Purpose: To investigate risk factors associated with developing polypoidal choroidal vasculopathy (PCV) lesions in the unaffected fellow eye of patients with unilateral PCV.Methods: We studied 179 patients with initial unilateral PCV who were followed up for a period of 24 months or longer to monitor for second eye involvement. All patients underwent genotyping for CFH I62V (rs800292) and ARMS2 A69S (rs10490924) using TaqMan technology.Results: During the follow-up period ranging from 5–180 months, 20 (11.2%) of 179 patients developed PCV in the initially unaffected fellow eye. The risk allele (T) of ARMS2 A69S was significantly more prevalent in patients with second eye involvement compared to those without PCV in the fellow eye (p = 0.0046). Cox regression analysis demonstrated that the ARMS2 A69S genotype is a risk factor for developing PCV in the fellow eye (p = 0.027, odds ratio 2.53, confidence interval 1.11–5.73). Survival analysis revealed that the fellow eye of patients with the risk-associated homozygous genotype (TT) of ARMS2 A69S was affected significantly earlier than those with other genotypes (p = 0.0177, log rank test).Conclusions: Development of PCV in the unaffected fellow eye is associated with ARMS2 A69S genotype in patients with unilateral PCV.
To assess whether lysyl oxidase-like 1 (LOXL1) polymorphisms are associated with primary open-angle glaucoma (POAG) and exfoliation syndrome (XFS).Japanese patients with POAG (n=213) or XFS (n=89) and 191 control subjects were analyzed for LOXL1 polymorphisms (rs1048661: 758G/T, Arg141Leu and rs3825942: 794G/A, Gly153Asp). Demographic and clinical features of POAG patients and control subjects were compared in terms of the TT/GG compound genotype of rs1048661 and rs3825942.There was a significant difference in the genotype frequencies between XFS patients and control subjects (p<0.0001). Frequencies of the T allele of rs1048661 and the G allele of rs3825942 were significantly higher in XFS patients than in control subjects (rs1048661: 99.4% versus 55.0%; rs3825942: 99.4% versus 85.3%; p<0.0001). Except for one who had the TG/AG compound genotype, all XFS patients had the TT/GG compound genotype. An almost 250 fold increase in the risk of XFS (p<0.0001; odds ratio: 252.2; 95% confidence interval: 32.7 to more than 1000) was found in patients with the TT/GG compound genotype compared to those without the genotype. There were no significant differences in the genotype and allele frequencies between POAG patients and control subjects. Furthermore, no significant differences were noted in the demographic and clinical features of POAG patients as well as control subjects with and without the TT/GG high-risk compound genotype.LOXL1 polymorphisms were associated with XFS. However, the frequencies of the polymorphisms differed between Japanese and Caucasian XFS patients. These polymorphisms had no influence on the phenotypic features of POAG patients.
purpose. To evaluate optic nerve damage in mice after laser-induced ocular hypertension. methods. Ocular hypertension was induced unilaterally in 13 NIH Black Swiss mice by laser photocoagulation of the limbus. Over the following 12 weeks, intraocular pressure (IOP) was measured at regular intervals by the microneedle method. The optic nerves of these mice and of seven normal untreated mice were then processed conventionally for electron microscopy, and cross sections of the nerve 300 μm posterior to the globe were collected. Low- and high-magnification images were collected systematically and masked before analysis. For each nerve, cross-sectional area was measured in low-magnification micrographs, and axon and glia numbers were counted in high-magnification micrographs. results. In normal untreated mice, the average number of axons was 59,597 ± 3,112 (mean ± SD). Variation among these measurements was 5.7% ± 3.9%. After laser treatment, the duration of high IOP ranged from 2 to 12 weeks (6.2 ± 3.6 weeks, mean ± SD). The mean IOP in the treated eyes was 1.3 times greater than the mean IOP in the control eyes (P = 0.0012). The maximum IOP in the treated eyes was 1.6 times greater than that observed in the control eyes (P < 0.0001). The optic nerve cross-sectional area, mean axon density, and total number of axons in the treated eyes were significantly less than in the control eyes (28.5% ± 23.4%, 57.8% ± 37.8%, and 63.1% ± 38.1%, respectively; P < 0.005 for each). The decrease in optic nerve cross-sectional area and the positive integral of elevated IOP and duration of IOP elevation correlated significantly with total axon loss (r 2 = 0.79, P < 0.0001 and r 2 = 0.36, P = 0.040, respectively). The number of astrocytes per cross section of optic nerve was significantly greater in the treated eyes than in the control eyes (P = 0.014). conclusions. Laser-induced ocular hypertension in mouse eyes can induce optic nerve axon loss that correlates with the magnitude and duration of elevated IOP.
