Noriko Yasuda

Association of Toll-like Receptor 4 Gene Polymorphisms in Japanese Subjects With Primary Open-Angle, Normal-Tension, and Exfoliation Glaucoma

PURPOSE To determine whether polymorphisms in the Toll-like receptor 4 (TLR4) gene are associated with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and exfoliation glaucoma (XFG) in Japanese individuals. DESIGN Genetic association study. METHODS SETTING Multicenter study. STUDY POPULATION One hundred eighty-four unrelated Japanese patients with POAG, 365 unrelated patients with NTG, and 109 unrelated patients with XFG from 5 hospitals. PROCEDURES Genomic DNA was extracted from leukocytes of the peripheral blood, and 8 polymorphisms in the TLR4 genes were amplified by polymerase chain reaction (PCR) and directly sequenced. Allele and genotype frequencies and the inferred haplotypes were estimated. MAIN OUTCOME MEASURES Differences in allele and genotype frequencies and haplotypes between subjects with POAG, NTG, and XFG. RESULTS The allele frequency of rs2149356 of the TLR4 gene in the POAG, NTG, and XFG groups was the most significantly different from that of the control group (minor allele frequency 0.446, 0.395, 0.404, vs 0.308; P = .000058, P = .0030, and P = .015). The allele frequencies of the 5 TLR4 SNPs were higher in all of the glaucoma groups than that in the control group. The statistics of genotypes of TLR4 were approximately the same for all allele frequencies. The haplotypic frequencies with Tag SNPs studied earlier showed that only POAG was statistically significant. Other haplotypes, such as rs10759930, rs1927914, rs1927911, and rs2149356, had higher statistical significance (overall P = .00078 in POAG, overall P = .018 in NTG, and overall P = .014 in XFG). CONCLUSIONS This study demonstrated that TLR4 polymorphisms are associated with NTG in the Japanese, and they also play a role in the pathogenesis of POAG and XFG.

Effect of concomitant use of latanoprost and brinzolamide on 24-hour variation of IOP in normal-tension glaucoma.

PurposeTo study the effect of the concomitant use of latanoprost and brinzolamide on the 24-hour variation in the intraocular pressure (IOP) in patients with normal-tension glaucoma (NTG). MethodsWe studied a total of 44 eyes from 22 NTG patients. Mean 24-hour IOP variation was determined after a washout period of ≥4 weeks. Latanoprost monotherapy was continued in both eyes for 8 weeks. Thereafter, patients were randomized to continue latanoprost monotherapy in 1 eye whereas brinzolamide was added as an adjunct to latanoprost therapy in the other eye. Eight weeks after the initiation of brinzolamide treatment, the 24-hour IOP variation was remeasured. IOP was measured in the sitting position 8 times daily using a Goldmann applanation tonometer before and after treatment. ResultsThe eyes treated with latanoprost monotherapy and those treated with latanoprost and brinzolamide showed a significant decrease in IOP at all time points. Percent reductions in the diurnal mean IOP (mean IOP at 10 AM, 1 PM, and 4 PM) and in nocturnal mean IOP (mean IOP at 10 PM, 1 AM, and 3 AM) were significantly greater in the eyes treated with the combination of latanoprost and brinzolamide than those with latanoprost alone (diurnal mean IOP: latanoprost and brinzolamide=19.8%, latanoprost=14.1%, P<0.001; nocturnal mean IOP: latanoprost and brinzolamide=13.4%, latanoprost=10.0%, P<0.05). ConclusionsFor the treatment of NTG, the combination of latanoprost and brinzolamide demonstrated additive effects in lowering IOP, not only during the day, but also at night.

Intraocular Pressure Change Over a Habitual 24-Hour Period After Changing Posture or Drinking Water and Related Factors in Normal Tension Glaucoma

