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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
- Source :
- The Myositis Genetics Consortium (MYOGEN) 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, vol. 75, no. 8, pp. 1558-1566 . https://doi.org/10.1136/annrheumdis-2015-208119
- Publication Year :
- 2015
- Publisher :
- BMJ Publishing Group, 2015.
-
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 −8 ). Nine regions were associated at a significance level of p −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.
- Subjects :
- 0301 basic medicine
Genetics and Molecular Biology (all)
2745 Rheumatology
Autoimmunity
Genome-wide association study
Polymyositis
Biochemistry
HLA Antigens
Risk Factors
Immunology and Allergy
Genetics
education.field_of_study
10051 Rheumatology Clinic and Institute of Physical Medicine
Idiopathic inflammatory myopathy
HLA
2723 Immunology and Allergy
Dermatomyositis
Gene Polymorphism
Rheumatology
Immunology
Biochemistry, Genetics and Molecular Biology (all)
Genotype
Quantitative Trait Loci
Population
610 Medicine & health
Human leukocyte antigen
Biology
Polymorphism, Single Nucleotide
Article
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
1300 General Biochemistry, Genetics and Molecular Biology
medicine
Humans
Genetic Predisposition to Disease
education
Alleles
2403 Immunology
Myositis
Haplotype
association
Protein Tyrosine Phosphatase, Non-Receptor Type 22
medicine.disease
030104 developmental biology
Case-Control Studies
Gene polymorphism
Inclusion body myositis
myositis
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- The Myositis Genetics Consortium (MYOGEN) 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, vol. 75, no. 8, pp. 1558-1566 . https://doi.org/10.1136/annrheumdis-2015-208119
- Accession number :
- edsair.doi.dedup.....51c05d9c3a0d6a10f804cc9919a1b4cf