[pubmed] Genomic insights into myasthenia gravis identify distinct immunological mechanisms in early and late onset dise

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Ann Neurol. 2021 Jul 19. doi: 10.1002/ana.26169. Online ahead of print.

ABSTRACT

OBJECTIVE: To identify disease relevant genes and explore underlying immunological mechanisms that contribute to early and late onset forms of myasthenia gravis.

METHODS: We used a novel genomic methodology to integrate genome wide association study (GWAS) findings in myasthenia gravis with cell-type specific information such as gene expression patterns and promotor-enhancer interactions, in order to identify disease relevant genes. Subsequently, we conducted additional genomic investigations including an expression quantitative analysis of 313 healthy people to provide mechanistic insights.

RESULTS: We identified genes that were specifically linked to early onset myasthenia gravis based on GWAS associated risk variants including TNIP1, ORMDL3, GSDMB and TRAF3. We showed that regulators of toll-like receptor 4 signalling were enriched only among the early onset disease genes (fold enrichment = 3.85, p = 6.4 x 10-3 ). In contrast, T-cell regulators CD28 and CTLA4 were exclusively linked to late onset disease. We identified two causal genetic variants (rs231770 and rs231735; posterior probability= 0.98 and 0.91) near the CTLA4 gene. Subsequently, we demonstrated that these causal variants result in low expression of CTLA4 (rho =-0.66, p = 1.28 x 10-38 and rho = -0.52, p = 7.01 x 10-22 , for rs231735 and rs231770 respectively).

INTERPRETATION: The disease relevant genes identified in this study are a unique resource for many disciplines including clinicians, scientists and the pharmaceutical industry. The distinct immunological pathways linked to early and late onset myasthenia gravis carry important implications for drug repurposing opportunities and for future studies of drug development. This article is protected by copyright. All rights reserved.

PMID:34279044 | DOI:10.1002/ana.26169


Source: https://pubmed.ncbi.nlm.nih.gov/3427904 ... 9&v=2.14.5