Association with Corneal Remodeling Related Genes, ALDH3A1, LOX, and SPARC Genes Variations in Korean Keratoconus Patients

Purpose@#To determine whether the cornea remodeling-related genes aldehyde dehydrogenase 3A1 (ALDH3A1), lysyl oxidase (LOX), and secreted protein acidic and rich in cysteine (SPARC) were potential susceptibility candidate genes for keratoconus in Korean patients, we investigated the associations of single nucleotide polymorphisms (SNPs) in these three genes in Korean patients with keratoconus. @*Methods@#Genomic DNA was extracted from blood samples of unrelated patients with keratoconus and healthy control individuals. For screening of genetic variations, all exons from the entire coding regions of the ALDH3A1, LOX, and SPARC genes were directly sequenced to determine the presence of mutations. Control individuals were selected from the general population without keratoconus. @*Results@#In this study, we detected nine SNPs in ALDH3A1, four SNPs in LOX, and 18 SNPs in SPARC. rs116992290, IVS3-62c>t, rs116962241, and rs2228100 in ALDH3A1 and rs2956540 and rs1800449 in LOX were significantly different between patient and control groups. In the SPARC gene, the distribution of the *G allele of EX10+225 T>G (p = 0.018; odds ratio, 1.869) was strongly associated with the risk of keratoconus in the Korean population. In haplotype analysis, C-G of rs2956540-rs2288393 in LOX(p = 0.046) and C-C-G and G-G-G of rs60610024-rs2228100-rs57555435 (p = 0.021 and p g - rs116962241 in ALDH3A1(p = 0.048) predisposed significantly to keratoconus. After cross-validation consistency and permutation tests, two locus model was the best SNP variations interaction pattern. @*Conclusions@#Our results suggested that genetic variations in ALDH3A1, LOX, and SPARC genes were associated with a predisposition for keratoconus in Korean individuals. Moreover, variations in ALDH3A1 and LOX may serve as strong biomarkers for keratoconus.

Association with Corneal Remodeling Related Genes, ALDH3A1, LOX, and SPARC Genes Variations in Korean Keratoconus Patients

Purpose@#To determine whether the cornea remodeling-related genes aldehyde dehydrogenase 3A1 (ALDH3A1), lysyl oxidase (LOX), and secreted protein acidic and rich in cysteine (SPARC) were potential susceptibility candidate genes for keratoconus in Korean patients, we investigated the associations of single nucleotide polymorphisms (SNPs) in these three genes in Korean patients with keratoconus. @*Methods@#Genomic DNA was extracted from blood samples of unrelated patients with keratoconus and healthy control individuals. For screening of genetic variations, all exons from the entire coding regions of the ALDH3A1, LOX, and SPARC genes were directly sequenced to determine the presence of mutations. Control individuals were selected from the general population without keratoconus. @*Results@#In this study, we detected nine SNPs in ALDH3A1, four SNPs in LOX, and 18 SNPs in SPARC. rs116992290, IVS3-62c>t, rs116962241, and rs2228100 in ALDH3A1 and rs2956540 and rs1800449 in LOX were significantly different between patient and control groups. In the SPARC gene, the distribution of the *G allele of EX10+225 T>G (p = 0.018; odds ratio, 1.869) was strongly associated with the risk of keratoconus in the Korean population. In haplotype analysis, C-G of rs2956540-rs2288393 in LOX(p = 0.046) and C-C-G and G-G-G of rs60610024-rs2228100-rs57555435 (p = 0.021 and p g - rs116962241 in ALDH3A1(p = 0.048) predisposed significantly to keratoconus. After cross-validation consistency and permutation tests, two locus model was the best SNP variations interaction pattern. @*Conclusions@#Our results suggested that genetic variations in ALDH3A1, LOX, and SPARC genes were associated with a predisposition for keratoconus in Korean individuals. Moreover, variations in ALDH3A1 and LOX may serve as strong biomarkers for keratoconus.

