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 Tallaksen & 9 others Hanne 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 journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)927-935
Number of pages9
JournalAnnals of Neurology
Volume72
Issue number6
DOIs
StatePublished - Dec 2012

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Myasthenia Gravis
HLA Antigens
Odds Ratio
Alleles
Genome-Wide Association Study
Ubiquitin
Major Histocompatibility Complex
T-Lymphocytes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08. / Gregersen, Peter K.; Kosoy, Roman; Lee, Annette T.; Lamb, Janine; Sussman, Jon; McKee, David; Simpfendorfer, Kim R.; Pirskanen-Matell, Ritva; Piehl, Frederik; Pan-Hammarstrom, Qiang; Verschuuren, Jan J G M; Titulaer, Maarten J.; Niks, Erik H.; Marx, Alexander; Ströbel, Philipp; Tackenberg, Björn; Pütz, Michael; Maniaol, Angelina; Elsais, Ahmed; Tallaksen, Chantal; Harbo, Hanne F.; Lie, Benedicte A.; Raychaudhuri, Soumya; De Bakker, Paul I W; Melms, Arthur; Garchon, Henri Jean; Willcox, Nicholas; Hammarstrom, Lennart; Seldin, Michael F.

In: Annals of Neurology, Vol. 72, No. 6, 12.2012, p. 927-935.

Research output: Contribution to journalArticle

Gregersen, PK, Kosoy, R, Lee, AT, Lamb, J, Sussman, J, McKee, D, Simpfendorfer, KR, Pirskanen-Matell, R, Piehl, F, Pan-Hammarstrom, Q, Verschuuren, JJGM, Titulaer, MJ, Niks, EH, Marx, A, Ströbel, P, Tackenberg, B, Pütz, M, Maniaol, A, Elsais, A, Tallaksen, C, Harbo, HF, Lie, BA, Raychaudhuri, S, De Bakker, PIW, Melms, A, Garchon, HJ, Willcox, N, Hammarstrom, L & Seldin, MF 2012, 'Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08', Annals of Neurology, vol. 72, no. 6, pp. 927-935. https://doi.org/10.1002/ana.23691
Gregersen, Peter K. ; Kosoy, Roman ; Lee, Annette T. ; Lamb, Janine ; Sussman, Jon ; McKee, David ; Simpfendorfer, Kim R. ; Pirskanen-Matell, Ritva ; Piehl, Frederik ; Pan-Hammarstrom, Qiang ; Verschuuren, Jan J G M ; Titulaer, Maarten J. ; Niks, Erik H. ; Marx, Alexander ; Ströbel, Philipp ; Tackenberg, Björn ; Pütz, Michael ; Maniaol, Angelina ; Elsais, Ahmed ; Tallaksen, Chantal ; Harbo, Hanne F. ; Lie, Benedicte A. ; Raychaudhuri, Soumya ; De Bakker, Paul I W ; Melms, Arthur ; Garchon, Henri Jean ; Willcox, Nicholas ; Hammarstrom, Lennart ; Seldin, Michael F. / Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08. In: Annals of Neurology. 2012 ; Vol. 72, No. 6. pp. 927-935.
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T1 - Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08

AU - Gregersen, Peter K.

AU - Kosoy, Roman

AU - Lee, Annette T.

AU - Lamb, Janine

AU - Sussman, Jon

AU - McKee, David

AU - Simpfendorfer, Kim R.

AU - Pirskanen-Matell, Ritva

AU - Piehl, Frederik

AU - Pan-Hammarstrom, Qiang

AU - Verschuuren, Jan J G M

AU - Titulaer, Maarten J.

AU - Niks, Erik H.

AU - Marx, Alexander

AU - Ströbel, Philipp

AU - Tackenberg, Björn

AU - Pütz, Michael

AU - Maniaol, Angelina

AU - Elsais, Ahmed

AU - Tallaksen, Chantal

AU - Harbo, Hanne F.

AU - Lie, Benedicte A.

AU - Raychaudhuri, Soumya

AU - De Bakker, Paul I W

AU - Melms, Arthur

AU - Garchon, Henri Jean

AU - Willcox, Nicholas

AU - Hammarstrom, Lennart

AU - Seldin, Michael F

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