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Sarcoidosis is a systemic inflammatory disease characterized by the formation of granulomas in affected organs. Genome-wide association studies (GWASs) of this disease have been conducted only in European population. We present the first sarcoidosis GWAS in African Americans (AAs, 818 cases and 1,088 related controls) followed by replication in independent sets of AAs (455 cases and 557 controls) and European Americans (EAs, 442 cases and 2,284 controls). We evaluated >6 million SNPs either genotyped using the Illumina Omni1-Quad array or imputed from the 1000 Genomes Project data. We identified a novel sarcoidosis-associated locus, NOTCH4, that reached genome-wide significance in the combined AA samples (rs715299, P(AA-meta) = 6.51 × 10(-10)) and demonstrated the independence of this locus from others in the MHC region in the same sample. We replicated previous European GWAS associations within HLA-DRA, HLA-DRB5, HLA-DRB1, BTNL2, and ANXA11 in both our AA and EA datasets. We also confirmed significant associations to the previously reported HLA-C and HLA-B regions in the EA but not AA samples. We further identified suggestive associations with several other genes previously reported in lung or inflammatory diseases.

Sarcoidosis is a multisystem disease of unknown cause. Löfgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis. To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects. A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated. Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region.

Sarcoidosis is a complex, multi-organ granulomatous disease with a likely genetic component. West African ancestry confers a higher risk for sarcoidosis than European ancestry. Admixture mapping provides the most direct method to locate genes that underlie such ethnic variation in disease risk. We sought to identify genetic risk variants within four previously-identified ancestry-associated regions-6p24.3-p12.1, 17p13.3-13.1, 2p13.3-q12.1, and 6q23.3-q25.2-in a sample of 2,727 African Americans. We used logistic regression fit by generalized estimating equations and the MIX score statistic to determine which variants within ancestry-associated regions were associated with risk and responsible for the admixture signal. Fine mapping was performed by imputation, based on a previous genome-wide association study; significant variants were validated by direct genotyping. Within the 6p24.3-p12.1 locus, the most significant ancestry-adjusted SNP was rs74318745 (p = 9.4*10-11), an intronic SNP within the HLA-DRA gene that did not solely explain the admixture signal, indicating the presence of more than a single risk variant within this well-established sarcoidosis risk region. The locus on chromosome 17p13.3-13.1 revealed a novel sarcoidosis risk SNP, rs6502976 (p = 9.5*10-6), within intron 5 of the gene X-linked Inhibitor of Apoptosis Associated Factor 1 (XAF1) that accounted for the majority of the admixture linkage signal. Immunohistochemical expression studies demonstrated lack of expression of XAF1 and a corresponding high level of expression of its downstream target, X-linked Inhibitor of Apoptosis (XIAP) in sarcoidosis granulomas. In conclusion, ancestry and association fine mapping revealed a novel sarcoidosis susceptibility gene, XAF1, which has not been identified by previous genome-wide association studies. Based on the known biology of the XIAP/XAF1 apoptosis pathway and the differential expression patterns of XAF1 and XIAP in sarcoidosis granulomas, we suggest that this pathway may play a role in the maintenance of sarcoidosis granulomas.

Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS). A meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden ( = 3,843), Germany ( = 3,342), and the United States ( = 2,918), followed by an SNP lookup in the UK Biobank (UKB, = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex. We identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and . Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified. Our findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis.

Sarcoidosis affects people of all racial and ethnic groups and occurs at any age, although usually before the age of 50 years. The incidence of sarcoidosis varies widely throughout the world, probably because of differences in environmental exposures, case-surveillance methods, and predisposing HLA alleles, along with other genetic factors. This article summarizes advances in our understanding of sarcoidosis and addresses pitfalls in its diagnosis and treatment. This article summarizes advances in our understanding of sarcoidosis and addresses pitfalls in its diagnosis and treatment. The modern history of sarcoidosis, an enigmatic multisystem disease, goes back to 1899, when the pioneering Norwegian dermatologist Caesar Boeck coined the term to describe skin nodules characterized by compact, sharply defined foci of “epithelioid cells with large pale nuclei and also a few giant cells.” 1 Thinking this resembled sarcoma, he called the condition “multiple benign sarcoid of the skin.” 1 Since sarcoidosis was last reviewed in the Journal 10 years ago, 2 more than 5000 articles related to this condition have been published. This review summarizes recent advances and addresses pitfalls in the diagnosis and treatment of sarcoidosis. Epidemiology Sarcoidosis affects . . .

[This corrects the article DOI: 10.3389/fmed.2023.1132799.].

Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms. Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.

Sarcoidosis is a systemic granulomatous disease with predominant pulmonary involvement and vast heterogeneity of clinical manifestations and disease outcomes. African American (AA) patients suffer greater morbidity and mortality. Using Multiple Correspondence Analysis, we identified seven clusters of organ involvement in European American (EA; n = 385) patients which were similar to those previously described in a Pan-European (GenPhenReSa) and a Spanish cohort (SARCOGEAS). In contrast, AA (n = 987) had six, less well-defined and overlapping clusters with little similarity to the cluster identified in the EA cohort evaluated at the same U.S. institutions. Association of cluster membership with two-digit HLA-DRB1 alleles demonstrated ancestry-specific patterns of association and replicated known HLA effects. These results further support the notion that genetically influenced immune risk profiles, which differ based on ancestry, play a role in phenotypic heterogeneity. Dissecting such risk profiles will move us closer to personalized medicine for this complex disease.

To determine whether certain occupations and occupationally related exposures were associated with a history of sarcoidosis in African-American siblings. We collected occupational data from 921 African Americans in 273 sibships that had been identified through a sarcoidosis case. Among the 648 siblings of sarcoidosis index cases enrolled, 30 (4.6%) also had a history of sarcoidosis. A detailed job history was obtained for any job held for ≥ 6 months throughout the subject’s life. Having a usual occupation in education (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.07 to 4.44), in metal machining (OR, 7.47; 95% CI, 1.19 to 47.06), and ever working in metalworking, not elsewhere classified (OR, 2.05; 95% CI, 1.14 to 3.70) were associated with increased sarcoidosis risk. Occupations ever held in the transportation services industry (OR, 12.71; 95% CI, 1.32 to 122.56) and usual occupations in the retail trade industry (OR, 0.49; 95% CI, 0.27 to 0.88) also were associated with sarcoidosis risk. Specific occupational exposures that were associated with sarcoidosis included titanium (OR, 3.15; 95% CI, 1.02 to 9.68) and vegetable dust (OR, 1.82; 95% CI, 1.01 to 3.27), and indoor exposure to high humidity (OR, 1.51; 95% CI, 1.13 to 2.02), water damage (OR, 1.50; 95% CI, 1.11 to 2.03), or musty odors (OR, 1.78; 95% CI, 1.32 to 2.40) for > 1 year. Individuals who work in occupations with potential metal exposures or in workplaces with high humidity may be at an increased risk for sarcoidosis, but the complexity of occupationally related exposures makes it difficult to identify specific agents by using job titles as a surrogate for exposure. A more detailed exposure assessment of such jobs, along with the incorporation of genetic risk factors, should help to uncover the complex etiology of sarcoidosis.

HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA-DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA-DRB1 alleles *12:01 (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.65-2.69; P = 3.2 × 10(-9)) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 × 10(-9)). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 × 10(-5)). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 × 10(-4)), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans.