Kelvin Y. Lee

Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Association Analysis of CFH, C2, BF, and HTRA1 Gene Polymorphisms in Chinese Patients with Polypoidal Choroidal Vasculopathy

PURPOSE Polypoidal choroidal vasculopathy (PCV) is a major cause of serosanguinous maculopathy in Chinese patients with age-related macular degeneration (AMD). Variants in the CFH and HTRA1/LOC387715 genes are strongly associated with AMD in Caucasians and Chinese. Variants in the C2 and BF genes have been found to confer a significantly reduced risk of AMD. This study was undertaken to determine whether these associations occur in Chinese patients with PCV. METHODS Patients of Chinese ethnicity with clinically and angiographically diagnosed PCV and normal control subjects were recruited from the Singapore National Eye Centre. Five single-nucleotide polymorphisms (SNPs) in the CFH gene, two each within the C2 and BF genes and two variants located in the LOC387715 and HTRA1 genes, were screened in all patients and control subjects. RESULTS Seventy-two patients with PCV and 93 normal control subjects were studied. A significant association was noted with CFH variants rs3753394 and rs800292 among the PCV cases (P = 0.0015 and P = 0.0045, respectively). Individuals homozygous for the TT genotype of rs3753394 had a significantly higher risk (P = 0.0076) of PCV (OR = 4.29; 95% CI: 1.47-12.50) than those carrying a single copy of the T allele (P = 0.3210; OR = 1.69; 95% CI: 0.60-4.78), after adjustment for such risk factors as age and sex. The genotype frequencies of rs11200638 and rs10490924 in HTRA1 and LOC387715, respectively, were also found to be significantly different between patients with PCV and normal control subjects (P = 0.00032 and P = 0.003, respectively). The AA genotype of rs11200638 and TT genotype of rs10490924 conferred a 4.9-fold (95% CI: 1.85-12.95) and 4.89-fold (95% CI: 1.85-12.90) increased risk of PCV, respectively, after adjustment for age and sex. The Y402H variant of CFH (rs1061170) and the BF and C2 variants were not significantly different in patients and normal control subjects. CONCLUSIONS The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV in Chinese patients.

Association of LOXL1 Gene Polymorphisms with Pseudoexfoliation in the Japanese

PURPOSE The single nucleotide polymorphisms (SNPs) rs1048661, rs3825942, and rs2165241 within the LOXL1 gene were recently found to confer risk of pseudoexfoliation glaucoma (XFG) through pseudoexfoliation syndrome (XFS) in Caucasians. The purpose of this study was to test this association in Japanese subjects with XFS/XFG. METHODS Japanese subjects with clinically diagnosed XFS/XFG and normal control subjects were recruited. Genomic DNA was extracted and the three SNPs of the LOXL1 gene were genotyped by bidirectional sequencing. The association of individual SNPs with XFG/XFS was evaluated by using chi(2) and the Fisher exact test. RESULTS Two hundred nine Japanese patients (106 XFG and 103 XFS) and 172 control subjects were studied. Strong associations were observed for all three SNPs of LOXL1 for XFS (odds ratio [OR] = 13.56, P = 3.39 x 10(-28) for allele T of rs1048661; OR = 10.71, P = 1.49 x 10(-7) for allele G of rs3825942; and OR = 4.55, P = 5.33 x 10(-4) for allele C of rs2165241) and XFG (OR = 25.21, P = 1.44 x 10(-34) for allele T of rs1048661; OR = 11.02, P = 1.40 x 10(-7) for allele G of rs3825942; and OR = 11.89, P = 4.76 x 10(-6) for allele C of rs2165241). The risk-associated alleles of rs1048661 and rs2165241 differed between the Japanese and Caucasians, whereas allele G of rs3825942 was associated with disease in both populations. Conditional analysis indicated that rs3825942 was not independent but correlated highly with rs1048661. The at-risk haplotype T-G-C was present at an approximately two times higher rate (94.7% vs. 50.6%, P = 4.22 x 10(-43)) in cases than in control subjects and conferred a 2.9-fold (95% confidence interval [CI], 2.357-3.464) increased likelihood of XFS. CONCLUSIONS Polymorphisms in the LOXL1 gene confer risk to XFS/XFG in the Japanese, but there are different risk-associated alleles and haplotypes in the Japanese.

