VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis

Abstract

ObjectiveTo identify novel genetic loci that predispose to early-onset myasthenia gravis (EOMG) applying a two-stage association study, exploration, and replication strategy.MethodsThirty-four loci and one confirmation loci, human leukocyte antigen (HLA)-DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG 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 patients and 814 controls, from nine European centres.ResultsAllele frequency differences were found in four novel loci: CD86, AKAP12, VAV1, B-cell activating factor (BAFF), and tumor necrosis factor-alpha (TNF-α), 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-DRA and TNF-α loci were observed.InterpretationThe genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for T- and B-cell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of B-cells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factor-kappaB (NFκB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG.

Estrogen Receptor, Inflammatory, and FOXO Transcription Factors Regulate Expression of Myasthenia Gravis-Associated Circulating microRNAs

“…NF-κB had 23 binding sites across all MG-associated miRNAs, the majority being located in the AChR+ MG-associated miRNA genes. This is in support of a large study on almost 1,200 European MG patients with early onset AChR+ MG, where several risk genes were found related to the NF-κB signaling pathway (35). Here, the genetic associations to MG outside the HLA complex indicate VAV1, a key signal transducer crucial for T and B cell activation and BAFF, a cytokine important in the proliferation and differentiation of B cells.…”

“…Here, the genetic associations to MG outside the HLA complex indicate VAV1, a key signal transducer crucial for T and B cell activation and BAFF, a cytokine important in the proliferation and differentiation of B cells. Combined VAV1 and BAFF haplotypes conferred a greater risk in combination and in addition to CD86, and these share the same signaling pathway, NF-κB (35). It was therefore not entirely surprising to find that NF-κB regulates transcription of the miRNAs found to be upregulated in AChR+ MG.…”

Thymoma related myasthenia gravis in humans and potential animal models

“…The triggers of the MG subtypes are only partially understood. Genome wide association studies and candidate gene sequencing approaches may help to detect new pathomechanisms [12,13].…”

Role of the thymus in autoimmune myasthenia gravis

“…TNF‐α, a critical Th1 cytokine, also plays a role in human MG. A genetic association has been described, and interestingly allele frequency difference in female versus male patients was observed at the TNF‐α loci . Also, TNF‐α is increased in the whole thymus and isolated CD4+ T cells, as well as in the sera of MG patients .…”