Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: Distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in Caucasians

Terrance P. O'Hanlon, Danielle Mercatante Carrick, Frank C. Arnett, John D. Reveille, Mary Carrington, Xiaojiang Gao, Chester V. Oddis, Penelope A. Morel, James D. Malley, Karen Malley, Jonathan Dreyfuss, Ejaz A. Shamim, Lisa G. Rider, Stephen J. Chanock, Charles B. Foster, Thomas Bunch, Paul H. Plotz, Lori A. Love, Frederick W. Miller

Research output: Contribution to journalArticle

Abstract

The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases in which autoimmune pathology is suspected to promote chronic muscle inflammation and weakness. We have performed low to high resolution genotyping to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci in a large population of North American Caucasian patients with IIM representing the major clinicopathologic groups (n = 571). We confirmed that alleles of the 8.1 ancestral haplotype were important risk markers for the development of IIM, and a random forests classification analysis suggested that within this haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal HLA risk factors. In addition, we identified several novel HLA factors associated distinctly with 1 or more clinicopathologic groups of IIM. The DQA1*0201 allele and associated peptide-binding motif ( 47KLPLFHRL54) were exclusive protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM) and inclusion body myositis (IBM) (pc <0.005). In contrast, HLA-A*68 alleles were significant risk factors for dermatomyositis (DM) (pc = 0.0021), a distinct clinical group thought to involve a humorally mediated immunopathology. While the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and DM patients (p <0.05), DQA1*03 alleles were protective factors for IBM (pc = 0.0002). Myositis associated with malignancies was the most distinctive group of IIM wherein HLA Class I alleles were the only identifiable susceptibility factors and a shared HLA-Cw peptide-binding motif ( 90AGSHTLQWM98) conferred significant risk (pc = 0.019). Together, these data suggest that HLA susceptibility markers distinguish different myositis phenotypes with divergent pathogenetic mechanisms. These variations in associated HLA polymorphisms may reflect responses to unique environmental triggers resulting in the tissue pathospecificity and distinct clinicopathologic syndromes of the IIM.

Original languageEnglish (US)
Pages (from-to)338-349
Number of pages12
JournalMedicine
Volume84
Issue number6
DOIs
StatePublished - Nov 2005
Externally publishedYes

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Immunogenetics
Myositis
HLA-A Antigens
HLA-B Antigens
Alleles
Inclusion Body Myositis
Dermatomyositis
Haplotypes
Protective Factors
Polymyositis
Peptides
Connective Tissue Diseases
Muscle Weakness
Pathology
Inflammation
T-Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies : Distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in Caucasians. / O'Hanlon, Terrance P.; Carrick, Danielle Mercatante; Arnett, Frank C.; Reveille, John D.; Carrington, Mary; Gao, Xiaojiang; Oddis, Chester V.; Morel, Penelope A.; Malley, James D.; Malley, Karen; Dreyfuss, Jonathan; Shamim, Ejaz A.; Rider, Lisa G.; Chanock, Stephen J.; Foster, Charles B.; Bunch, Thomas; Plotz, Paul H.; Love, Lori A.; Miller, Frederick W.

In: Medicine, Vol. 84, No. 6, 11.2005, p. 338-349.

