title: Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profiles distinguish European American patients with different myositis autoantibodies.
abstract: The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases defined by chronic muscle inflammation and weakness associated with autoimmunity. We have performed low to high resolution molecular typing to assess the genetic variability of major histocompatibility complex loci (HLA-A, -B, -Cw, -DRB1, and -DQA1) in a large population of European American patients with IIM (n = 571) representing the major myositis autoantibody groups. We established that alleles of the 8.1 ancestral haplotype (8.1 AH) are important risk factors for the development of IIM in patients producing anti-synthetase/anti-Jo-1, -La, -PM/Scl, and -Ro autoantibodies. Moreover, a random forests classification analysis suggested that 8.1 AH-associated alleles B*0801 and DRB1*0301 are the principal HLA risk markers. In addition, we have identified several novel HLA susceptibility factors associated distinctively with particular myositis-specific (MSA) and myositis-associated autoantibody (MAA) groups of the IIM. IIM patients with anti-PL-7 (anti-threonyl-tRNA synthetase) autoantibodies have a unique HLA Class I risk allele, Cw*0304 (pcorr = 0.046), and lack the 8.1 AH markers associated with other anti-synthetase autoantibodies (for example, anti-Jo-1 and anti-PL-12). In addition, HLA-B*5001 and DQA1*0104 are novel potential risk factors among anti-signal recognition particle autoantibody-positive IIM patients (pcorr = 0.024 and p = 0.010, respectively). Among those patients with MAA, HLA DRB1*11 and DQA1*06 alleles were identified as risk factors for myositis patients with anti-Ku (pcorr = 0.041) and anti-La (pcorr = 0.023) autoantibodies, respectively. Amino acid sequence analysis of the HLA DRB1 third hypervariable region identified a consensus motif, 70D (hydrophilic)/71R (basic)/74A (hydrophobic), conferring protection among patients producing anti-synthetase/anti-Jo-1 and -PM/Scl autoantibodies. Together, these data demonstrate that HLA signatures, comprising both risk and protective alleles or motifs, distinguish IIM patients with different myositis autoantibodies and may have diagnostic and pathogenic implications. Variations in associated polymorphisms for these immune response genes may reflect divergent pathogenic mechanisms and/or responses to unique environmental triggers in different groups of subjects resulting in the heterogeneous syndromes of the IIM.
authors.affiliation: From National Institute of Environmental Health Sciences (TPO, DMC, EAS, LGR, PJB, FWM), Center for Information Technology (JDM), National Cancer Institute (SJC), and National Institute of Arthritis and Musculoskeletal Disease (PHP) National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; Veterans Affairs Medical Center (IRT), University of Oklahoma Health Sciences Center, and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; University of Texas-Houston Health Science Center (FCA, JDR), Houston, Texas; Basic Research Program (MC, XG), SAIC Frederick National Cancer Institute, Frederick, Maryland; University of Pittsburgh School of Medicine (CVO, PAM), Pittsburgh, Pennsylvania; Malley Research Programming Inc (KM), Rockville, Maryland; Department of Pediatrics (CBF), Johns Hopkins University School of Medicine, Baltimore, Maryland; Mayo Clinic (TB), Rochester, Minnesota; and United States Food and Drug Administration (LAL), Rockville, Maryland.
authors.forename: Terrance P
authors.initials: TP
authors.lastname: O'Hanlon
authors.forename: Danielle Mercatante
authors.initials: DM
authors.lastname: Carrick
authors.forename: Ira N
authors.initials: IN
authors.lastname: Targoff
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Gao
authors.forename: Chester V
authors.initials: CV
authors.lastname: Oddis
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Morel
authors.forename: James D
authors.initials: JD
authors.lastname: Malley
authors.forename: Karen
authors.initials: K
authors.lastname: Malley
authors.forename: Ejaz A
authors.initials: EA
authors.lastname: Shamim
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Rider
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Charles B
authors.initials: CB
authors.lastname: Foster
authors.forename: Thomas
authors.initials: T
authors.lastname: Bunch
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.forename: Paul H
authors.initials: PH
authors.lastname: Plotz
authors.forename: Lori A
authors.initials: LA
authors.lastname: Love
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Miller
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D001323:Autoantibodies / Q000032:analysis*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D059848:HLA-DQ alpha-Chains; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D009220:Myositis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D011485:Protein Binding; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; D006680:HLA Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen