{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:38:05Z","timestamp":1790249885412,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,4,11]],"date-time":"2014-04-11T00:00:00Z","timestamp":1397174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2014,5]]},"abstract":"Abstract<\/jats:title>Objective<\/jats:title>To identify novel genetic loci that predispose to early\u2010onset myasthenia gravis (EOMG<\/jats:styled-content>) applying a two\u2010stage association study, exploration, and replication strategy.<\/jats:p><\/jats:sec>Methods<\/jats:title>Thirty\u2010four loci and one confirmation loci, human leukocyte antigen (HLA<\/jats:styled-content>)\u2010DRA<\/jats:styled-content>, were selected as candidate genes by team members of groups involved in different research aspects of MG<\/jats:styled-content>. In the exploration step, these candidate genes were genotyped in 384 EOMG<\/jats:styled-content> and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG<\/jats:styled-content> patients and 814 controls, from nine European centres.<\/jats:p><\/jats:sec>Results<\/jats:title>Allele frequency differences were found in four novel loci: CD<\/jats:styled-content>86, AKAP<\/jats:styled-content>12, VAV<\/jats:styled-content>1, B\u2010cell activating factor (BAFF<\/jats:styled-content>), and tumor necrosis factor\u2010alpha (TNF<\/jats:styled-content>\u2010\u03b1<\/jats:italic>), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLA<\/jats:styled-content>\u2010DRA<\/jats:styled-content><\/jats:italic> and TNF<\/jats:styled-content>\u2010\u03b1<\/jats:italic> loci were observed.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>The genetic associations to EOMG<\/jats:styled-content> outside the HLA<\/jats:styled-content> complex are novel and of interest as VAV<\/jats:styled-content>1 is a key signal transducer essential for T\u2010 and B\u2010cell activation, and BAFF<\/jats:styled-content> is a cytokine that plays important roles in the proliferation and differentiation of B\u2010cells. Moreover, we noted striking epistasis between the predisposing VAV<\/jats:styled-content>1 and BAFF<\/jats:styled-content> haplotypes; they conferred a greater risk in combination than alone. These, and CD<\/jats:styled-content>86, share the same signaling pathway, namely nuclear factor\u2010kappaB (NF<\/jats:styled-content>\u03baB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51","type":"journal-article","created":{"date-parts":[[2014,4,11]],"date-time":"2014-04-11T18:07:48Z","timestamp":1397239668000},"page":"329-339","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["VAV<\/scp>1 and BAFF<\/scp>, via NF<\/scp>\u03baB pathway, are genetic risk factors for myasthenia gravis"],"prefix":"10.1002","volume":"1","author":[{"given":"Nili","family":"Avidan","sequence":"first","affiliation":[{"name":"Pharmacogenetics and Translational Genetics Center The Rappaport Faculty of Medicine and Research Institute Technion\u2010Israel Institute of Technology Haifa 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