Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2016 Aug;75(8):1558-66.
doi: 10.1136/annrheumdis-2015-208119. Epub 2015 Sep 11.

Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups

Simon Rothwell  1 , Robert G Cooper  2 , Ingrid E Lundberg  3 , Frederick W Miller  4 , Peter K Gregersen  5 , John Bowes  1 , Jiri Vencovsky  6 , Katalin Danko  7 , Vidya Limaye  8 , Albert Selva-O'Callaghan  9 , Michael G Hanna  10 , Pedro M Machado  10 , Lauren M Pachman  11 , Ann M Reed  12 , Lisa G Rider  4 , Joanna Cobb  13 , Hazel Platt  14 , Øyvind Molberg  15 , Olivier Benveniste  16 , Pernille Mathiesen  17 , Timothy Radstake  18 , Andrea Doria  19 , Jan De Bleecker  20 , Boel De Paepe  20 , Britta Maurer  21 , William E Ollier  14 , Leonid Padyukov  3 , Terrance P O'Hanlon  4 , Annette Lee  5 , Christopher I Amos  22 , Christian Gieger  23 , Thomas Meitinger  24 , Juliane Winkelmann  25 , Lucy R Wedderburn  26 , Hector Chinoy  27 , Janine A Lamb  14 ; Myositis Genetics Consortium
Collaborators, Affiliations
Multicenter Study

Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups

Simon Rothwell et al. Ann Rheum Dis. 2016 Aug.

Abstract

Objectives: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium.

Results: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM.

Conclusions: This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.

Keywords: Dermatomyositis; Gene Polymorphism; Polymyositis.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Manhattan plots of the IIM, PM and DM+JDM analyses, with the MHC region removed
The red and blue lines represent genome-wide level of significance (p=5×10−8) and suggestive significance (p=2.25×10−5) respectively. A) Analysis of 2,566 IIM cases and 15,651 controls. B) Analysis of 931PM cases and 15,651 controls. C) Analysis of 1,360 DM+JDM cases and 15,651 controls.
Figure 1
Figure 1. Manhattan plots of the IIM, PM and DM+JDM analyses, with the MHC region removed
The red and blue lines represent genome-wide level of significance (p=5×10−8) and suggestive significance (p=2.25×10−5) respectively. A) Analysis of 2,566 IIM cases and 15,651 controls. B) Analysis of 931PM cases and 15,651 controls. C) Analysis of 1,360 DM+JDM cases and 15,651 controls.
Figure 1
Figure 1. Manhattan plots of the IIM, PM and DM+JDM analyses, with the MHC region removed
The red and blue lines represent genome-wide level of significance (p=5×10−8) and suggestive significance (p=2.25×10−5) respectively. A) Analysis of 2,566 IIM cases and 15,651 controls. B) Analysis of 931PM cases and 15,651 controls. C) Analysis of 1,360 DM+JDM cases and 15,651 controls.
See this image and copyright information in PMC

References

    1. Rider LG, Miller FW. Deciphering the clinical presentations, pathogenesis, and treatment of the idiopathic inflammatory myopathies. JAMA. 2011;305:183–90. - PMC - PubMed
    1. Love LA, Leff RL, Fraser DD, Targoff IN, Dalakas M, Plotz PH, et al. A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine (Baltimore) 1991;70:360–74. - PubMed
    1. Chinoy H, Platt H, Lamb JA, Betteridge Z, Gunawardena H, Fertig N, et al. The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients. Arthritis Rheum. 2008;58:3247–54. - PMC - PubMed
    1. Miller FW, Cooper RG, Vencovsky J, Rider LG, Danko K, Wedderburn LR, et al. Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders. Arthritis Rheum. 2013;65:3239–47. - PMC - PubMed
    1. Jani M, Massey J, Wedderburn LR, Vencovsky J, Danko K, Lundberg IE, et al. Genotyping of immune-related genetic variants identifies TYK2 as a novel associated locus for idiopathic inflammatory myopathies. Ann Rheum Dis. 2014;73:1750–2. - PMC - PubMed

Publication types

Substances