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.

Novel genetic loci, lifestyle factors, and inflammatory markers identified as risk factors for sarcoidosis

“…This study confirmed eight reported sarcoidosis-associated loci that are rs2024825 near IL23R, 16,17 rs72928971 near FAM117B, 16 rs3131856 near HLA-DQA1, [11][12][13] rs873973 near CCL24, 17 rs2573346 near ANXA11, 12,13,17,43 rs663743 near CCDC88B, 16 rs3184504 near SH2B3, 16 and rs34536443 near TYK2 16 in independent data. Successful replication of these findings in our data reflects a good validity of our analysis.…”

“…HLA-DQA1 is a key genomic area implicated in immune-mediated diseases, suggests its potential involvement in the genetic underpinnings of sarcoidosis. 11,44 However, given the complexity of HLA gene region, the roles of variants in HLA region varied by ancestry. 45,46 For example, the HLA-DRB1*03:01 allele demonstrated a dual association with augmented susceptibility and disease resolution among patients with Löfgren's syndrome of European ancestry.…”

“…9 In recent decades, considerable efforts have been directed toward unveiling the genetic foundation of sarcoidosis. 10 While many genetic loci nearby genes, like MHC, [11][12][13] ANXA11, 13,14 CCDC88B, 15 and IL23, 16,17 linked to sarcoidosis susceptibility have been pinpointed, the complete genetic spectrum influencing predisposition to the disease remains obscured. Many of these earlier investigations might have been limited by modest sample sizes 11 or the dependence on targeted genotyping platforms such as ImmunoChip, 12,16,18 potentially overlooking broader genetic variations associated with sarcoidosis risk.…”

“…10 While many genetic loci nearby genes, like MHC, [11][12][13] ANXA11, 13,14 CCDC88B, 15 and IL23, 16,17 linked to sarcoidosis susceptibility have been pinpointed, the complete genetic spectrum influencing predisposition to the disease remains obscured. Many of these earlier investigations might have been limited by modest sample sizes 11 or the dependence on targeted genotyping platforms such as ImmunoChip, 12,16,18 potentially overlooking broader genetic variations associated with sarcoidosis risk. To address these gaps, we conducted a genome-wide association study (GWAS), harnessing data from two large-scale studies, aiming to capture a more comprehensive genetic landscape of sarcoidosis.…”

Exploring the Role of Genetics in Sarcoidosis and Its Impact on the Development of Cardiac Sarcoidosis

“…The significance of these genetic imprints is important in the phenotypic classification of patients and in recognizing the predictive value of the prognosis of sarcoidosis. HLA-B7 [73] HLA-B8 [74] HLA-B*51 [75] HLA-C [58] HLA-DPA1/DPB1 [58] HLA-DPB1 (*0101) [61] HLA-DQA1*0301 [76] HLA-DQA1*0501 [77]: HLA-DQA1*0505 [58] HLA-DQB1*0201 [76] HLA-DQB1*0302 [58] HLA-DQB1*0503/4 [76] HLA-DQB1*0601 [78]:…”