Research output: Contribution to journalArticle

O'Hanlon, TP, Carrick, DM, Arnett, FC, Reveille, JD, Carrington, M, Gao, X, Oddis, CV, Morel, PA, Malley, JD, Malley, K, Dreyfuss, J, Shamim, EA, Rider, LG, Chanock, SJ, Foster, CB, Bunch, T, Plotz, PH, Love, LA & Miller, FW 2005, 'Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: Distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in Caucasians', Medicine, vol. 84, no. 6, pp. 338-349. https://doi.org/10.1097/01.md.0000189818.63141.8c
O'Hanlon, Terrance P. ; Carrick, Danielle Mercatante ; Arnett, Frank C. ; Reveille, John D. ; Carrington, Mary ; Gao, Xiaojiang ; Oddis, Chester V. ; Morel, Penelope A. ; Malley, James D. ; Malley, Karen ; Dreyfuss, Jonathan ; Shamim, Ejaz A. ; Rider, Lisa G. ; Chanock, Stephen J. ; Foster, Charles B. ; Bunch, Thomas ; Plotz, Paul H. ; Love, Lori A. ; Miller, Frederick W. / Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies : Distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in Caucasians. In: Medicine. 2005 ; Vol. 84, No. 6. pp. 338-349.
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abstract = "The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases in which autoimmune pathology is suspected to promote chronic muscle inflammation and weakness. We have performed low to high resolution genotyping to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci in a large population of North American Caucasian patients with IIM representing the major clinicopathologic groups (n = 571). We confirmed that alleles of the 8.1 ancestral haplotype were important risk markers for the development of IIM, and a random forests classification analysis suggested that within this haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal HLA risk factors. In addition, we identified several novel HLA factors associated distinctly with 1 or more clinicopathologic groups of IIM. The DQA1*0201 allele and associated peptide-binding motif ( 47KLPLFHRL54) were exclusive protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM) and inclusion body myositis (IBM) (pc <0.005). In contrast, HLA-A*68 alleles were significant risk factors for dermatomyositis (DM) (pc = 0.0021), a distinct clinical group thought to involve a humorally mediated immunopathology. While the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and DM patients (p <0.05), DQA1*03 alleles were protective factors for IBM (pc = 0.0002). Myositis associated with malignancies was the most distinctive group of IIM wherein HLA Class I alleles were the only identifiable susceptibility factors and a shared HLA-Cw peptide-binding motif ( 90AGSHTLQWM98) conferred significant risk (pc = 0.019). Together, these data suggest that HLA susceptibility markers distinguish different myositis phenotypes with divergent pathogenetic mechanisms. These variations in associated HLA polymorphisms may reflect responses to unique environmental triggers resulting in the tissue pathospecificity and distinct clinicopathologic syndromes of the IIM.",
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T2 - Distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in Caucasians

AU - O'Hanlon, Terrance P.

AU - Carrick, Danielle Mercatante

AU - Arnett, Frank C.

AU - Reveille, John D.

AU - Carrington, Mary

AU - Gao, Xiaojiang

AU - Oddis, Chester V.

AU - Morel, Penelope A.

AU - Malley, James D.

AU - Malley, Karen

AU - Dreyfuss, Jonathan

AU - Shamim, Ejaz A.

AU - Rider, Lisa G.

AU - Chanock, Stephen J.

AU - Foster, Charles B.

AU - Bunch, Thomas

AU - Plotz, Paul H.

AU - Love, Lori A.

AU - Miller, Frederick W.

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N2 - The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases in which autoimmune pathology is suspected to promote chronic muscle inflammation and weakness. We have performed low to high resolution genotyping to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci in a large population of North American Caucasian patients with IIM representing the major clinicopathologic groups (n = 571). We confirmed that alleles of the 8.1 ancestral haplotype were important risk markers for the development of IIM, and a random forests classification analysis suggested that within this haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal HLA risk factors. In addition, we identified several novel HLA factors associated distinctly with 1 or more clinicopathologic groups of IIM. The DQA1*0201 allele and associated peptide-binding motif ( 47KLPLFHRL54) were exclusive protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM) and inclusion body myositis (IBM) (pc <0.005). In contrast, HLA-A*68 alleles were significant risk factors for dermatomyositis (DM) (pc = 0.0021), a distinct clinical group thought to involve a humorally mediated immunopathology. While the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and DM patients (p <0.05), DQA1*03 alleles were protective factors for IBM (pc = 0.0002). Myositis associated with malignancies was the most distinctive group of IIM wherein HLA Class I alleles were the only identifiable susceptibility factors and a shared HLA-Cw peptide-binding motif ( 90AGSHTLQWM98) conferred significant risk (pc = 0.019). Together, these data suggest that HLA susceptibility markers distinguish different myositis phenotypes with divergent pathogenetic mechanisms. These variations in associated HLA polymorphisms may reflect responses to unique environmental triggers resulting in the tissue pathospecificity and distinct clinicopathologic syndromes of the IIM.

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