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1.  Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open angle glaucoma 
Cooke Bailey, Jessica N. | Loomis, Stephanie J. | Kang, Jae H. | Allingham, R. Rand | Gharahkhani, Puya | Khor, Chiea Chuen | Burdon, Kathryn P. | Aschard, Hugues | Chasman, Daniel I. | Igo, Robert P. | Hysi, Pirro G. | Glastonbury, Craig A. | Ashley-Koch, Allison | Brilliant, Murray | Brown, Andrew A. | Budenz, Donald L. | Buil, Alfonso | Cheng, Ching-Yu | Choi, Hyon | Christen, William G. | Curhan, Gary | De Vivo, Immaculata | Fingert, John H. | Foster, Paul J. | Fuchs, Charles | Gaasterland, Douglas | Gaasterland, Terry | Hewitt, Alex W. | Hu, Frank | Hunter, David J. | Khawaja, Anthony P. | Lee, Richard K. | Li, Zheng | Lichter, Paul R. | Mackey, David A. | McGuffin, Peter | Mitchell, Paul | Moroi, Sayoko E. | Perera, Shamira A. | Pepper, Keating W. | Qi, Qibin | Realini, Tony | Richards, Julia E. | Ridker, Paul M | Rimm, Eric | Ritch, Robert | Ritchie, Marylyn | Schuman, Joel S. | Scott, William K. | Singh, Kuldev | Sit, Arthur J. | Song, Yeunjoo E. | Tamimi, Rulla M. | Topouzis, Fotis | Viswanathan, Ananth C. | Verma, Shefali Setia | Vollrath, Douglas | Wang, Jie Jin | Weisschuh, Nicole | Wissinger, Bernd | Wollstein, Gadi | Wong, Tien Y. | Yaspan, Brian L. | Zack, Donald J. | Zhang, Kang | Weinreb, Robert N. | Pericak-Vance, Margaret A. | Small, Kerrin | Hammond, Christopher J. | Aung, Tin | Liu, Yutao | Vithana, Eranga N. | MacGregor, Stuart | Craig, Jamie E. | Kraft, Peter | Howell, Gareth | Hauser, Michael A. | Pasquale, Louis R. | Haines, Jonathan L. | Wiggs, Janey L.
Nature genetics  2016;48(2):189-194.
Primary open angle glaucoma (POAG) is a leading cause of blindness world-wide. To identify new susceptibility loci, we meta-analyzed GWAS results from 8 independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significant SNPs in two Australian studies (1,252 cases and 2,592 controls), 3 European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of top SNPs identified three novel loci: rs35934224[T] within TXNRD2 (odds ratio (OR) = 0.78, P = 4.05×10−11 encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] within ATXN2 (OR = 1.17, P = 8.73×10−10), and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76×10−10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest novel targets for preventative therapies.