Confirmation of the presence of uveal effusion in Asian eyes with primary angle closure glaucoma: an ultrasound biomicroscopy study.

OBJECTIVE To confirm the presence of uveal effusion in the eyes of Asian patients with primary angle closure glaucoma (PACG) using ultrasound biomicroscopy (UBM). METHODS In this observational case series, 70 patients with PACG (28 untreated patients with newly diagnosed PACG and 42 patients who had undergone previous laser iridotomy and were being monitored) and 12 patients with acute primary angle closure (APAC) were recruited. Eyes of patients with newly diagnosed PACG and APAC underwent UBM before and after laser iridotomy, whereas eyes of patients with treated PACG underwent UBM at enrollment. Uveal effusion was defined as a clear space between the choroid and sclera and was graded as follows: grade 0, none; grade 1, slitlike; grade 2, bandlike; and grade 3, obvious. RESULTS Overall, uveal effusion was found in 11 of 70 eyes with PACG (15.7%; 95% confidence interval, 8.8%-26.2%) and in 3 of 12 eyes with APAC (25%; 95% confidence interval, 8.0%-53.4%). For patients with newly diagnosed PACG, uveal effusion was found in 4 of 28 eyes (14.2%; 95% confidence interval, 5.1%-32.1%) before laser iridotomy; 2 eyes had effusion after laser iridotomy. When present, the effusion was grade 1 in PACG eyes and grade 2 or 3 in APAC eyes. CONCLUSIONS Uveal effusion was present in a significant proportion of Asian eyes with PACG and APAC, confirming a recent report of this finding.

Plateau Iris in Asian Subjects With Primary Angle Closure Glaucoma

OBJECTIVE To determine the prevalence of plateau iris in Asian eyes with primary angle closure glaucoma (PACG) using ultrasound biomicroscopy (UBM). METHODS In this cross-sectional observational study, subjects older than 40 years with PACG who had a patent laser peripheral iridotomy underwent UBM in 1 eye. Ultrasound biomicroscopy images were qualitatively analyzed using standardized criteria. Plateau iris in a quadrant was defined by anteriorly directed ciliary body, absent ciliary sulcus, steep iris root from its point of insertion followed by a downward angulation, flat iris plane, and irido-angle contact. At least 2 quadrants had to fulfill these UBM criteria for an eye to be classified as having plateau iris. RESULTS One hundred eleven subjects (70 from Singapore, 41 from Thailand) with PACG were recruited. The mean (SD) age was 65.6 (8.1) years, and 63.9% were female. Based on standardized UBM criteria, plateau iris was found in 36 of 111 eyes (32.4%; 95% confidence interval, 24.4%-41.6%). In these 36 eyes, quadrant-wise analysis showed 66.7% had plateau iris in 2 quadrants; 22.2%, in 3 quadrants; and 11.1%, in all quadrants. CONCLUSIONS About 30% of PACG eyes with a patent laser peripheral iridotomy were found to have plateau iris on UBM, highlighting the importance of non-pupil block mechanisms in Asian individuals.

Spectral-Domain Optical Coherence Tomography ofβ-zone Peripapillary Atrophy: Influence of Myopiaand Glaucoma

