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; 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

doi:10.1002/ana.23691

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

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

^*Corresponding author for this work

Feinstein Institute for Medical Research
University of California at Davis
University of Manchester
Greater Manchester Neuroscience Centre
Karolinska University Hospital
Leiden University Medical Centre
Heidelberg University
Universität Marburg
Oslo University Hospital
University of Oslo
Harvard Medical School
Massachusetts Institute of Technology
Utrecht University
University Hospital Tübingen
University Hospital Erlangen
CNRS
University of Oxford

Research output: Contribution to journal › Article › Academic › peer-review

153 Citations (Scopus)

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 language	English
Pages (from-to)	927-935
Number of pages	9
Journal	Annals of Neurology
Volume	72
Issue number	6
DOIs	https://doi.org/10.1002/ana.23691
Publication status	Published - Dec 2012
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1002/ana.23691

Cite this

Gregersen, P. K., Kosoy, R., Lee, A. T., Lamb, J., Sussman, J., McKee, D., Simpfendorfer, K. R., Pirskanen-Matell, R., Piehl, F., Pan-Hammarstrom, Q., Verschuuren, J. J. G. M., Titulaer, M. J., Niks, E. H., Marx, A., Ströbel, P., Tackenberg, B., Pütz, M., Maniaol, A., Elsais, A., ... Seldin, M. F. (2012). Risk for myasthenia gravis maps to a ¹⁵¹Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08. Annals of Neurology, 72(6), 927-935. https://doi.org/10.1002/ana.23691

@article{492bb92ef7a54417afab3f30678c6d24,

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

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.",

author = "Gregersen, \{Peter K.\} and Roman Kosoy and Lee, \{Annette T.\} and Janine Lamb and Jon Sussman and David McKee and Simpfendorfer, \{Kim R.\} and Ritva Pirskanen-Matell and Frederik Piehl and Qiang Pan-Hammarstrom and Verschuuren, \{Jan J.G.M.\} and Titulaer, \{Maarten J.\} and Niks, \{Erik H.\} and Alexander Marx and Philipp Str{\"o}bel and Bj{\"o}rn Tackenberg and Michael P{\"u}tz and Angelina Maniaol and Ahmed Elsais and Chantal Tallaksen and Harbo, \{Hanne F.\} and Lie, \{Benedicte A.\} and Soumya Raychaudhuri and \{De Bakker\}, \{Paul I.W.\} and Arthur Melms and Garchon, \{Henri Jean\} and Nicholas Willcox and Lennart Hammarstrom and Seldin, \{Michael F.\}",

year = "2012",

month = dec,

doi = "10.1002/ana.23691",

language = "English",

volume = "72",

pages = "927--935",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley \& Sons Inc.",

number = "6",

}

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

TY - JOUR

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.

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84871950028

U2 - 10.1002/ana.23691

DO - 10.1002/ana.23691

M3 - Article

C2 - 23055271

AN - SCOPUS:84871950028

SN - 0364-5134

VL - 72

SP - 927

EP - 935

JO - Annals of Neurology

JF - Annals of Neurology

IS - 6

ER -

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

Abstract

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