title: Admixture fine-mapping in African Americans implicates XAF1 as a possible sarcoidosis risk gene.
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.
authors.affiliation: Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, United States of America.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Levin
authors.affiliation: Department of Medicine, Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Iannuzzi
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Montgomery
authors.affiliation: Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, United States of America.
authors.forename: Sheri
authors.initials: S
authors.lastname: Trudeau
authors.affiliation: Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, United States of America.
authors.forename: Indrani
authors.initials: I
authors.lastname: Datta
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
authors.forename: Indra
authors.initials: I
authors.lastname: Adrianto
authors.affiliation: Department of Pathology, Henry Ford Health System, Detroit, Michigan, United States of America.
authors.forename: Dhananjay A
authors.initials: DA
authors.lastname: Chitale
authors.affiliation: Public Health Sciences Section, University of Edinburgh Medical School, Edinburgh, Scotland, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: McKeigue
authors.affiliation: Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, United States of America.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Rybicki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D051017:Apoptosis Regulatory Proteins; D002874:Chromosome Mapping; D019295:Computational Biology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D011859:Radiography; D012507:Sarcoidosis / Q000000981:diagnostic imaging / Q000208:ethnology* / Q000235:genetics*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C417551:XAF1 protein, human