Investigation of Association between Autophagy-Related Gene Polymorphisms and Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population.

PURPOSE: Cellular stress conditions are important mechanisms implicated in the pathogenesis of pseudoexfoliation syndrome. One of the potential cellular responses to these stress conditions is induction of autophagy. The purpose of this study was to evaluate whether genetic variants in three critical genes of autophagy (ATG16L, ATG2B, ATG5) may be involved in the development of pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG) in a Spanish population. METHODS: 108 patients (64 XFS, 44XFG) and 118 healthy controls were evaluated. The analysis of genetic polymorphisms was performed by standard TaqMan allelic discrimination technique. RESULTS: No significant differences in either genotype distributions or allelic frequencies of the tested polymorphisms were found between patients with XFS/XFG and control subjects. CONCLUSIONS: Our results suggest that these three genes that are critical components of the autophagy pathway (ATG16L, ATG2B, ATG5) are not significant risk factors among Spanish patients with either XFS or XFG.

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Influence of CFH, HTRA1 and ARMS2 polymorphisms in the response to intravitreal ranibizumab treatment for wet age-related macular degeneration in a Spanish population.

AIM: To determine whether gene polymorphisms of the major genetic risk loci for age-related macular degeneration (AMD): ARMS2 (rs10490923), the complement factor H (CFH) (rs1410996) and HTRA1 (rs11200638) influence the response to a treatment regimen with ranibizumab for exudative AMD. METHODS: This study included 100 patients (100 eyes) with exudative AMD. Patients underwent a treatment with ranibizumab injections monthly during three months. Reinjections were made when the best corrected visual acuity (BCVA) decrease five letters (ETDRS) or central subfield retinal thickness gained 100 µm in optical coherence tomography image. Genotypes (rs10490923, rs1410996 and rs11200638) were analyzed using TaqMan probes or polymerase chain reaction-restricted fragment length polymorphisms analysis. RESULTS: There were no statistically significant differences in allelic distribution of CFH (rs1410996), ARMS2 (rs10490923) and HTRA1 (rs11200638) polymorphisms regarding to response to ranibizumab treatment. CONCLUSION: Ranibizumab treatment response is not related to CFH (rs1410996), ARMS2 (rs10490923) and HTRA1 (rs11200638) poymorphisms.

Association of Lysyl Oxidase-Like 1 Gene Polymorphisms in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population.

PURPOSE: To evaluate the association of the lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) in a Spanish population with pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG). MATERIALS AND METHODS: The present case-control study included 100 Spanish patients (60 patients with XFS and 40 patients with XFG) and 90 control subjects. Genotypes of the three single nucleotide polymorphisms of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing. RESULTS: The G allele and the GG genotype of SNP rs3825942 were detected at a statistically higher frequency in pseudoexfoliation patients than in control subjects (p = 3.36 × 10(-5), OR = 5.71, 95% CI: 2.30-14.18; p = 3.38 × 10(-5), OR = 6.91, 95% CI: 2.51-19.03 respectively). The T allele and the TT genotype of SNP rs2165241 presented at significantly higher frequencies in pseudoexfoliation patients than in controls (p = 2.50 × 10(-4), OR = 2.18, 95% CI: 1.43-3.33; p = 1.21 × 10(-2), OR = 2.13, 95% CI: 1.75-3.85 respectively). No significant association between XFS/XFG and the rs1048661 was observed. The GGT haplotype composed of all three risk alleles was determined to be significantly associated with pseudoexfoliation. The genotypic and allelic distributions of the three SNPs were similar between XFS and XFG. CONCLUSIONS: This is the first study associating two SNPs of LOXL1 (rs3825942 and rs2165241) and XFS/XFG in a Spanish population, confirming findings in patients from Europe. However rs1048661 SNP did not show an association with XFS.

Association between SNPs of Metalloproteinases and Prostaglandin F2α Receptor Genes and Latanoprost Response in Open-Angle Glaucoma.

PURPOSE: To determine whether single nucleotide polymorphisms (SNPs) of genes coding for matrix metalloproteinases (MMPs) and the prostaglandin F2α receptor gene (PTGFR) are related to a response to latanoprost in a white Spanish population of glaucomatous patients. DESIGN: Case-control study. PARTICIPANTS: One hundred twenty-four patients with open-angle glaucoma. METHODS: Genotyping was performed in 117 patients with primary open-angle glaucoma with a minimum treatment duration of 4 weeks. Candidate genes and individual polymorphisms were selected according to the effect on the mechanism of action of latanoprost. Multi-SNP haplotype analyses for associations also were tested. MAIN OUTCOME MEASURES: Diurnal intraocular pressure reduction and genotyping of the SNPs in the MMPs and PTGFR. RESULTS: The PTGFR SNPs were associated with positive (rs6686438, rs10786455) and negative (rs3753380, rs6672484, rs11578155) responses to latanoprost. Multiple testing found 2 genes, PTGFR and MMP-1, were related to refractoriness to latanoprost. CONCLUSIONS: The SNPs of the PTGFR and MMP-1 genes may determine the latanoprost response in a white European Spanish population. This study identified 5 SNPs related to the latanoprost response; 1 SNP, rs3753380, already has been associated with a poor response to latanoprost in a healthy Japanese population. Latanoprost is a commonly used antiglaucomatous drug, and increased knowledge of its mechanism of action will lead to advances in pharmacogenetics.

