapies modulating CHRNB1 and ERBB2 expression may benefit treatment-refractory patients. To demonstrate how genomic information can provide useful starting points to consider for therapeutic interventions, we performed in silico druggability testing on additional gene targets identified from the prioritization analysis of our genome-wide association study data ( 5). This approach identified 14 gene targets as potentially druggable, three of which have existing approved drugs or therapeutic agents in clinical testing (milatuzumab, forigerimod, and oprozomib; see Table 1) ( 6– 8). Table 1. List of prioritized druggable genes ranked according to their priority index (PI) scores Drug Current disease indication Mechanism of action Gene PI rank PI rating Druggability Seed gene Milatuzumab Orphan drug status for MM and CLL HLA-DR antigens- associated invariant chain antagonist CD74 2 4.59 1 N Forigerimod Phase III trial for SLE Heat-shock cognate 71-kDa protein inhibitor HSPA8 12 4.11 8 N Oprozomib Orphan drug status for MM and Waldenstrom's macroglobulinaemia 26S proteosome inhibitor PSMD4 20 3.96 15 N — — — HLA-DRA 4 4.48 21 Y — — — HLA-DQA1 5 4.44 8 Y — — — UBA52 6 4.42 19 N — — — HLA-DQB1 17 4.05 8 N — — — AP1G1 18 4.00 1 N — — — SH3GL2 19 3.96 3 N — — — ARF1 22 3.93 4 N — — — AP2B1 23 3.92 2 N — — — AP1B1 25 3.87 1 N — — — HLA-C 28 3.76 1 Y — — — AP1S3 29 3.75 1 N Drugs that are approved or in clinical testing are highlighted in yellow. MM, multiple myeloma; CLL, chronic lymphocytic leukemia; SLE, systemic lupus erythematosus; Seed gene indicates if the prioritized gene was used as a seed gene (yes [Y] or no [N]). The work presented by Zhu et al. ( 1), together with our recent publication ( 2), demonstrates the value of genomic research in unraveling the pathogenesis of neurological diseases. Most notably, the insights provided by such large collaborative efforts pave the way for rational drug development and precision medicine efforts.