Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08

Peter K. Gregersen, Roman Kosoy, Annette T. Lee, Janine Lamb, Jon Sussman, David McKee, Kim R. Simpfendorfer, Ritva Pirskanen-Matell, Frederik Piehl, Qiang Pan-Hammarstrom, Jan J G M Verschuuren, Maarten J. Titulaer, Erik H. Niks, Alexander Marx, Philipp Ströbel, Björn Tackenberg, Michael Pütz, Angelina Maniaol, Ahmed Elsais, Chantal TallaksenHanne F. Harbo, Benedicte A. Lie, Soumya Raychaudhuri, Paul I W De Bakker, Arthur Melms, Henri Jean Garchon, Nicholas Willcox, Lennart Hammarstrom, Michael F. Seldin

    Research output: Contribution to journalArticlepeer-review


    Objective: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). Methods: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. Results: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10 -92; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B08 proves to be the major associated allele (p = 2.87 × 10 -113; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 × 10-10), an imputed coding variant (rs2233290) at position 151 (Pro→Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 × 10-10). Interpretation: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B08 allele suggests that CD8+ T cells may play a key role in disease initiation or pathogenesis. Copyright © 2012 American Neurological Association.
    Original languageEnglish
    Pages (from-to)927-935
    Number of pages8
    JournalAnnals of Neurology
    Issue number6
    Publication statusPublished - Dec 2012


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