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, Robert G. Cooper, Ingrid E. Lundberg, Frederick W. Miller, Peter K. Gregersen, John Bowes, Jiri Vencovsky, Katalin Danko, Vidya Limaye, Albert Selva O'Callaghan, Michael G. Hanna, Pedro M. Machado, Lauren M. Pachman, Ann M. Reed, Lisa G. Rider, Joanna Cobb, Hazel Platt, Øyvind Molberg, Olivier Benveniste, Pernille MathiesenTimothy Radstake, Andrea Doria, Jan De Bleecker, Boel De Paepe, Britta Maurer, William E. Ollier, Leonid Padyukov, Terrance P. O'Hanlon, Annette Lee, Christopher I. Amos, Christian Gieger, Thomas Meitinger, Juliane Winkelmann, Lucy R. Wedderburn, Hector Chinoy, Janine A. Lamb, Christopher Denton, Herman Mann, David Hilton-Jones, Patrick Kiely, Paul H. Plotz, Mark Gourley, Kelly Rouster-Stevens, Adam M. Huber, Galina Marder, Mazen Dimachkie

Research output: Contribution to journalArticle

55 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAnnals of the Rheumatic Diseases
DOIs
StateAccepted/In press - Sep 11 2015
Externally publishedYes

Fingerprint

Myositis
HLA Antigens
Alleles
Rare Diseases
Haplotypes
Genes
TNF Receptor-Associated Factor 6
Inclusion Body Myositis
Genome
Polymyositis
Pulmonary diseases
Dermatomyositis
Interstitial Lung Diseases
Muscle Weakness
Exanthema
Autoimmune Diseases
Muscle
Genetic Background
Skin
Amino Acids

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

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. / Rothwell, Simon; Cooper, Robert G.; Lundberg, Ingrid E.; Miller, Frederick W.; Gregersen, Peter K.; Bowes, John; Vencovsky, Jiri; Danko, Katalin; Limaye, Vidya; O'Callaghan, Albert Selva; Hanna, Michael G.; Machado, Pedro M.; Pachman, Lauren M.; Reed, Ann M.; Rider, Lisa G.; Cobb, Joanna; Platt, Hazel; Molberg, Øyvind; Benveniste, Olivier; Mathiesen, Pernille; Radstake, Timothy; Doria, Andrea; Bleecker, Jan De; Paepe, Boel De; Maurer, Britta; Ollier, William E.; Padyukov, Leonid; O'Hanlon, Terrance P.; Lee, Annette; Amos, Christopher I.; Gieger, Christian; Meitinger, Thomas; Winkelmann, Juliane; Wedderburn, Lucy R.; Chinoy, Hector; Lamb, Janine A.; Denton, Christopher; Mann, Herman; Hilton-Jones, David; Kiely, Patrick; Plotz, Paul H.; Gourley, Mark; Rouster-Stevens, Kelly; Huber, Adam M.; Marder, Galina; Dimachkie, Mazen.

In: Annals of the Rheumatic Diseases, 11.09.2015.

