A genome-wide association study reveals evidence of association with sarcoidosis at6p12.1

Abstract

Sarcoidosis is a complex systemic inflammatory disease of unknown aetiology that is influenced by a variety of genetic and environmental factors.\ud To identify further susceptibility loci for sarcoidosis, a genome-wide association study (GWAS) was conducted in 381 patients and 392 control individuals based on Affymetrix 100k GeneChip data. The top 25 single-nucleotide polymorphisms (SNPs) were selected for validation in an independent study panel (1,582 patients versus 1,783 controls).\ud Variant rs10484410 on chromosome 6p12.1 was significantly associated, with a Bonferroni-corrected p-value of 2.90×10−2 in the validation sample and a nominal p-value of 2.64×10−4 in the GWAS. Extensive fine mapping of the novel locus narrowed down the signal to a region comprising the genes BAG2, C6orf65, KIAA1586, ZNF451 and RAB23. Verification of the sarcoidosis-associated nonsynonymous SNP rs1040461 in a further independent case–control sample and quantitative mRNA expression studies point to the RAB23 gene as the most likely risk factor. RAB23 is proposed to be involved in antibacterial defence processes and regulation of the sonic hedgehog signalling pathway.\ud The identified association of the 6p12.1 locus with sarcoidosis implicates this locus as a further susceptibility factor and RAB23 as a potential signalling component that may open up new perspectives in the pathophysiology of sarcoidosis

Update in Diffuse Parenchymal Lung Disease 2011

“…Thus, in susceptible individuals, inanimate remnants of bacteria or remote infection may be capable of inducing sustained sarcoid-like inflammation (51,52). The nature of these disease susceptibilities may be queried in genome-wide association studies, which have identified a number of gene variants associated with sarcoidosis and other granulomatous disorders (53)(54)(55). Another approach is the identification of molecular signatures by systems biology approaches using peripheral blood cells or lung tissue.…”

Specific antigen(s) in sarcoidosis: a link to autoimmunity?

“…Autoantigens may derive from misfolded proteins that are insufficiently cleared. It could be demonstrated that single-nucleotide polymorphisms in the OS9 [21] and RAB23 [22] genes are associated with an increased risk of sarcoidosis. Both genes are assumed to be involved in the regulation of the degradation of misfolded proteins or the generation of autophagosomes.…”

Sarcoidosis from bench to bedside: a state-of-the-art series for the clinician

“…Familial clustering of sarcoidosis may be found in 5-10% of patients, and represents, together with genome-wide scanning for susceptibility genes [28], one of the best ways to progress in the understanding of this disease of elusive aetiology. In 2005, dentification of butyrophilin-like-2 as a main genetic determinant of sarcoidosis was reported [29].…”