PURPOSE We investigated the correlation between 24-hour IOP in the habitual (sitting during day and supine during night) position (H24h-IOP) and IOP after a postural-change test (PCT-IOP) and a water-drinking test (WDT-IOP). We also investigated ocular and systemic factors related with them in patients with normal tension glaucoma (NTG). METHODS Japanese NTG patients underwent H24h-IOP, PCT-IOP, and WDT-IOP measurements during a 24-hour period. Correlations among H24h-IOP, PCT-IOP, and WDT-IOP, and contributing ocular/systemic factors were investigated using regression analysis. RESULTS There were 33 patients included. Peak H24h-IOP correlated positively with peak PCT-IOP and peak WDT-IOP (estimate = 0.422 and 0.419, P ≤ 0.010), and peak PCT-IOP with WDT-IOP (0.44, P = 0.002). Peak H24h-IOP correlated with refraction (0.36, P = 0.048) and negatively with the mean deviation (MD, -0.066, P = 0.031). MD and baseline IOP (the mean of H24h-IOP) correlated negatively with the H24h-IOP fluctuation (-0.058 and -0.58, P ≤ 0.050). Refraction, baseline IOP, mean blood pressure (mBP), and body mass index (BMI) correlated with peak PCT-IOP (0.23, 0.52, 0.097, and 0.32, respectively, P ≤ 0.038). PCT-IOP difference correlated with refraction and mBP (0.31 and 0.093, P ≤ 0.016) and negatively with age (-0.069, P = 0.003). Central corneal thickness, baseline IOP, age, and BMI correlated with peak WDT-IOP (0.030, 0.40, 0.088, and 0.26, P ≤ 0.050). Age and BMI correlated with WDT-IOP difference (0.086 and 0.20, P < 0.032). CONCLUSIONS Positive correlation was found among the peaks of H24h-, PCT-, and WDT-IOP. A worse visual field was associated with higher peak and greater fluctuation of H24h-IOP in NTG. Several ocular/systemic factors were important in interpreting H24h-, PCT-, and WDT-IOP.

Novel myoc Gene Mutation, Phe369leu, in Japanese Patients with Primary Open-angle Glaucoma Detected by Denaturing High-performance Liquid Chromatography

Purpose:To screen for mutations in the MYOC gene in Japanese patients with primary open-angle glaucoma (POAG) using denaturing high-performance liquid chromatography (DHPLC). Patients and Methods:Blood samples were collected from 171 patients with POAG and 100 controls from seven institutions in Japan. For high-throughput analysis, seven exonic regions were amplified by polymerase chain reaction using DNA pooled from three patients; each DNA pool was then analyzed chromatographically. For analysis of a small number of samples, 7 exonic regions were amplified separately but simultaneously with annealing at 58°C in each patient and then chromatographed, using 7 wells of the same 96-well plate per sample. When chromatographic patterns were abnormal by either method, the PCR products of the individual samples were sequenced. Results:Four glaucoma-causing mutations were identified in five POAG patients (2.9%). One missense mutation, Phe369Leu, is new; and three others, Ile360Asn, Ala363Thr, and Thr448Pro, have been reported in Japanese patients. Phe369Leu was associated with adult onset POAG. Conclusions:Mutations in the MYOC gene were demonstrated chromatographically in 2.9% of our Japanese POAG patients. The use of pooled DNAs with DHPLC analysis is a time- and labor-saving technique. All mutations detected appear to be specific to Japanese patients.

Paraoxonase 1 gene polymorphisms influence clinical features of open-angle glaucoma

BackgroundThe purpose of this study was to determine whether genetic polymorphisms affecting high-density lipoprotein (HDL)-associated antioxidant enzymes were associated with open-angle glaucoma (OAG). The rationale for this study was that the modification of low-density lipoprotein (LDL) by HDL prevents oxidative modification which can then cause dysfunction of endothelial cells.MethodsWe studied 284 normal Japanese controls and 555 Japanese patients with OAG, including primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG). The possible associations of polymorphisms of PON1/L55M, PON1/Q192R, PON2/S311C, and PAF-AH/V279F with OAG were investigated. We compared the genotype distributions and allele frequency in controls and patient groups. The age at diagnosis, intraocular pressure (IOP) at diagnosis, and visual field score at diagnosis were examined for association with polymorphisms.ResultsThe distributions of genotypes and allele frequency for the four polymorphisms were not significantly different between any patient group and controls. In NTG patients, 55M carriers of the PON1 gene were significantly older at diagnosis than 55M non-carriers (P=0.001). The IOP at diagnosis was significantly higher in glaucoma patients carrying 192R in the PON1 gene than in patients not carrying 192R (P=0.006). No significant differences were seen in clinical characteristics of OAG patients in relation to other polymorphisms.ConclusionPON1 gene polymorphisms may influence the features of Japanese patients with OAG.

