ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2953

International Immunochip Study in the Idiopathic Inflammatory Myopathies Identifies Novel Susceptibility Loci and Confirms HLA As Strongest Genetic Risk Factor

Simon Rothwell1, Robert G. Cooper2, Ingrid E. Lundberg3, Frederick W. Miller4, Peter K. Gregersen5, Jiri Vencovsky6, Katalin Danko7, Lucy R Wedderburn8, Vidya Limaye9, Albert Selva O'Callaghan10, Michael G. Hanna11, Pedro Machado11, Lauren M. Pachman12, Ann M. Reed13, Lisa G. Rider4, Joanna Cobb1, Hazel Platt14, Øyvind Molberg15, Olivier Benveniste16, Pernille Mathiesen17, Timothy Radstake18, Andrea Doria19, Jan De Bleecker20, Boel De Paepe21, Britta Maurer22, William E. Ollier14, Leonid Padyukov3, Terrance P. O'Hanlon4, Annette Lee23, Hector Chinoy1 and Janine Lamb14, 1Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, United Kingdom, 2MRC/ARUK Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom, 3Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden, 4Environmental Autoimmunity Group, NIEHS, NIH, Bethesda, MD, 5The Feinstein Institute for Medical Research, Manhasset, NY, 6Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 7University of Debrecen, University of Debrecen, Debrecan, Hungary, 8Rheumatology Unit, Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, United Kingdom, 9Royal Adelaide Hospital, Adelaide, Australia, 10Vall d'Hebron General Hospital, Barcelona, Spain, 11MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom, 12Cure JM Myositis Center, Ann & Robert H. Lurie Children's Hospital of Chicago Research Center, Chicago, IL, 13Rheumatology, Mayo Clinic, Rochester, MN, 14Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, United Kingdom, 15Department of Rheumatology, Oslo University Hospital Rikshospitalet, Oslo, Norway, 16Internal Medecine Dpt 1, Pitié-Salpêtrière Hospital, APHP, Paris, France, 17Paediatric Department, Holbaek University Hospital, Holbaek, Denmark, 18University Medical Center Utrecht, Utrecht, Netherlands, 19Department of Medicine - DIMED, University of Padova, Padova, Italy, 20University of Ghent, Ghent, Belgium, 21Neuromuscular Reference Center, University of Ghent, Ghent, Belgium, 22Division of Rheumatology, University Hospital Zurich, Zurich, Switzerland, 23Genomics & Human Genetics, Feinstein Institute Med Rsch, Manhasset, NY

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Genetics, Genomics and Proteomics II: Genetics of Autoimmunity

Session Type: Abstract Submissions (ACR)

Background/Purpose: The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease and with increased association with malignancy. Recent candidate gene studies in IIM and a genome-wide association study in dermatomyositis suggest a shared genetic architecture with other autoimmune diseases. We therefore conducted a genetic association study using the Immunochip; a custom Illumina array containing coverage of 186 established autoimmune susceptibility loci.

Methods: We genotyped 2,740 IIM cases of Caucasian descent comprising of dermatomyositis, juvenile dermatomyositis and polymyositis fulfilling Bohan and Peter classification criteria, and inclusion body myositis fulfilling Griggs/ENMC/Hilton-Jones criteria.  Samples have been collected from 14 countries through the Myositis Genetics Consortium (MYOGEN). Data from all cases and 15,754 matched Caucasian control samples were combined for clustering, and SNPs were called using GenCall. SNP QC was based on a call rate >98% and/or cluster separation score >0.4. Sample QC was based on a call rate >98%. Samples with extreme heterozygosity, related individuals and ancestral outliers were also removed. Analysis was performed in PLINK v1.07 using logistic regression adjusting for the top 10 principal components.

Results: Initial analysis of 113,272 SNPs confirmed the MHC as the most strongly associated region. PTPN22 was the only non-HLA region to reach genome-wide significance of p=5×10-8, previously associated in a candidate gene study. Using a second suggestive tier of significance at p=5×10-5, there was evidence for association at additional loci, including STAT4, UBE2L3, SH2B3/ATXN2 and RPL31P10.

Conclusion: This is the largest genetic association study to date in IIM. The data confirm that HLA and PTPN22 are associated at genome-wide significance, and identification of further novel loci at a suggestive level of significance indicates genetic overlap with other autoimmune diseases. These loci may differ from previously reported dermatomyositis specific associations. The IIMs are a heterogeneous set of diseases; additional clinical subgroup specific analyses are thus planned.

Disclosure:

S. Rothwell,
None;

R. G. Cooper,
None;

I. E. Lundberg,
None;

F. W. Miller,
None;

P. K. Gregersen,
None;

J. Vencovsky,
None;

K. Danko,
None;

L. R. Wedderburn,
None;

V. Limaye,
None;

A. Selva O’Callaghan,
None;

M. G. Hanna,
None;

P. Machado,
None;

L. M. Pachman,
None;

A. M. Reed,
None;

L. G. Rider,
None;

J. Cobb,
None;

H. Platt,
None;

Molberg,
None;

O. Benveniste,
None;

P. Mathiesen,
None;

T. Radstake,
None;

A. Doria,

Investigator,

5;

J. De Bleecker,
None;

B. De Paepe,
None;

B. Maurer,
None;

W. E. Ollier,
None;

L. Padyukov,
None;

T. P. O’Hanlon,
None;

A. Lee,
None;

H. Chinoy,
None;

J. Lamb,
None.

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