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

Shu-Yi Liao; Sean Jacobson; Nabeel Y Hamzeh; Daniel A Culver; Briana Q Barkes; Margarita Mroz; Kristyn Macphail; Karin Pacheco; Divya C Patel; Yasmine S Wasfi; Laura L Koth; Carl D Langefeld; Sonia M Leach; Elizabeth White; Courtney Montgomery; Lisa A Maier; Tasha E Fingerlin; GRADs Investigators

doi:10.1093/hmg/ddad067

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

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

Shu-Yi Liao, Sean Jacobson, Nabeel Y Hamzeh, Daniel A Culver, Briana Q Barkes, Margarita Mroz, Kristyn Macphail, Karin Pacheco, Divya C Patel, Yasmine S Wasfi, …

Human molecular genetics, Vol.32(16), pp.2669-2678

08/15/2023

DOI: 10.1093/hmg/ddad067

PMCID: PMC10407706

PMID: 37399103

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Abstract

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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Title: Subtitle: Genome-wide association study identifies multiple HLA loci for sarcoidosis susceptibility
Creators: Shu-Yi Liao
Sean Jacobson
Nabeel Y Hamzeh
Daniel A Culver
Briana Q Barkes
Margarita Mroz
Kristyn Macphail
Karin Pacheco
Divya C Patel
Yasmine S Wasfi
Laura L Koth
Carl D Langefeld
Sonia M Leach
Elizabeth White
Courtney Montgomery
Lisa A Maier
Tasha E Fingerlin
GRADs Investigators
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.32(16), pp.2669-2678
DOI: 10.1093/hmg/ddad067
PMID: 37399103
PMCID: PMC10407706
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: 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
Language: English
Electronic publication date: 07/03/2023
Date published: 08/15/2023
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
Record Identifier: 9984443159902771

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