Genome-wide association study identifies multiple HLA loci for sarcoidosis susceptibility

Abstract

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; 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 1,335 sarcoidosis cases and 1,264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1,487 cases and 1,504 controls). The EA cohort was recruited from National Jewish Health, Cleveland Clinic, University of California San Francisco, and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis. The AA cohort was from a previous study with subjects enrolled 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. 49 SNPs in HLA-DRA, -DRB9, -DRB5, -DQA1, and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA. Among them, 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. In summary, we identified several novel SNPs and three HLA alleles associated with sarcoidosis susceptibility in the largest EA population evaluated to date using an integrative analysis of genetics and transcriptomics. We also replicated our findings in an AA population.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was funded by National Institutes of Health Grants U01 HL112707, U01 HL112694, U01 HL112695, U01 HL112696, U01 HL112702, U01 HL112708, U01 HL112711, U01 HL112712, UL1 RR029882, UL1 RR025780, R01 HL110883, R01 HL114587, R01HL114587; Clinical and Translational Science Institute Grant U54 9 UL1 TR000005; and Centers for Disease Control and Prevention National Mesothelioma Virtual Bank for Translational Research Grant 5 U24 OH009077; and Foundation for Sarcoidosis Research (FSR).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Institutional Review Board at National Jewish Health (HS2765) gave ethical approval for this work. Institutional review board through Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) (HS2780) gave ethical approval for this work.

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Yes

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Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors

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