A Family with Axenfeld-Rieger Syndrome: Report of the Clinical and Genetic Findings

PURPOSE: To describe clinical findings in a Korean family with Axenfeld-Rieger syndrome. METHODS: A retrospective review of clinical data about patients with diagnosed Axenfeld-Rieger syndrome. Five affected members of the family underwent a complete ophthalmologic examination. We screened the forkhead box C1 gene and the pituitary homeobox 2 gene in patients. Peripheral blood leukocytes and buccal mucosal epithelial cells were obtained from seven members of a family with Axenfeld-Rieger syndrome. DNA was extracted and amplified by polymerase chain reaction, followed by direct sequencing. RESULTS: The affected members showed iris hypoplasia, iridocorneal adhesions, posterior embryotoxon, and advanced glaucoma in three generation. None had systemic anomalies. Two mutations including c.1362_1364insCGG and c.1142_1144insGGC were identified in forkhead box C1 in four affected family members. CONCLUSIONS: This study may help to understand clinical findings and prognosis for patients with Axenfeld-Rieger syndrome.

Epidemiologic and Genetic Studies of Keratoconus Patients in Korea

PURPOSE: To report the characteristics and genetic epidemiology of keratoconus patients in the Korean population based on questionnaires, ophthalmologic findings, and genetic studies. METHODS: From September 2007 through August 2009, an epidemiologic investigation was performed through questionnaires and ocular examination of 190 keratoconus patients. To investigate the genetic cause, blood samples were taken from the keratoconus patients. Genetic analysis of keratoconus was performed through the analysis of sensitive candidate genes. RESULTS: The mean age of the study subjects was 29.6 years. Seventy-seven percent of the subjects rubbed their eyes with 17 percent suffering from atopy, allergy, and asthma. Thirty-two percent of subjects demonstrated Vogt's striae as the most frequent biomicroscopic keratoconus finding. No family history was found. Genetic analysis showed sensitive genetic variations of VSX1, LUM, and IL1B. CONCLUSIONS: Epidemiology of Korean keratoconus patients was investigated through research and genetic study resulting in discovery of sensitive genes.

Behcet's Disease: The First Mongolian Case in Literature Showing HLA B51, MICA Gene Type *5/*6

Behcet's disease is a chronic multi-systemic disease of unknown origin that includes mucocutaneous, ocular, cardiac, vascular, renal, gastrointestinal, neurologic and cutaneous involvement. The disease is spread throughout the world, but it is most prevalent in the eastern Mediterranean region-along the Silk Road-, and in Japan, China, and Korea. Recently, we treated a Mongolian patient who had complete-type Behcet's disease. As far as we know, this case is the first report of a Mongolian with Behcet's disease in the English literature. HLA typing in this patient revealed A2, A24; B51, B35; Cw4, Cw7; DR9, DR11. Study of the MICA genetype showed *5, *6 positive. Our data provided adequate evidence, from an epidemiological aspect, to support the belief that Behcet's disease is most prevalent along the old Silk Road.

Intercellular adhesion molecule-1 polymorphisms in Korean patients with Behcet's disease

Intercellular adhesion molecule-1 (ICAM-1) is expressed on vascular endothelial cells and its expression increases during the inflammatory response in patients with active Behcet's disease (BD). The ICAM1 gene mutations are associated with BD in Caucasians, but clinical features of the mutation phenotype are unknown. We analyzed ICAM1 polymorphisms in Korean BD patients to determine if there was an association between particular mutations and clinical symptoms. The prevalence of ICAM1R241G and ICAM1K469E polymorphisms was determined among 197 patients with BD and 248 healthy controls using BsrG1 and BstU1 PCR-RFLP. The frequency of both genotypes ICAM1469 * K/ * E and ICAM-1469 * E/ * E was significantly higher in BD patients compared with controls (66.0% vs 52.4%, p=0.004, OR=1.28, 95% CI 1.08-1.50) and the allele frequency of ICAM1469 * E was higher in patients with skin lesions (0.41), genital ulcers (0.41), vasculitis (0.43), ocular lesions (0.41) and arthritis (0.39) than in controls (0.31). Only one heterozygote, ICAM1241G/R, was detected in BD patients but the ICAM1241 * R mutation was not found in any of the 248 healthy controls. These results show that the ICAM1 mutation is associated with BD susceptibility, and is another genetic risk factor for BD among the Korean population.

