Association between Heat Shock Protein 70/Hom Genetic Polymorphisms and Uveitis in Patients with Sarcoidosis

Abstract

PURPOSE. The predisposition to sarcoidosis, a systemic granulomatous disorder of unknown etiology, is genetically determined, and genetics appears also to drive the disease down distinct phenotypic pathways. This study was undertaken to test the hypothesis that sarcoidosis-related uveitis represents a genetically distinct disease subset, by investigating single nucleotide polymorphisms (SNPs) in the HSP-70/1 and HSP-70/ Hom genes. HSP70 molecules play a key role in the immune response by functioning both as chaperones and as inducers of proinflammatory cytokine secretion. METHODS. By sequence-specific primers-polymerase chain reaction (SSP-PCR) five SNPs were evaluated in 270 white patients with sarcoidosis, including 88 with sarcoid-related uveitis, and in 347 matched control subjects. One hundred twentyfive patients with idiopathic anterior uveitis (IAU) and 56 with idiopathic intermediate uveitis (IIU) were also included in the study as disease control subjects. RESULTS. The HSP-70/Hom rs2075800 G allele frequency was higher in the sarcoid-uveitis group than in both the sarcoidnon-uveitis and control groups (83% vs. 71%, OR ϭ 2.00, P c ϭ 0.01; and 83% vs. 66%, OR ϭ 2.45, P c ϭ 0.00005, respectively). Similar results were observed when considering the carriage frequency of the associated haplotype (HSP-70 haplotype 2) across the three study groups (47% vs. 29%, OR ϭ 2.17, P c ϭ 0.03; and 47% vs. 21%, OR ϭ 3.26, P c ϭ 0.0003, respectively). In addition, the carriage frequency of the HSP-70 haplotype 2 discriminated among sarcoid-related uveitis, IAU, and IIU (47% vs. 19%, OR ϭ 3.26, P c ϭ 0.001; and 47% vs. 23%, OR ϭ 2.81, P c ϭ 0.04, respectively). CONCLUSIONS. A strong association was found between HSP-70/ Hom rs2075800 G and uveitis in patients with sarcoidosis. Further studies are needed to understand the molecular mechanisms underlying this association.

Heat Shock Protein 70 Gene Polymorphisms in Sudden Sensorineural Hearing Loss

“…Further studies are needed to address the molecular mechanisms by which the HSP70 gene is involved in the development of SSNHL. The associations of the HSPA1L (HSP70-Hom) SNP rs2075800 with the predisposition to some autoimmune diseases has been documented previously [Jenkins et al, 2000;Bogunia-Kubik et al, 2006;Spagnolo et al, 2007]. The HSPA1L (HSP70-Hom) rs2075800 T allele is associated with rheumatoid arthritis [Jenkins et al, 2000], and the HSPA1L SNP rs2075800 C allele is associated with the susceptibility to sarcoidosis and Lofgren's syndrome [Bogunia-Kubik et al, 2006].…”

“…The HSPA1L (HSP70-Hom) rs2075800 T allele is associated with rheumatoid arthritis [Jenkins et al, 2000], and the HSPA1L SNP rs2075800 C allele is associated with the susceptibility to sarcoidosis and Lofgren's syndrome [Bogunia-Kubik et al, 2006]. A strong association between HSPA1L SNP rs2075800 and the increased risk of uveitis has been reported in patients with sarcoidosis, which suggests that the C allele of this SNP is a risk factor of sarcoidosis-related uveitis [Spagnolo et al, 2007]. Spagnolo et al [2007] postulated that the altered expression of HSPA1L influences the ability of the cell to withstand inflammation or alters the apoptotic threshold within the eye.…”

“…A strong association between HSPA1L SNP rs2075800 and the increased risk of uveitis has been reported in patients with sarcoidosis, which suggests that the C allele of this SNP is a risk factor of sarcoidosis-related uveitis [Spagnolo et al, 2007]. Spagnolo et al [2007] postulated that the altered expression of HSPA1L influences the ability of the cell to withstand inflammation or alters the apoptotic threshold within the eye. However, SNP rs2075800 has not been associated with hearing impairment.…”

“…Extracellular heat shock proteins process and present immunogenic peptides to cytotoxic T cells, activate the innate immune system, and induce proinflammatory cytokine secretion from monocytes [Asea et al, 2000;Srivastava et al, 1994]. Heat shock protein 70 (HSP70) molecules play a key role in the immune response by functioning both as chaperones and inducers of proinflammatory cytokine secretion [Spagnolo et al, 2007].…”

Association of Polymorphisms of Heat Shock Protein 70 with Susceptibility to Noise-Induced Hearing Loss in the Taiwanese Population

“…SNP1 of the HSPA1L gene is a non-synonymous variation; lysine is substituted for glutamate. Spagnolo et al [2007] reported a strong association between HSPA1L SNP rs2075800 and the increased risk of uveitis in patients with sarcoidosis, and suggested that the C allele of this SNP is a risk factor of sarcoidosis-related uveitis. They postulated that the altered expression of HSPA1L may influence the ability of the cell to withstand inflammation or alter the apoptotic threshold within the eye.…”