purpose. Toll-like receptor 4 (TLR4) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands and interacts with heat shock proteins, which are reportedly involved in normal tension glaucoma (NTG). This study was undertaken to investigate whether TLR4 polymorphisms are associated with NTG. methods. Two hundred fifty Japanese patients with NTG and 318 Japanese healthy control subjects were recruited. Eight single-nucleotide polymorphisms (SNPs) in the TLR4 gene were genotyped, and allelic and phenotypic diversity was assessed between cases and control subjects. results. Strong linkage disequilibrium was observed among all SNPs (D′ ≥ 0.85), which were located in one haplotype block. With respect to allelic diversity, the minor allele of three SNPs (rs10759930, rs1927914, and rs7037117) carried a significantly increased risk of NTG. With regard to genotypic diversity, individuals with the minor allele of six SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, and rs7037117) had a 1.47- to 1.65-fold increased risk of NTG. rs7037117, located in the 3′-untranslated region of TLR4, was most strongly associated with NTG, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 0.0038, P c = 0.0095). conclusions. Multiple SNPs in the TLR4 gene are associated with the risk of NTG. This finding suggests that the ligands and/or cytokines involved in the TLR4 signaling network may be risk factors for the development of NTG.
To compare the clinical and genetic characteristics of simple and complex central serous chorioretinopathy using central serous chorioretinopathy international group criteria.Patients with idiopathic central serous chorioretinopathy were included. Depending on the presence or absence of retinal pigment alterations greater than 2-disc areas in either eye, patients were classified into complex or simple types. Demographic factors and clinical findings were compared between groups. CFH variants, including rs800292 and rs1329428, were genotyped using TaqMan technology.A total of 319 consecutive patients were evaluated at the initial presentation. Of them, 53 (16.6%) had the complex type. The complex type was exclusively seen in men (100% vs. 79.0%, P = 2.0 × 10 -4 ) and demonstrated a significantly higher proportion of bilateral involvement (75.5% vs. 17.7%, P = 6.2 × 10 -18 ) and descending tract(s) (83.0% vs. 0%, P = 1.2 × 10 -57 ) than the simple type. Increased choroidal thickness (425 ± 131 vs. 382 ± 110, P = 0.02) and decreased central retinal thickness (274 ± 151 vs. 337 ± 136, P = 2.9 × 10 -4 ) were observed for the complex versus simple type. The risk allele frequencies of both variants were significantly higher in the complex versus simple type (rs800292: 61.3% vs. 48.7%, P = 0.018; rs1329428: 65.1% vs. 54.3%, P = 0.04).In this new classification system, the complex type has distinct genetic and clinical characteristics compared with the simple type.
To assess whether or not the c.677C/T and c.1298A/C genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are associated with open angle glaucoma (OAG).Genomic DNA was examined in a cohort of 131 Japanese patients with normal tension glaucoma (NTG), 133 patients with primary open angle glaucoma (POAG), and 106 control subjects. The mean age at the time of blood sampling was 62.8+/-13.3 years (mean+/-SD) in the patients with NTG, 61.8+/-15.4 years in the patients with POAG, and 65.0+/-10.5 years in the control subjects. MTHFR c.677C/T and c.1298A/C genotype and allele frequencies were determined using pyrosequencing analysis, and the findings were compared between the OAG patients and control subjects. The frequencies of compound MTHFR c.677C/T and c.1298A/C genotypes were also compared between OAG patients and control subjects.No significant differences were observed (p>0.05, chi2 test or Fisher's exact test) regarding the MTHFR c.677C/T genotype (TT: 14.5%, CT: 44.3%, CC: 41.2% for patients with NTG; TT: 20.3%, CT: 41.4%, CC: 38.3% for patients with POAG; TT: 17.9%, CT: 36.8%, CC: 45.3% for control subjects) and c.1298A/C (CC: 0%, AC: 38.9%, AA: 61.1% for patients with NTG; CC: 2.3%, AC: 32.3%, AA: 65.4% for patients with POAG; CC: 0.9%, AC: 41.5%, AA: 57.6% for control subjects). There were no allele frequencies between the NTG or POAG patients and the control subjects. In addition, no significant differences (p>0.05, chi2 test) were found in the frequencies of the compound MTHFR c.677C/T and c.1298A/C genotypes between the NTG or POAG patients and the control subjects.The MTHFR c.677C/T and c.1298A/C polymorphisms were not found to be associated with NTG and POAG. Further studies in the different ethnic populations should be performed to elucidate the relationship between MTHFR and OAG.
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