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Fas promoter polymorphisms: genetic predisposition to sarcoidosis in African-Americans.

ABSTRACT: Apoptosis may perpetuate some forms of inflammation. Of the apoptotic pathway proteins, Fas is particularly overexpressed in sarcoidosis. We hypothesized that Fas promoter single nucleotide polymorphisms (SNPs) contribute to the development and severity of sarcoidosis. Associations of known Fas promoter SNPs (-670, -690 and -1377) and deduced haplotypes with sarcoidosis and sarcoidosis severity were evaluated using matched case-control (n = 656 pairs) and case-comparison (n = 656) studies, respectively, using conditional logistic regression. Hardy-Weinberg equilibrium was confirmed for all three polymorphisms in African-Americans (AA), and for the -670 and -1377 in whites. Genotype and allele frequencies were significantly different between whites and AA. Race-stratified analysis revealed that a common haplotype, -1377G/-690T/-670G, was associated with sarcoidosis [odds ratio (OR) = 1.78, P = 0.05] only in AA. The haplotype -1377G/-690C/-670A was negatively associated with sarcoidosis (OR = 0.39, P = 0.03) only in AA. In conclusion, the consistency of these findings suggests that Fas promoter genetic variants may be related to sarcoidosis disease risk in AA.

SUBMITTER: Wasfi YS

PROVIDER: S-EPMC3061555 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Fas promoter polymorphisms: genetic predisposition to sarcoidosis in African-Americans.

Wasfi Y S YS Silveira L J LJ Jonth A A Hokanson J E JE Fingerlin T T Sato H H Parsons C E CE Lympany P P Welsh K K du Bois R M RM Newman L S LS Maier L A LA

Tissue antigens 20080701 1

Apoptosis may perpetuate some forms of inflammation. Of the apoptotic pathway proteins, Fas is particularly overexpressed in sarcoidosis. We hypothesized that Fas promoter single nucleotide polymorphisms (SNPs) contribute to the development and severity of sarcoidosis. Associations of known Fas promoter SNPs (-670, -690 and -1377) and deduced haplotypes with sarcoidosis and sarcoidosis severity were evaluated using matched case-control (n = 656 pairs) and case-comparison (n = 656) studies, respe ...[more]

PMID: 18588573

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Project description: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.

Project description: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.

Dataset Information

Fas promoter polymorphisms: genetic predisposition to sarcoidosis in African-Americans.

Publications

Fas promoter polymorphisms: genetic predisposition to sarcoidosis in African-Americans.

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