ArticlePloS one2014
Admixture fine-mapping in African Americans implicates XAF1 as a possible sarcoidosis risk gene.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis.Communications biology · 2020Pooled it
- Immune mechanisms of granuloma formation in sarcoidosis and tuberculosis.The Journal of clinical investigation · 2024Review
- Identification of Environmental Exposures Associated with Risk of Sarcoidosis in African Americans.Annals of the American Thoracic Society · 2023Article
- Genome-wide association study identifies multiple HLA loci for sarcoidosis susceptibility.Human molecular genetics · 2023Article
- Offense and Defense in Granulomatous Inflammation Disease.Frontiers in cellular and infection microbiology · 2022Review
- Epigenetics and sarcoidosis.European respiratory review : an official journal of the European Respiratory Society · 2021Review
- Current Insights in Genetics of Sarcoidosis: Functional and Clinical Impacts.Journal of clinical medicine · 2020Review
- Next-Generation Sequencing Profiles of the Methylome and Transcriptome in Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis.Journal of clinical medicine · 2019Article
- A robust and powerful two-step testing procedure for local ancestry adjusted allelic association analysis in admixed populations.Genetic epidemiology · 2018Article
- Genetic, Immunologic, and Environmental Basis of Sarcoidosis.Annals of the American Thoracic Society · 2017Review
- Application of "Omics" and Systems Biology to Sarcoidosis Research.Annals of the American Thoracic Society · 2017Review
- Polygenic risk assessment reveals pleiotropy between sarcoidosis and inflammatory disorders in the context of genetic ancestry.Genes and immunity · 2017Article
- Fine mapping of chromosome 15q25 implicates ZNF592 in neurosarcoidosis patients.Annals of clinical and translational neurology · 2015Article
- Granuloma genes in sarcoidosis: what is new?Current opinion in pulmonary medicine · 2015Review
- Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans.American journal of respiratory cell and molecular biology · 2015Article
- Performance of HLA allele prediction methods in African Americans for class II genes HLA-DRB1, -DQB1, and -DPB1.BMC genetics · 2014Article
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9 authors at 5 institutions in 2 countries.
Funding
Abstract
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.
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