Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10-8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

Valsalva retinopathy developing during Japanese cheerleading training ("ouendan").

PURPOSE: Valsalva hemorrhagic retinopathy is characterized by retinal hemorrhages that develop after a Valsalva maneuver that consists of a forcible exhalation against a closed glottis, thereby creating a sudden increase in the intrathoracic or intraabdominal pressure. We present a patient who developed retinal and vitreous hemorrhages with multiple retinal nonperfused areas after extreme physical training with shouting on a mountainous area. This exercise was part of his training as a member of a Japanese traditional cheerleading team. METHOD: Case presentation. RESULTS: A 19-year-old man developed an acute decrease in the vision to 0.3 in his left eye after running on hilly roads at approximately 800 m while shouting fight songs for several hours. Ophthalmoscopy showed a fresh vitreous hemorrhage that covered the entire macula and was connected to the optic disk in the left eye. The vitreous hemorrhage spontaneously resolved and an intraretinal hemorrhage and nonperfused area emerged. His visual acuity returned to 1.2. CONCLUSION: Prolonged, strenuous physical exertion with shouting during training exercises can lead to Valsalva hemorrhagic retinopathy. Several other factors, such as hot weather, altitude, and dehydration, may have played an additive role in increasing the venous pressure and hypoxia in the retinal vessels, which then caused the retinopathy.

Genetic characterization and susceptibility for sarcoidosis in Japanese patients: risk factors of BTNL2 gene polymorphisms and HLA class II alleles.

PURPOSE: Sarcoidosis is a heterogeneous and multisystem granulomatous disorder. The etiology still is uncertain, but the disease currently is thought to be triggered by various genetic as well as environmental factors. Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene located in close proximity to the HLA-DRB1 gene was reported. The purpose of our study was to verify the relationship between BTNL2 and HLA risk alleles for the susceptibility to sarcoidosis, and to assess whether the BTNL2 association is independent of the HLA risk alleles. METHODS: In our study, 11 single nucleotide polymorphisms (rs28362677, rs2076533, rs2076530, rs2076529, rs2294881, rs3763304, rs2076523, rs28362682, rs3806156, rs9268499, rs3763317), including the functional rs2076530 (G > A) of the BTNL2 gene, and HLA-DRB1 and -DQB1 alleles, were genotyped in 237 Japanese patients diagnosed with sarcoidosis and 287 healthy Japanese control subjects. RESULTS: In the patient group, the HLA-DRB1*08:03 (P = 6.15 × 10(-5), odds ratio [OR] = 2.43) and BTNL2 rs2076530_A (P = 6.90 × 10(-6), OR = 1.84) were associated with disease susceptibility. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium between BTNL2 rs2076530_A and HLA-DRB1*08:03, our results suggested that the risk-bearing allele of these two loci interact negatively. No significant differences were observed in allele frequencies for alleles in patients with ocular and other systemic sarcoidosis. CONCLUSIONS: Our studies implicated that the HLA-DRB1 allele is a major contributing genetic factor in the development of sarcoidosis in Japan. However, further studies are needed to verify how HLA or BTNL2 alleles confer the disease phenotype, severity of sarcoidosis.

Wavy and elevated retinal pigment epithelial line in optical coherence tomographic images of eyes with atypical Vogt-Koyanagi-Harada disease.

PURPOSE: We report the changes of the retinal pigment epithelium (RPE) determined by optical coherence tomography in a patient with atypical Vogt-Koyanagi-Harada (VKH) disease during the recovery phase. METHOD: Case presentation. RESULTS: A 74-year-old woman presented with a central scotoma associated with disc hyperemia, serous retinal detachment, and scleral thickening in her left eye, and was diagnosed with VKH. OCT showed a serous retinal detachment and a wavy RPE contour that corresponded to the choroidal folds. The OCT images clearly showed the dynamic changes of the retina, RPE, and choroid during the recovery phase. CONCLUSIONS: The OCT was found to be more sensitive in detecting the choroidal folds than angiography. OCT images are valuable not only in the diagnosis, but also for monitoring the morphology of the retina and choroid during the course of VKH.

Lack of association between IL10 polymorphisms and sarcoidosis in Japanese patients.