Funduscopic results after 4-year follow-up treatment with ranibizumab for age-related macular degeneration in a region of Spain.

BACKGROUND: The study aims to survey longstanding funduscopic and functional outcomes of age-related macular degeneration (AMD) after ranibizumab treatment and verify the accuracy of a new method to compare the retinal thickness measured with different optical coherence tomography (OCT) tools. METHODS: Case series included 314 eyes with 2-4 years of follow-up. Main Outcome Measures were visual acuity (VA), number of injections, retinal thickness, OCT morphology, and final macular funduscopic status. RESULTS: One hundred twenty-two men and 177 women (mean age, 78.3 years) were included. The mean time to the first injection was 17.3 ± 14.6 days. Initial VA was O.8(20/125) ± 0.5; 0.7(20/100) ± 0.5 at 3 months; 0.8(20/125) ± 0.5 at a year; 1(20/200) ± 0.6 at year 2; 1(20/200) ± 0.6 at year 3 and 1.1(20/250) ± 0.6 at year 4. Number of visits at 3 months was 2.7 ± 0.8; 7.3 ± 2.1 at a year; 5.2 ± 2.7 along the 2nd year; 3.9 ± 2.3 at year 3 and 3.6 ± 2.2 at year 4. Number of injections at 3 months was 2.6 ± 0.5; 3.9 ± 1.5 at a year; 1.1 ± 1.5 along the 2nd year; 1.5 ± 2.4 at year 3 and 1.8 ± 3.1 at year 4. Patients with worse VA outcomes received more injections and were older. The formula to calculate changes in retinal thickness showed a 30% reduction in thickness, which correlated well with the OCT morphology. Patients with polypoidal choroidal vasculopathy (PCV) had a worse final outcome. The final disciform macular status (37%) was related to fewer injections and a greater decrease in thickness. Final well-preserved maculas (12.%) needed more injections and treatment changes; those that were atrophic at the final visit (30.8%) had a worse initial VA and greater decrease in thickness at the 3-month visit. CONCLUSIONS: Younger patients had better final outcomes. Our method to compare retinal thickness using different OCT tools worked well. The final visual outcome after a long follow-up was poor, which may be related to advanced age, poor initial VA, and the high incidence of final fibrosis or atrophy.

Cistoid macular edema as first manifestation of sarcoidosis.

The purpose of this study is to report a case of cystoid macular edema (CME) as a rare first manifestation of ocular sarcoidosis after cataract surgery. A 60-year-old male developed a CME following uneventful phacoemulsification cataract extraction on his left eye. It resolved with conventional medical therapy. One year later the patient was diagnosed with bilateral CME. Oral corticosteroid therapy produced a significant regression. His medical and ocular histories were unremarkable and all tests for etiological diagnosis were negative. There were inflammation recurrences in his left eye, which were also treated with steroids. Optical coherence tomography showed complete resolution of foveal thickening without improvement in vision. Four years later, the patient presented with CME in both eyes. The laboratory tests included high angiotensin-converting enzyme levels and a gallium scan which were also consistent with sarcoidosis. Azathioprine was needed for management of ocular involvement, but it was withheld due to side-effects. At the present time, the CME is controlled with low-dose corticoids. Ocular involvement in sarcoidosis occurs in 20-50 % of patients. CME is not often the initial manifestation of the disease, but ocular sarcoidosis may present with a wide variety of ocular symptoms in all parts of the eye. Therefore, sarcoidosis should be kept in mind when evaluating a patient with ocular inflammation.

Visual function and quality of life in pseudophakic patients before and after capsulotomy.

PURPOSE: To assess the correlation between visual acuity, visual function, and health-related quality of life before and after neodymium:YAG laser posterior capsulotomy. METHODS: A total of 150 patients with posterior capsule opacification (PCO) were examined before and after capsulotomy. Ocular examination, visual acuity, patient reports of satisfaction with vision, and disease-specific (VF-14 Index of Visual Functions) and generic (EuroQol: EQ-5D) outcomes were measured at baseline and 3 weeks after treatment. RESULTS: After capsulotomy, patients showed significant improvements in binocular visual acuity, VF-14 index, satisfaction with vision, and EQ-5D measures. The average gains in visual function and quality of life were apparent in groups with good visual outcome and poor visual outcome. The VF-14 score improvement was moderately correlated with the EuroQol Visual Analogue Scale score improvement, showing stronger correlations with changes in self-reported satisfaction with vision than did gains in binocular visual acuity. CONCLUSIONS: Measuring of the outcomes of capsulotomy by clinical indicators alone may underestimate the overall benefits of treatment. Visual acuity in conjunction with visual function and health-related quality of life questionnaires will likely prove to be better indicators of the need for and outcome of capsulotomy.