doi:10.1038/ng.3482
PMCID: PMC4731307  PMID: 26752265
2.  A common variant mapping to CACNA1A is associated with susceptibility to Exfoliation syndrome 
Aung, Tin | Ozaki, Mineo | Mizoguchi, Takanori | Allingham, R Rand | Li, Zheng | Haripriya, Aravind | Nakano, Satoko | Uebe, Steffen | Harder, Jeffrey M. | Chan, Anita S.Y. | Lee, Mei Chin | Burdon, Kathryn P. | Astakhov, Yury S. | Abu-Amero, Khaled K. | Zenteno, Juan C. | Nilgün, Yildirim | Zarnowski, Tomasz | Pakravan, Mohammad | Safieh, Leen Abu | Jia, Liyun | Wang, Ya Xing | Williams, Susan | Paoli, Daniela | Schlottmann, Patricio G | Huang, Lulin | Sim, Kar Seng | Foo, Jia Nee | Nakano, Masakazu | Ikeda, Yoko | Kumar, Rajesh S | Ueno, Morio | Manabe, Shin-ichi | Hayashi, Ken | Kazama, Shigeyasu | Ideta, Ryuichi | Mori, Yosai | Miyata, Kazunori | Sugiyama, Kazuhisa | Higashide, Tomomi | Chihara, Etsuo | Inoue, Kenji | Ishiko, Satoshi | Yoshida, Akitoshi | Yanagi, Masahide | Kiuchi, Yoshiaki | Aihara, Makoto | Ohashi, Tsutomu | Sakurai, Toshiya | Sugimoto, Takako | Chuman, Hideki | Matsuda, Fumihiko | Yamashiro, Kenji | Gotoh, Norimoto | Miyake, Masahiro | Astakhov, Sergei Y. | Osman, Essam A. | Al-Obeidan, Saleh A. | Owaidhah, Ohoud | Al-Jasim, Leyla | Al Shahwan, Sami | Fogarty, Rhys A. | Leo, Paul | Yetkin, Yaz | Oğuz, Çilingir | Kanavi, Mozhgan Rezaei | Beni, Afsaneh Naderi | Yazdani, Shahin | Akopov, Evgeny L. | Toh, Kai-Yee | Howell, Gareth R | Orr, Andrew C. | Goh, Yufen | Meah, Wee Yang | Peh, Su Qin | Kosior-Jarecka, Ewa | Lukasik, Urszula | Krumbiegel, Mandy | Vithana, Eranga N | Wong, Tien Yin | Liu, Yutao | Ashley Koch, Allison E. | Challa, Pratap | Rautenbach, Robyn M | Mackey, David A. | Hewitt, Alex W | Mitchell, Paul | Wang, Jie Jin | Ziskind, Ari | Carmichael, Trevor | Ramakrishnan, Rangappa | Narendran, Kalpana | Venkatesh, Rangaraj | Vijayan, Saravanan | Zhao, Peiquan | Chen, Xueyi | Guadarrama-Vallejo, Dalia | Cheng, Ching Yu | Perera, Shamira A | Husain, Rahat | Ho, Su-Ling | Welge-Luessen, Ulrich-Christoph | Mardin, Christian | Schloetzer-Schrehardt, Ursula | Hillmer, Axel M. | Herms, Stefan | Moebus, Susanne | Nöthen, Markus M. | Weisschuh, Nicole | Shetty, Rohit | Ghosh, Arkasubhra | Teo, Yik Ying | Brown, Matthew A | Lischinsky, Ignacio | Crowston, Jonathan G | Coote, Michael | Zhao, Bowen | Sang, Jinghong | Zhang, Nihong | You, Qisheng | Vysochinskaya, Vera | Founti, Panayiota | Chatzikyriakidou, Anthoula | Lambropoulos, Alexandros | Anastasopoulos, Eleftherios | Coleman, Anne L | Wilson, M Roy | Rhee, Douglas J | Kang, Jae Hee | May-Bolchakova, Inna | Heegaard, Steffen | Mori, Kazuhiko | Alward, Wallace L.M. | Jonas, Jost B | Xu, Liang | Liebmann, Jeffrey M | Chowbay, Balram | Schaeffeler, Elke | Schwab, Matthias | Lerner, Fabian | Wang, Ningli | Yang, Zhenglin | Frezzotti, Paolo | Kinoshita, Shigeru | Fingert, John H. | Inatani, Masaru | Tashiro, Kei | Reis, André | Edward, Deepak P. | Pasquale, Louis R. | Kubota, Toshiaki | Wiggs, Janey L. | Pasutto, Francesca | Topouzis, Fotis | Dubina, Michael | Craig, Jamie E. | Yoshimura, Nagahisa | Sundaresan, Periasamy | John, Simon W.M. | Ritch, Robert | Hauser, Michael A | Khor, Chiea-Chuen
Nature genetics  2015;47(4):387-392.
