Home LiteratureArticle Details
PMID: 23055271 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Annals of neurology ·Vol. 72 ·No. 6 ·2012-12-00 ·Pages 927-35

Gregersen PK, Kosoy R, Lee AT, Lamb J, Sussman J, McKee D, Simpfendorfer KR, Pirskanen-Matell R, Piehl F, Pan-Hammarstrom Q, Verschuuren JJ, 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 PI, Melms A, Garchon HJ, Willcox N, Hammarstrom L, Seldin MF

Abstract

The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). 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. 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-B*08 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) ). 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-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis.

MeSH Terms
Adult Age of Onset Alanine/genetics Case-Control Studies DNA-Binding Proteins/genetics Europe Female Gene Frequency Genetic Predisposition to Disease Genome-Wide Association Study Genotype HLA-B8 Antigen/genetics Humans Male Meta-Analysis as Topic Myasthenia Gravis/genetics Polymorphism, Single Nucleotide/genetics Proline/genetics Whites/genetics Young Adult
Chemicals
DNA-Binding Proteins HLA-B8 Antigen TNIP1 protein, human Proline Alanine
Authors & Affiliations
29 authors, click to expand affiliations / ORCID
Gregersen Peter K
Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA. [email protected]
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
References (47)
47 references, click to expand
  1. A systematic review of population based epidemiological studies in Myasthenia Gravis.
    BMC Neurol. 2010 Jun 18;10:46 PMID: 20565885
  2. Myasthenia gravis.
    Lancet. 2001 Jun 30;357(9274):2122-8 PMID: 11445126
  3. Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves' disease.
    Genes Immun. 2008 Jun;9(4):358-63 PMID: 18449200
  4. ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development.
    Nature. 2009 Feb 12;457(7231):906-9 PMID: 19060883
  5. Frequency of autoimmune diseases in myasthenia gravis: a systematic review.
    Int J Neurosci. 2011 Mar;121(3):121-9 PMID: 21142828
  6. PLINK: a tool set for whole-genome association and population-based linkage analyses.
    Am J Hum Genet. 2007 Sep;81(3):559-75 PMID: 17701901
  7. Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies.
    Genetics. 2003 Aug;164(4):1567-87 PMID: 12930761
  8. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans.
    J Clin Invest. 2011 Sep;121(9):3635-44 PMID: 21804190
  9. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.
    Nat Genet. 2010 Jun;42(6):508-14 PMID: 20453842
  10. Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia.
    Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15464-9 PMID: 15489265
  11. Linkage of HLA to myasthenia gravis and genetic heterogeneity depending on anti-titin antibodies.
    Neurology. 2001 Nov 13;57(9):1555-60 PMID: 11706089
  12. Thymus, thymoma, and specific T cells in myasthenia gravis.
    Ann N Y Acad Sci. 1998 May 13;841:371-87 PMID: 9668262
  13. ABINs: A20 binding inhibitors of NF-kappa B and apoptosis signaling.
    Biochem Pharmacol. 2009 Jul 15;78(2):105-14 PMID: 19464428
  14. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.
    Nat Genet. 2009 Jun;41(6):703-7 PMID: 19430480
  15. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity.
    Lancet Neurol. 2009 May;8(5):475-90 PMID: 19375665
  16. Confirmation of TNIP1 and IL23A as susceptibility loci for psoriatic arthritis.
    Ann Rheum Dis. 2011 Sep;70(9):1641-4 PMID: 21623003
  17. Genetic associations between myasthenia gravis and the HL-A system.
    J Neurol Neurosurg Psychiatry. 1976 Jan;39(1):23-33 PMID: 1255208
  18. Polyubiquitin binding to ABIN1 is required to prevent autoimmunity.
    J Exp Med. 2011 Jun 6;208(6):1215-28 PMID: 21606507
  19. Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis.
    Ann Neurol. 2006 Feb;59(2):404-7 PMID: 16437561
  20. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases.
    Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18680-5 PMID: 19846760
