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. 2023 Aug 7;32(16):2669-2678.
doi: 10.1093/hmg/ddad067.

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

Shu-Yi Liao  1   2   3 , Sean Jacobson  1 , Nabeel Y Hamzeh  4 , Daniel A Culver  5 , Briana Q Barkes  1 , Margarita Mroz  1 , Kristyn Macphail  1 , Karin Pacheco  1   2   3 , Divya C Patel  6 , Yasmine S Wasfi  7 , Laura L Koth  8 , Carl D Langefeld  9   10 , Sonia M Leach  1 , Elizabeth White  1 , Courtney Montgomery  11 , Lisa A Maier  1   2   3 , Tasha E Fingerlin  2   3   12 ; GRADs Investigators
Affiliations

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

Shu-Yi Liao et al. Hum Mol Genet. .

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 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.

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Conflict of interest statement

None declared.

Figures

Figure 1
Figure 1
CONSORT flow chart for the GWAS samples. This figure outlines the exclusion of the subject in Phase 1 and Phase 2, respectively.
Figure 2
Figure 2
(A) Manhattan plot for SNP associations, with significant associations in the HLA region of chromosome 6. Upper line: genome-wide significance line (P = 5 × 10−8). Lower line: (P = 10−5). (B) Locus-zoom plot for significant SNPs on chromosome 6 (position: 32381726–32 984 689); rs9269233 is the most significant SNP and r2 values with other significant SNPs are low.
Figure 3
Figure 3
(A) PBMC DQB1 gene expression (variance stabilizing transformation [VST] normalized counts) and presence/absence of DRB1*0101 allele. Individuals with one DRB1*0101 allele have higher PBMC DQB1 gene expression compared with those with none. (B) BAL DRB9 gene expression (VST normalized counts) and presence/absence of DRB1*0101 allele. Individuals with one DRB1*0101 allele have higher BAL DRB9 gene expression.
See this image and copyright information in PMC

References

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