Exfoliation syndrome (XFS) is the commonest recognizable cause of open angle glaucoma world-wide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) on 1,484 patients and 1,188 controls from Japan, and followed up the most significant findings on a further 6,901 patients and 20,727 controls from 17 countries across 6 continents. We discovered a significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (Odds ratio [OR] = 1.16, P = 3.36 × 10−11). Although overwhelming association at the LOXL1 locus was confirmed, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on ethnic grouping (In Japanese: ORA-allele= 9.87, P = 2.13 × 10−217; In non-Japanese: ORA-allele= 0.49, P = 2.35 × 10−31). Our findings represent the first genetic locus outside of LOXL1 which surpasses genome-wide significance for XFS, and provides insight into the biology and pathogenesis of the disease.
doi:10.1038/ng.3226
PMCID: PMC4605818  PMID: 25706626
3.  Increasing Prevalence of Myopia in Europe and the Impact of Education 
Ophthalmology  2015;122(7):1489-1497.
Purpose
To investigate whether myopia is becoming more common across Europe and explore whether increasing education levels, an important environmental risk factor for myopia, might explain any temporal trend.
Design
Meta-analysis of population-based, cross-sectional studies from the European Eye Epidemiology (E3) Consortium.
Participants
The E3 Consortium is a collaborative network of epidemiological studies of common eye diseases in adults across Europe. Refractive data were available for 61 946 participants from 15 population-based studies performed between 1990 and 2013; participants had a range of median ages from 44 to 78 years.
Methods
Noncycloplegic refraction, year of birth, and highest educational level achieved were obtained for all participants. Myopia was defined as a mean spherical equivalent ≤−0.75 diopters. A random-effects meta-analysis of age-specific myopia prevalence was performed, with sequential analyses stratified by year of birth and highest level of educational attainment.
Main Outcome Measures
Variation in age-specific myopia prevalence for differing years of birth and educational level.
Results
There was a significant cohort effect for increasing myopia prevalence across more recent birth decades; age-standardized myopia prevalence increased from 17.8% (95% confidence interval [CI], 17.6–18.1) to 23.5% (95% CI, 23.2–23.7) in those born between 1910 and 1939 compared with 1940 and 1979 (P = 0.03). Education was significantly associated with myopia; for those completing primary, secondary, and higher education, the age-standardized prevalences were 25.4% (CI, 25.0–25.8), 29.1% (CI, 28.8–29.5), and 36.6% (CI, 36.1–37.2), respectively. Although more recent birth cohorts were more educated, this did not fully explain the cohort effect. Compared with the reference risk of participants born in the 1920s with only primary education, higher education or being born in the 1960s doubled the myopia prevalence ratio–2.43 (CI, 1.26–4.17) and 2.62 (CI, 1.31–5.00), respectively—whereas individuals born in the 1960s and completing higher education had approximately 4 times the reference risk: a prevalence ratio of 3.76 (CI, 2.21–6.57).
Conclusions
Myopia is becoming more common in Europe; although education levels have increased and are associated with myopia, higher education seems to be an additive rather than explanatory factor. Increasing levels of myopia carry significant clinical and economic implications, with more people at risk of the sight-threatening complications associated with high myopia.
doi:10.1016/j.ophtha.2015.03.018
PMCID: PMC4504030  PMID: 25983215
CI, confidence interval; D, diopters; E3, European Eye Epidemiology
4.  Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma 
Nature genetics  2014;46(10):1120-1125.
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 advanced POAG cases and 1,992 controls. Association of the top SNPs from the discovery stage was investigated in two Australian replication cohorts (total 932 cases, 6,862 controls) and two US replication cohorts (total 2,616 cases, 2,634 controls). Meta-analysis of all cohorts revealed three novel loci associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493 [G] OR=1.31, P= 2.1 × 10-19), within AFAP1 (rs4619890 [G] OR=1.20, P= 7.0 × 10-10) and within GMDS (rs11969985 [G] OR=1.31, and P= 7.7 × 10-10). Using RT-PCR and immunolabelling, we also showed that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
doi:10.1038/ng.3079
PMCID: PMC4177327  PMID: 25173105
5.  Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma 
Nature genetics  2014;46(10):1120-1125.