Association of MICA Polymorphism with HLA-B51 and Disease Severity in Korean Patients with Behcet's Disease

The HLA-B51 allele is known to be associated with Behcet's disease (BD) in many ethnic group. However, it has not yet been clarified whether the HLA-B51 gene itself is the pathogenic gene related to BD or whether it is some other gene in linkage disequlibrium with HLA-B51. Recently, the Triplet repeat (GCT/AGC) polymorphism in transmembrane region of the MHC class I chain-related A (MICA) gene was identified. To investigate the association of MICA with BD, we studied the MICA polymorphism in 108 Korean BD patients and 204 healthy controls in relation to the presence of HLA-B51 and clinical manifestations. The triplet repeat polymorphism was determined by polymerase chain reaction (PCR)-denaturing polyacrylamide gel electrophoresis (PAGE). The phenotype frequency of the MICA*A6 allele (relative risk, RR=2.15, p=0.002) and HLA-B51(RR=1.87, p=0.022) were significantly increased in the Korean patients with BD. A strong linkage disequilibrium was observed between the MICA*A6 and HLA-B51 in both the patients with BD and control subjects. Stratification analysis showed that MICA*A6 homozygosity was strongly associated with BD in the HLA-B51-negative population, and HLA-B51 was also associated with MICA*A6-negative population. In conclusion, MICA*A6 rather than HLA-B51 was strongly associated with Korean patients with BD, and the MICA*A6 allele is a useful susceptibility marker of BD, especially in the HLA-B5-negative

Tumor Necrosis Factor Alpha Promoter Polymorphism of Systemic Lupus Erythematosus in Korean / 대한면역학회지

"It was reported that polymorphism of TNF alpha gene was present in promoter region and involves the substitution of guanine by adenosine in the uncommon (TNFA 2) allele. In this study, we investigated the significance of TNFA gene polymorphism in relation to various clinical characteristics and autoantibody profiles in SLE as well as comparing it with that of other countries, and also studied its association with peripheral TNF-a production in vitro. TNFA genotyping was performed in 126 SLE patients and 300 controls using DNA extracted from peripheral leucocytes. The biallelic polymorphism at position -308 of the TNFA promotor was determined by Ncol- RFLP. Peripheral mononuclear cell production of TNF-a was investigated by bioassay using L-929 cell cytotoxicity. The TNFA ""1 homozygote was a predominant allele (77.0%) in SLE, which was not different from the controls. TNFA ""2 homozygate was extremely rare in both patients and controls (0.8%, 1.3% respectively). The clinical manifestations between TNFA '1 and TNFA""2 did not differ. The production of autoantibodies including dsDNA, anti-La, anti-nRNP and anti-Sm was not different between two alleles, whereas anti- Ro antibody was more frequent in TNFA""1/TNFA '1 than in TNFA'1/TNFA'2 (62.1% vs 38.4%, P=0.022). The polymorphism of TNFA gene did not influence the lipopolysaccharide stimulated peripheral mononuclear cell production of TNF-a (1356+/-293 vs 1119+/-385 pg/ml; TNFA'1/TNFA'1, TNFA'1/TNFA'2 respectively). These results suggested that promoter polymorphism of TNFA was not directly involved in the susceptibility of SLE and was not responsible for differential peripheral TNF-a production, but TNFA ' may be associated with anti-Ro antibody production."