title: Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans.
abstract: HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA-DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA-DRB1 alleles *12:01 (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.65-2.69; P = 3.2 × 10(-9)) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 × 10(-9)). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 × 10(-5)). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 × 10(-4)), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans.
authors.affiliation: 1 Department of Public Health Sciences and.|2 Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Levin
authors.affiliation: 3 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
authors.forename: Indra
authors.initials: I
authors.lastname: Adrianto
authors.affiliation: 1 Department of Public Health Sciences and.|2 Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan.
authors.forename: Indrani
authors.initials: I
authors.lastname: Datta
authors.affiliation: 4 Department of Medicine, Upstate Medical University, Syracuse, New York; and.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Iannuzzi
authors.affiliation: 1 Department of Public Health Sciences and.
authors.forename: Sheri
authors.initials: S
authors.lastname: Trudeau
authors.affiliation: 1 Department of Public Health Sciences and.|2 Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: 5 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Wonder P
authors.initials: WP
authors.lastname: Drake
authors.affiliation: 3 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Montgomery
authors.affiliation: 1 Department of Public Health Sciences and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Rybicki
mesh_terms: D001741:Black or African American / Q000235:genetics; D016022:Case-Control Studies; D018450:Disease Progression; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D017565:Sarcoidosis, Pulmonary / Q000208:ethnology / Q000235:genetics* / Q000473:pathology
chemical_list: D059811:HLA-DRB1 Chains
keywords: HLA-DRB1 chains; SNPs; association studies; genetic; molecular docking simulation; pulmonary sarcoidosis