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 advanced POAG cases and 1,992 controls. Association of the top SNPs from the discovery stage was investigated in two Australian replication cohorts (total 932 cases, 6,862 controls) and two US replication cohorts (total 2,616 cases, 2,634 controls). Meta-analysis of all cohorts revealed three novel loci associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493 [G] OR=1.31, P= 2.1 × 10−19), within AFAP1 (rs4619890 [G] OR=1.20, P= 7.0 × 10−10) and within GMDS (rs11969985 [G] OR=1.31, and P= 7.7 × 10−10). Using RT-PCR and immunolabelling, we also showed that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
doi:10.1038/ng.3079
PMCID: PMC4177327  PMID: 25173105
6.  Prevalence of refractive error in Europe: the European Eye Epidemiology (E3) Consortium 
European Journal of Epidemiology  2015;30(4):305-315.
To estimate the prevalence of refractive error in adults across Europe. Refractive data (mean spherical equivalent) collected between 1990 and 2013 from fifteen population-based cohort and cross-sectional studies of the European Eye Epidemiology (E3) Consortium were combined in a random effects meta-analysis stratified by 5-year age intervals and gender. Participants were excluded if they were identified as having had cataract surgery, retinal detachment, refractive surgery or other factors that might influence refraction. Estimates of refractive error prevalence were obtained including the following classifications: myopia ≤−0.75 diopters (D), high myopia ≤−6D, hyperopia ≥1D and astigmatism ≥1D. Meta-analysis of refractive error was performed for 61,946 individuals from fifteen studies with median age ranging from 44 to 81 and minimal ethnic variation (98 % European ancestry). The age-standardised prevalences (using the 2010 European Standard Population, limited to those ≥25 and <90 years old) were: myopia 30.6 % [95 % confidence interval (CI) 30.4–30.9], high myopia 2.7 % (95 % CI 2.69–2.73), hyperopia 25.2 % (95 % CI 25.0–25.4) and astigmatism 23.9 % (95 % CI 23.7–24.1). Age-specific estimates revealed a high prevalence of myopia in younger participants [47.2 % (CI 41.8–52.5) in 25–29 years-olds]. Refractive error affects just over a half of European adults. The greatest burden of refractive error is due to myopia, with high prevalence rates in young adults. Using the 2010 European population estimates, we estimate there are 227.2 million people with myopia across Europe.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-015-0010-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s10654-015-0010-0
PMCID: PMC4385146  PMID: 25784363
Refractive error; Myopia; Epidemiology; Prevalence; Consortium
7.  Comparison of the effects of bimatoprost and a fixed combination of latanoprost and timolol on 24-hour blood and ocular perfusion pressures: the results of a randomized trial 
BMC Ophthalmology  2015;15:7.
Background
To compare the effect of bimatoprost and the fixed combination latanoprost-timolol (LTFC) on 24-hour systolic (SBP) and diastolic (DBP) blood pressure and on 24-hour ocular perfusion pressure (OPP).
Methods
200 patients with glaucoma or ocular hypertension, controlled on the unfixed combination of latanoprost and timolol or eligible for dual therapy being not being fully controlled on monotherapy were enrolled in a randomized, double-masked, placebo-controlled, multicentre clinical trial. They were randomized to LTFC (8 a.m.) or bimatoprost (8 p.m.) and received 24-hour IOP curve at baseline, 6 and 12 weeks (supine and sitting position IOPs were recorded at 8 p.m., midnight, 5 a.m., 8a.m., noon and 4 p.m.). Holter 24-hour blood pressure curve was obtained between weeks 2 and 12. SBP, DBP, OPP were calculated and compared with ANOVA. Rates of diastolic OPP (DPP) ≤50, ≤40, ≤30 mmHg in the 2 groups were calculated and compared using Fisher’s test.