PURPOSE: To investigate whether interleukin 10 (IL10) gene polymorphisms are associated with the development of sarcoidosis in Japanese patients. METHODS: Two hundred and eighty-eight Japanese sarcoidosis patients and 310 Japanese healthy controls were recruited. We genotyped 9 single-nucleotide polymorphisms in IL10 and assessed the allelic diversity between cases and controls. RESULTS: No significant differences in the frequency of IL10 alleles, genotypes, and haplotypes in the sarcoidosis cases compared to the controls were detected. CONCLUSIONS: Our results suggest that IL10 polymorphisms are not significantly related to the pathogenesis of sarcoidosis in the Japanese population.

Toll-like receptor 2 (TLR2) gene polymorphisms are not associated with sarcoidosis in the Japanese population.

PURPOSE: Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas, with varied clinical manifestations. The common etiology of sarcoidosis is uncertain, but it is thought to be triggered by an exogenous antigenic stimulus, such as some bacterial proteins. Toll-like receptors (TLRs) recognize microbial components and elicit innate as well as adaptive immune responses. It has been reported that polymorphisms in TLR2 might be important in a small group of Caucasian sarcoidosis patients. The present study aimed to establish whether these findings are relevant to the Japanese population. METHODS: We genotyped 5 single-nucleotide polymorphisms (SNPs) in TLR2 and assessed the allelic diversity between 257 Japanese sarcoidosis patients and 193 Japanese healthy controls. RESULTS: No significant differences in the frequency of TLR2 alleles and haplotypes in the sarcoidosis cases were found in comparison with the controls. However, marginal associations were observed for TLR2 at rs3804099 and rs3804100 in sarcoidosis patients with cutaneous manifestations. CONCLUSIONS: Our results suggest that TLR2 polymorphisms are not significantly related to the pathogenesis of sarcoidosis in the Japanese population.

Lack of association between toll-like receptor 4 gene polymorphisms and sarcoidosis-related uveitis in Japan.

PURPOSE: Toll-like receptors (TLRs) are pattern-recognition receptors that play an important role in innate and adaptive immune responses to microbial pathogens. Among TLRs, TLR4 recognizes lipopolysaccharides of Gram-negative bacteria. Genetic polymorphisms within the TLR4 gene have been reported to be associated with various inflammatory diseases; therefore, TLR4 appears to be a susceptibility gene for sarcoidosis. Although sarcoidosis has various clinical manifestations, its association with uveitis is more common in Japan than in other countries. The aim of this study was to investigate whether TLR4 polymorphisms were associated with sarcoidosis-related uveitis in a Japanese population. METHODS: Two hundred twenty-three patients with sarcoidosis and 206 healthy control subjects were recruited at seven sites in Japan. Eight single-nucleotide polymorphisms (SNPs) in TLR4 were genotyped with a TaqMan assay, and allelic and phenotypic diversity were assessed in affected and control subjects. RESULTS: We found no association with susceptibility to sarcoid-related uveitis for any of the SNPs analyzed. Strong linkage disequilibrium was observed among all the SNPs analyzed (D'>/=0.78), which were located in one haplotype block. CONCLUSION: TLR4 polymorphisms do not play an important role in the development of uveitis in Japanese patients with sarcoidosis.

Quantitative analyses of cytomegalovirus genome in aqueous humor of patients with cytomegalovirus retinitis.

PURPOSE: To investigate copy numbers of cytomegalovirus (CMV) in CMV retinitis patients during ganciclovir treatment using real-time polymerase chain reaction (PCR). METHODS: Thirteen aqueous humor samples obtained from 6 patients with clinically diagnosed CMV retinitis were analyzed. As controls, aqueous humor samples were obtained at the time of surgery from patients with senile cataracts. RESULTS: The CMV genome was detected in the range from 10(1) to 10(4) copies/microL of aqueous humor before antiviral treatment. The samples obtained from retinitis patients showing widespread retinal changes contained much higher copy numbers than those from patients with focal lesions. After treatment, the copy number decreased to one hundredth of that observed prior to treatment, but the CMV genome was detectable for 4 to 8 weeks after ganciclovir administration to 4 patients. CONCLUSION: These results revealed the correlation between the copy numbers of the CMV genome and the extent of the area affected by CMV retinitis before antiviral treatment, and the prolonged retention of CMV genome after antiviral treatment. Quantitation of the viral genome after the start of therapy will be of value in determining whether to continue or intensify the dosage of antiviral agents.