Association of HK2 and NCK2 with normal tension glaucoma in the Japanese population.

Although family studies and genome-wide association studies have shown that genetic factors play a role in glaucoma, it has been difficult to identify the specific genetic variants involved. We tested 669 single nucleotide polymorphisms (SNPs) from the region of chromosome 2 that includes the GLC1B glaucoma locus for association with primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) in the Japanese population. We performed a two-stage case-control study. The first cohort consisted of 123 POAG cases, 121 NTG cases and 120 controls: the second cohort consisted of 187 POAG cases, 286 NTG cases, and 271 controls. Out of six SNPs showing significant association with POAG in the first round screening, seven SNPs were tested in the second round. Rs678350 in the HK2 gene coding sequence showed significant allelic (p = 0.0027 in Stage Two, 2.7XE-4 in meta-analysis) association with POAG, and significant allelic (p = 4.7XE-4 in Stage Two, 1.0XE-5 in meta-analysis) association with NTG. Although alleles in the TMEM182 gene did not show significant association with glaucoma in the second round, subjects with the A/A allele in TMEM182 rs869833 showed worse visual field mean deviation (p = 0.01). Even though rs2033008 in the NCK2 gene coding sequence did not show significant association in the first round, it had previously shown association with NTG so it was tested for association with NTG in round 2 (p = 0.0053 in Stage Two). Immunohistochemistry showed that both HK2 and NCK2 are expressed in the retinal ganglion cell layer. Once multi-testing was taken into account, only HK2 showed significant association with POAG and NTG in Stage Two. Our data also support previous reports of NCK2 association with NTG, and raise questions about what role TMEM182 might play in phenotypic variability. Our data suggest that HK2 may play an important role in NTG in the Japanese population.

Effect of carteolol hydrochloride on 24-hour variation of intraocular pressure in normal-tension glaucoma

PurposeTo evaluate the effects of carteolol hydrochloride (carteolol) on 24-h variations in intraocular pressure (IOP) in patients with normal-tension glaucoma (NTG).MethodsTwelve patients with NTG were treated with carteolol 2% solution for ≥8 weeks; their pretreatment 24-h IOP variations, blood pressure (BP), and pulse rate (PR) were compared with those measured after the treatment period.ResultsDaytime IOP (at 07:00, 10:00, 13:00, and 16:00), maximum IOP, and the mean 24-h IOP were significantly reduced after treatment, as was the 24-h IOP range. Systolic BP in the morning and both systolic and diastolic BP in the afternoon were significantly decreased by the treatment, whereas no significant change of PR was observed.ConclusionsCarteolol had no effect on nocturnal IOP but significantly helped reduce daytime IOP, maximum IOP, mean 24-h IOP, and the 24-h IOP range. The drug exerted no statistically significant effect on the PR.

Twenty-Four-Hour Variation of Intraocular Pressure in Primary Open-Angle Glaucoma Treated with Triple Eye Drops

Objectives. To evaluate 24-hour intraocular pressure (IOP) variation in patients with primary open-angle glaucoma (POAG) treated with triple eye drops. Subjects and Methods. The IOP was measured in 74 eyes in 74 POAG patients (seated) on triple therapy (PG analogue, β-blocker, carbonic anhydrase inhibitor) at about every 3 hours. Results. The peak IOP was 13.5 ± 3.1 at 1:00, and the trough IOP was at 12.6 ± 2.4 mmHg at 7:00. The IOP at 7:00 was significantly lower than that at 10:00, 1:00, and 3:00 (p < 0.05). Based on the time of the peak IOP, we classified the patients into two groups: diurnal (28 eyes) and nocturnal types (37 eyes). There was significant difference at the spherical equivalent between diurnal and nocturnal types (p = 0.014). To assess the influence of reflective error, we conducted subanalysis for two groups: high myopic (26 eyes, ≤−6D) and low/nonmyopic (24 eyes, ≥−2D) groups. In the low/nonmyopia group, the IOP was significantly higher at 1:00 and 3:00 than at 13:00, 16:00, and 7: 00 (p < 0.05). Conclusion. The mean of IOP elevated outside of clinic hour in the POAG patients on triple therapy. The low/nonmyopia patient should be carefully treated because the IOP of the patients at night elevated significantly.