Research output: Contribution to journalArticle

Rothwell, S, Cooper, RG, Lundberg, IE, Miller, FW, Gregersen, PK, Bowes, J, Vencovsky, J, Danko, K, Limaye, V, O'Callaghan, AS, Hanna, MG, Machado, PM, Pachman, LM, Reed, AM, Rider, LG, Cobb, J, Platt, H, Molberg, Ø, Benveniste, O, Mathiesen, P, Radstake, T, Doria, A, Bleecker, JD, Paepe, BD, Maurer, B, Ollier, WE, Padyukov, L, O'Hanlon, TP, Lee, A, Amos, CI, Gieger, C, Meitinger, T, Winkelmann, J, Wedderburn, LR, Chinoy, H, Lamb, JA, Denton, C, Mann, H, Hilton-Jones, D, Kiely, P, Plotz, PH, Gourley, M, Rouster-Stevens, K, Huber, AM, Marder, G & Dimachkie, M 2015, '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', Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2015-208119
Rothwell, Simon ; Cooper, Robert G. ; Lundberg, Ingrid E. ; Miller, Frederick W. ; Gregersen, Peter K. ; Bowes, John ; Vencovsky, Jiri ; Danko, Katalin ; Limaye, Vidya ; O'Callaghan, Albert Selva ; Hanna, Michael G. ; Machado, Pedro M. ; Pachman, Lauren M. ; Reed, Ann M. ; Rider, Lisa G. ; Cobb, Joanna ; Platt, Hazel ; Molberg, Øyvind ; Benveniste, Olivier ; Mathiesen, Pernille ; Radstake, Timothy ; Doria, Andrea ; Bleecker, Jan De ; Paepe, Boel De ; Maurer, Britta ; Ollier, William E. ; Padyukov, Leonid ; O'Hanlon, Terrance P. ; Lee, Annette ; Amos, Christopher I. ; Gieger, Christian ; Meitinger, Thomas ; Winkelmann, Juliane ; Wedderburn, Lucy R. ; Chinoy, Hector ; Lamb, Janine A. ; Denton, Christopher ; Mann, Herman ; Hilton-Jones, David ; Kiely, Patrick ; Plotz, Paul H. ; Gourley, Mark ; Rouster-Stevens, Kelly ; Huber, Adam M. ; Marder, Galina ; Dimachkie, Mazen. / 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. In: Annals of the Rheumatic Diseases. 2015.
@article{9b6af5f4d63241589ec92b2fd347a4fa,
title = "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",
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.",
author = "Simon Rothwell and Cooper, {Robert G.} and Lundberg, {Ingrid E.} and Miller, {Frederick W.} and Gregersen, {Peter K.} and John Bowes and Jiri Vencovsky and Katalin Danko and Vidya Limaye and O'Callaghan, {Albert Selva} and Hanna, {Michael G.} and Machado, {Pedro M.} and Pachman, {Lauren M.} and Reed, {Ann M.} and Rider, {Lisa G.} and Joanna Cobb and Hazel Platt and {\O}yvind Molberg and Olivier Benveniste and Pernille Mathiesen and Timothy Radstake and Andrea Doria and Bleecker, {Jan De} and Paepe, {Boel De} and Britta Maurer and Ollier, {William E.} and Leonid Padyukov and O'Hanlon, {Terrance P.} and Annette Lee and Amos, {Christopher I.} and Christian Gieger and Thomas Meitinger and Juliane Winkelmann and Wedderburn, {Lucy R.} and Hector Chinoy and Lamb, {Janine A.} and Christopher Denton and Herman Mann and David Hilton-Jones and Patrick Kiely and Plotz, {Paul H.} and Mark Gourley and Kelly Rouster-Stevens and Huber, {Adam M.} and Galina Marder and Mazen Dimachkie",
year = "2015",
month = "9",
day = "11",
doi = "10.1136/annrheumdis-2015-208119",
language = "English (US)",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",

}

TY - JOUR

T1 - 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

AU - Rothwell, Simon

AU - Cooper, Robert G.

AU - Lundberg, Ingrid E.

AU - Miller, Frederick W.

AU - Gregersen, Peter K.

AU - Bowes, John

AU - Vencovsky, Jiri

AU - Danko, Katalin

AU - Limaye, Vidya

AU - O'Callaghan, Albert Selva

AU - Hanna, Michael G.

AU - Machado, Pedro M.

AU - Pachman, Lauren M.

AU - Reed, Ann M.

AU - Rider, Lisa G.

AU - Cobb, Joanna

AU - Platt, Hazel

AU - Molberg, Øyvind

AU - Benveniste, Olivier

AU - Mathiesen, Pernille

AU - Radstake, Timothy

AU - Doria, Andrea

AU - Bleecker, Jan De

AU - Paepe, Boel De

AU - Maurer, Britta

AU - Ollier, William E.

AU - Padyukov, Leonid

AU - O'Hanlon, Terrance P.

AU - Lee, Annette

AU - Amos, Christopher I.

AU - Gieger, Christian

AU - Meitinger, Thomas

AU - Winkelmann, Juliane

AU - Wedderburn, Lucy R.

AU - Chinoy, Hector

AU - Lamb, Janine A.

AU - Denton, Christopher

AU - Mann, Herman

AU - Hilton-Jones, David

AU - Kiely, Patrick

AU - Plotz, Paul H.

AU - Gourley, Mark

AU - Rouster-Stevens, Kelly

AU - Huber, Adam M.

AU - Marder, Galina

AU - Dimachkie, Mazen

PY - 2015/9/11

Y1 - 2015/9/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84941695475&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941695475&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2015-208119

DO - 10.1136/annrheumdis-2015-208119

M3 - Article

C2 - 26362759

AN - SCOPUS:84941695475

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

ER -