PURPOSE To investigate the influence of glaucoma and myopia on the cross-sectional configuration of the β-zone of peripapillary atrophy (PPA-β) using spectral-domain optical coherence tomography (SD-OCT). METHODS Cross-sectional B-scan images of PPA-β obtained with SD-OCT were evaluated in 100 eyes of 100 consecutive patients with POAG, regardless of intraocular pressure level, and in 100 eyes of 100 normal subjects. PPA bed configurations were classified, and associated factors were studied with multivariate analysis. RESULTS In 147 eyes with PPA-β (84 POAG and 63 normal eyes; P = 0.0012), the PPA bed was composed of straight (14 POAG and 27 normal eyes) or downward-curved (19 and 8 eyes) Bruchs membrane (BM) or of a downward-bending slope lacking BM (BM defect; 51 and 28 eyes). Multivariate analysis revealed that absence of POAG (odds ratio [OR], 0.36; P = 0.034) and less myopic refractive error (OR, 1.43; P = 0.009) were significantly associated with straight-BM-type, presence of POAG (OR, 5.74; P = 0.008) and less myopic refractive error (OR, 3.02; P < 0.001) with curved-BM-type, and myopic refractive error (OR, 0.34; P < 0.001) with BM-defect-type. Within the PPA-β region, all retinal layers except for the nerve fiber layer frequently disappeared before reaching the disc edge, showing no significant intergroup difference (P > 0.05) between POAG and normal eyes. CONCLUSIONS PPA bed configurations detected by SD-OCT were classified into three types. The lack of BM on the PPA bed was closely associated with myopia. The downward-curved appearance of BM may be related to the anatomic changes associated with glaucoma.

Peripapillary atrophy after acute primary angle closure.

Aim: To determine the changes in peripapillary atrophy after episodes of acute primary angle closure (APAC). Methods: Prospective observational study of 40 eyes in 38 patients of predominantly Chinese ethnicity. The mean (SD) intraocular pressure at the time of presentation was 51.7 (12) mm Hg (median, 55 mm Hg) and the mean duration of the symptoms was 37.7 (69.4) hours. A laser iridotomy was undertaken 3.2 (8.4) days after the APAC episode, leading to normalisation of intraocular pressure in all cases. Colour optic disc photographs taken at 2 and 16 weeks after APAC were examined morphometrically. Peripapillary atrophy was divided into α and β zones. Results: Comparing measurements at baseline with week 16, the minimum width of the α zone (0.013 (0.056) v 0.016 (0.001) arbitrary units; p = 0.23), the maximum width of the α zone (1.11 (1.31) v 1.31 (0.79) arbitrary units; p = 0.22), the minimum width of the β zone (0.030 (0.122) v 0.033 (0.166) arbitrary units; p = 0.93), and the maximum width of the β zone (0.62 (0.94) v 0.73 (0.98) arbitrary units; p = 0.42) did not vary significantly. The mean cup to disc ratio increased from 0.56 (0.05) to 0.62 (0.07) (p<0.0001) at the end of follow up. Conclusions: The α and β zones of peripapillary atrophy did not enlarge markedly in patients after APAC, despite an enlargement of the optic cup during a follow up of four months.

Bietti’s crystalline dystrophy in Asians: clinical, angiographic and electrophysiological characteristics

This article describes nine Chinese patients with Bietti’s crystalline dystrophy, including two families, one consisting of three siblings and the other a pair of sisters. All patients had the classic refractile deposits located in all layers of the retina, with varying degrees of pigment epithelium atrophy. However, paralimbal crystals were not seen in the anterior corneal stroma. We describe clinical, angiographical and electrophysiological characteristics, and also review the literature on Bietti’s crystalline dystrophy. All patients had full eye examination, including best corrected visual acuity, biomicroscopy, applanation tonometry and dilated funduscopy. Fluorescein angiography and indocyanine green angiography were performed, together with visual fields and electrophysiologic studies. All nine of our patients were phenotypically heterogeneous, with varying age and symptoms at presentation, as well as different degrees of progression. Age was not found to be a predictor of severity. The differences in disease severity, even within sibling groups, suggested that perhaps other factors were at play in phenotypic expression. We found that in early ICGA, all stages of BCD had delayed choroidal filling, which has not been previously described. We also observed a relative derangement of inner choroidal circulation as evidenced by late hypofluorescence on the ICGA. However, it is as yet unclear whether this circulatory disturbance is due to primary involvement of the posterior ciliary arteries, or secondary to choroidal and/or retinal pigment epithelial atrophy. While the FA and ICGA findings were similar, we found that the true extent of the atrophic areas was better delineated by ICGA. ICGA was also superior in outlining the degree and extent of choroidal vascular compromise.