  21. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus.
    Nat Genet. 2009 Nov;41(11):1228-33 PMID: 19838195
  22. Recent advances in the genetics of systemic lupus erythematosus.
    Expert Rev Clin Immunol. 2010 May;6(3):461-79 PMID: 20441431
  23. Genomics and the multifactorial nature of human autoimmune disease.
    N Engl J Med. 2011 Oct 27;365(17):1612-23 PMID: 22029983
  24. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.
    Science. 2010 Dec 10;330(6010):1551-7 PMID: 21051598
  25. Thymoma and paraneoplastic myasthenia gravis.
    Autoimmunity. 2010 Aug;43(5-6):413-27 PMID: 20380583
  26. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals.
    Am J Hum Genet. 2009 Feb;84(2):210-23 PMID: 19200528
  27. Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus.
    Am J Hum Genet. 2002 Sep;71(3):543-53 PMID: 12145745
  28. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases.
    Immunol Rev. 1999 Feb;167:257-74 PMID: 10319267
  29. Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.
    Ann Rheum Dis. 2012 May;71(5):694-9 PMID: 22110124
  30. SNPs3D: candidate gene and SNP selection for association studies.
    BMC Bioinformatics. 2006 Mar 22;7:166 PMID: 16551372
  31. Genotype imputation for genome-wide association studies.
    Nat Rev Genet. 2010 Jul;11(7):499-511 PMID: 20517342
  32. Autoimmunizing mechanisms in thymoma and thymus.
    Ann N Y Acad Sci. 2008;1132:163-73 PMID: 18567866
  33. A second generation human haplotype map of over 3.1 million SNPs.
    Nature. 2007 Oct 18;449(7164):851-61 PMID: 17943122
  34. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.
    PLoS Genet. 2011 Jul;7(7):e1002091 PMID: 21750679
  35. A method and server for predicting damaging missense mutations.
    Nat Methods. 2010 Apr;7(4):248-9 PMID: 20354512
  36. Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE.
    Eur J Hum Genet. 2007 Aug;15(8):823-30 PMID: 17406641
  37. Current and emerging therapies for the treatment of myasthenia gravis.
    Neuropsychiatr Dis Treat. 2011;7:151-60 PMID: 21552317
  38. Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America.
    Hum Mutat. 2009 Jan;30(1):69-78 PMID: 18683858
  39. Inference of population structure using multilocus genotype data.
    Genetics. 2000 Jun;155(2):945-59 PMID: 10835412
  40. Recent advances in the genetics of autoimmune disease.
    Annu Rev Immunol. 2009;27:363-91 PMID: 19302045
  41. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness.
    Nat Genet. 2011 Aug 14;43(9):902-7 PMID: 21841778
  42. A susceptibility region for myasthenia gravis extending into the HLA-class I sector telomeric to HLA-C.
    Hum Immunol. 1999 Sep;60(9):909-17 PMID: 10527401
  43. Preferential expression of AChR epsilon-subunit in thymomas from patients with myasthenia gravis.
    J Neuroimmunol. 2008 Sep 15;201-202:28-32 PMID: 18657869
  44. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus.
    Nature. 2007 Aug 23;448(7156):934-7 PMID: 17687331
  45. Differential estrogen receptor expression in autoimmune myasthenia gravis.
    Endocrinology. 2005 May;146(5):2345-53 PMID: 15661863
  46. A20-binding inhibitor of NF-κB (ABIN1) controls Toll-like receptor-mediated CCAAT/enhancer-binding protein β activation and protects from inflammatory disease.
    Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):E998-1006 PMID: 22011580
  47. LYP inhibits T-cell activation when dissociated from CSK.
    Nat Chem Biol. 2012 Mar 18;8(5):437-46 PMID: 22426112
Article Info
Journal
Annals of neurology
Abbr.
Ann Neurol
ISSN
1531-8249
DOI
10.1002/ana.23691
Email
[email protected]
Published
2012-12-00
Epub
2012-00-10
Pages
927-35
Language
English
Region
United States
NLM ID
7707449
PMCID
PMC3535539
Subset
IM
Grants
NIAID NIH HHS · R01 AI068759 · United States
NIAMS NIH HHS · R01 AR062886 · United States
Medical Research Council · United Kingdom
NIAID NIH HHS · R01-AI-68759 · United States
External Links
PubMed source DOI: 10.1002/ana.23691 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2