Genome-Wide Association Study Identifies Multiple HLA Loci for Sarcoidosis Susceptibility

Details

• Personal Author:
  Barkes BQ ; Culver DA ; Fingerlin TE ; GRADs Investigators ; Hamzeh NY ; Jacobson S ; Koth LL ; Langefeld CD ; Leach SM ; Liao S-Y ; Macphail K ; Maier LA ; Montgomery C ; Mroz M ; Pacheco, Karin ; Patel DC ; Wasfi YS ; White E
• Description:
  Sarcoidosis is a complex systemic disease. Our study aimed to (1) identify novel alleles associated with sarcoidosis susceptibility; (2) provide an in-depth evaluation of HLA alleles and sarcoidosis susceptibility and (3) integrate genetic and transcription data to identify risk loci that may more directly impact disease pathogenesis. We report a genome-wide association study of 1335 sarcoidosis cases and 1264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1487 cases and 1504 controls). The EA and AA cohort was recruited from multiple United States sites. HLA alleles were imputed and tested for association with sarcoidosis susceptibility. Expression quantitative locus and colocalization analysis were performed using a subset of subjects with transcriptome data. Forty-nine SNPs in the HLA region in HLA-DRA, -DRB9, -DRB5, -DQA1 and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA, rs3129888 was also a risk variant for sarcoidosis in AA. Classical HLA alleles DRB1*0101, DQA1*0101 and DQB1*0501, which are highly correlated, were also associated with sarcoidosis. rs3135287 near HLA-DRA was associated with HLA-DRA expression in peripheral blood mononuclear cells and bronchoalveolar lavage from subjects and lung tissue and whole blood from GTEx. We identified six novel SNPs (out of the seven SNPs representing the 49 significant SNPs) and nine HLA alleles associated with sarcoidosis susceptibility in the largest EA population. We also replicated our findings in an AA population. Our study reiterates the potential role of antigen recognition and/or presentation HLA class II genes in sarcoidosis pathogenesis. [Description provided by NIOSH]
• Subjects:
  Antigens Cohort Studies Genetics Immune System Occupational Health Safety
• Keywords:
  Cohort Studies Genes Genomics Immune Reaction Leukocytes Pathogenesis Sarcoidosis
• ISSN:
  0964-6906
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  California ; Colorado ; Florida ; Iowa ; North Carolina ; Ohio ; Oklahoma ; OSHA Region 3 ; OSHA Region 4 ; OSHA Region 5 ; OSHA Region 6 ; OSHA Region 7 ; OSHA Region 8 ; OSHA Region 9 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  32
• Issue:
  16
• NIOSHTIC Number:
  nn:20068538
• Citation:
  Hum Mol Genet 2023 Aug; 32(16):2669-2678
• Contact Point Address:
  Tasha E Fingerlin, Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA
• Email:
  fingerlint@njhealth.org
• Federal Fiscal Year:
  2023
• NORA Priority Area:
  Construction ; Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20060901
• Source Full Name:
  Human Molecular Genetics
• End Date:
  20260831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:1847659f163c4e1efb946d0157038b32247e3e03215f0d7851ee12d1062f1c7ff504799878ffbd39bab51d14fbcda543cf88e7ab2c5c73aa95bf070d310d95cc
• Download URL:
  https://stacks.cdc.gov/view/cdc/207149/cdc_207149_DS1.pdf
• File Type:
  [PDF - 697.49 KB ]