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.

Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans

“…To test for heterogeneity of each allelic association by study, multiplicative interaction terms comprising the specific allele and study terms were included in each model, with statistical significance evaluated using a two-degree-of-freedom Wald test. Heterogeneity by local West African ancestry at DRB1 (0, 1, or 2 African segments) was evaluated in the same manner, where local West African ancestry was estimated using the Local Ancestry in Admixed Populations method (36) as part of a prior publication (37). Except where otherwise noted, all analyses were performed using the R programming language (version 2.15.1; R Foundation for Statistical Computing, Vienna, Austria).…”

Sarcoidosis: the links between epidemiology and aetiology

“…More recently, several studies have identified multiple gene loci associated with the risk of sarcoidosis, on chromosomes 1, 2, 5, 6, 9, 11, 12, and 20 33–36. Differences in disease susceptibility between ancestral populations have also been used to identify genetic loci associated with disease and ancestry 47 48. The genetic influence on the clinical presentation is illustrated by those of African origin having a preponderance for extra-thoracic involvement, more severe disease, and a lower likelihood of spontaneous remission 7 49…”

A robust and powerful two‐step testing procedure for local ancestry adjusted allelic association analysis in admixed populations

“…A number of advanced LA inference methods have been developed to infer LA down to the marker level from high throughput genotyping or sequencing data in admixed samples (Baran, et al., ; Patterson, et al., ; Price, et al., ; Wang, et al., ). Using the estimated LA for each marker and the derived global ancestry, association studies have been performed by adjusting for LA as a covariate (Levin, et al., ), by conducting Single Nucleotide Polymorphism (SNP) and admixture mapping separately using the same set of markers (Chen, et al., ; Reiner, et al., ) or by selecting a subset of African ancestry individuals for subsequent analysis (Li, et al., ).…”