Randomized, Controlled Trial of a Sustained Delivery Formulation of 5-Fluorouracil for the Treatment of Failing Blebs

PURPOSE To determine the efficacy of a subconjunctival injection of hyaluronic acid (HA) with 5-fluorouracil (5FU) formulation as an adjunct in reviving bleb function by needling. DESIGN Prospective, randomized, controlled trial. PARTICIPANTS Fifty patients with previous trabeculectomy and scheduled by the managing physician for a needling intervention. METHODS One eye of each patient was randomized to receive needling with HA-5FU mixture or needling with subconjunctival injection of 5FU solution alone. MAIN OUTCOME MEASURES The primary outcome was the percentage of subjects with an intraocular pressure (IOP) <15 mmHg without any medications at 3 months. Secondary outcomes included the need for additional needling procedures and changes in bleb morphology. RESULTS Forty-nine subjects (25 in the HA-5FU group and 24 in the 5FU group) completed 3 months of follow-up. At baseline, there was no significant difference between the groups in terms of demographic features, subtype of glaucoma, vertical cup-to-disc ratio, or visual field indices. The mean number of glaucoma medications at baseline was higher in the 5FU group (0.8±1.1 [mean ± standard deviation] vs. 0.2±0.6, P = 0.04). An IOP <15 mmHg without medications was reached in 48.0% of subjects in the HA-5FU group and in 33.3% of subjects in the 5FU group (P = 0.2). At 3 months, both groups demonstrated a significant decrease in IOP from baseline (HA-5FU: decrease of 5.9 mmHg [95% confidence interval, 3.4-8.4]; 5FU: decrease of 6.0 mmHg [95% confidence interval, 3.2-8.2]; P<0.001 for both). Intergroup comparisons for IOP change from baseline was not significant (P = 0.9). However, repeat needling was required more frequently in the 5FU group compared with the HA-5FU group (50.0% vs. 12.0%; P = 0.004). There were no significant differences in the number of reported adverse events, bleb vascularity, or morphology between the 2 groups. CONCLUSIONS Subconjunctival injection of HA-5FU to revive bleb function after bleb needling is as effective as 5FU solution. Fewer repeat needlings were required after treatment with HA-5FU, suggesting that the use of a combined formulation of HA-5FU may improve the overall outcomes of bleb needlings.

Central corneal thickness in Chinese subjects with primary angle closure glaucoma.

PurposeTo characterize central corneal thickness (CCT) in Chinese eyes with primary angle closure glaucoma (PACG). MethodsCCT was measured by ultrasound pachymetry in PACG eyes and compared with primary open-angle glaucoma (POAG) eyes. POAG eyes were further subdivided into high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) for analysis. PACG eyes had glaucomatous optic neuropathy and visual field loss, an angle in which at least 180 degrees of angle in which the posterior trabecular meshwork was not visible, and raised intraocular pressure (IOP) and/or peripheral anterior synechiae. Both HTG (IOP >21 mm Hg) and NTG (IOP consistently <21 mm Hg) eyes had glaucomatous optic neuropathy with compatible visual field defects and open angles. Further comparison was made with CCT data of 1067 normal subjects previously enrolled in a population-based study. ResultsWe enrolled 154 patients with PACG and 300 with POAG. Mean age of PACG patients was 68.1±8.3 years compared with 71.1±12.4 years in POAG patients (P=0.002). There was no difference in mean CCT of PACG eyes (541.28±33.95 &mgr;m) and POAG eyes (539.28±34.84 &mgr;m, P=0.56) or normal eyes of control subjects (536.74±31.08 &mgr;m) (P=0.07). However, mean CCT of NTG eyes (535.23±36.10 &mgr;m) was significantly lower than that of HTG eyes (543.44±33.10 &mgr;m, P=0.04), and HTG eyes had thicker CCT than normal eyes (P=0.01). ConclusionsPACG eyes had similar CCT as those with POAG or normal eyes in Chinese subjects.