Results
Mean baseline SBP and DBP were 136.5 ± 18.3 vs 134.2 ± 20.1 mmHg (p = 0.1) and 79.1 ± 10.2 vs 78.2 ± 10.1 mmHg (p = 0.4) in the bimatoprost and LTFC groups respectively. Holter SBP was significantly higher for bimatoprost (135.1 mmHg vs 128.1 mmHg, p = 0.04), while no statistically significant difference in DBP was found. DPP was similar in the 2 groups, and proportions of patients with at least one value of the 24-hour curve ≤50, ≤40, ≤30 mmHg were 94%, 86%, 41% respectively.
Conclusions
Bimatoprost and LTFC had similar DBPs and OPPs; SBP was significantly lower with LTFC. In this study, the percentage of “dippers” was considerably higher than the one described in previous studies on the role of perfusion pressure in glaucoma.
Trial registration
NCT02154217, May 21, 2014.
doi:10.1186/1471-2415-15-7
PMCID: PMC4320581  PMID: 25613811
8.  Association of LOXL1 Polymorphisms With Pseudoexfoliation, Glaucoma, Intraocular Pressure, and Systemic Diseases in a Greek Population. The Thessaloniki Eye Study 
Purpose.
To investigate the association of the two single-nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene with pseudoexfoliation syndrome (PEX), pseudoexfoliative glaucoma (PEXG), and primary open-angle glaucoma (POAG) in a Greek population–based setting, from the Thessaloniki Eye study.
Methods.
A total of 233 subjects with successful DNA extraction, PCR amplification, and genotyping were included in the genetic analysis of G153D and R141L SNPs of LOXL1 gene and classified into four groups: controls (n = 93); subjects with PEX (n = 40); POAG (n = 66); and PEXG (n = 34). Multinomial logistic regression was used to test their association with LOXL1 SNPs with adjustment for covariates. The association of LOXL1 with IOP (in untreated subjects) and with systemic diseases was explored.
Results.
Both LOXL1 SNPs were present in high frequencies in controls and cases. The G153D was strongly associated with both PEX (odds ratio [OR] = 23.2, P = 0.003 for allele G) and PEXG (OR = 24.75, P = 0.003 for allele G) and was not associated with POAG (P = 0.451). In contrast, the R141L was not associated with PEX (P = 0.81), PEXG (P = 0.063), or POAG (P = 0.113). No association of the G153D with either intraocular pressure (IOP) or systemic diseases was found.
Conclusions.
In the Thessaloniki Eye Study, the G153D SNP of LOXL1 gene was strongly associated with both PEX and PEXG, whereas the R141L was not associated. No association of the LOXL1 with IOP or with systemic diseases was found. These findings further support the hypothesis that the LOXL1 gene contributes to onset of PEXG through PEX. Gene variants of LOXL1 do not help to identify those with PEX at increased risk for glaucoma development.
In the Thessaloniki Eye Study, the G153D SNP of LOXL1 was associated with PEX and PEXG, whether the R141L was or not. No association was found for the LOXL1 with intraocular pressure and systemic diseases.
doi:10.1167/iovs.14-13991
PMCID: PMC4095722  PMID: 24917141
LOXL1; pseudoexfoliation; pseudoexfoliative glaucoma
9.  Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error 
Human Molecular Genetics  2013;22(13):2754-2764.
Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (‘Cooperative Health Research in the Region of Augsburg’); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10−9) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.
doi:10.1093/hmg/ddt116
PMCID: PMC3674806  PMID: 23474815
10.  Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus 
Human Molecular Genetics  2013;22(22):4653-4660.
To discover quantitative trait loci for intraocular pressure, a major risk factor for glaucoma and the only modifiable one, we performed a genome-wide association study on a discovery cohort of 2175 individuals from Sydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10−8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30–0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.
doi:10.1093/hmg/ddt293
PMCID: PMC3904806  PMID: 23836780
11.  Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype 
Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case–control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, ‘Y402H’) with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene–smoking interaction; and 16 published studies from non-European ancestry.
Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10–2.45; P = 1.1 x 10−161]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
doi:10.1093/ije/dyr204
PMCID: PMC3304526  PMID: 22253316
Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis
12.  Cross-Linking as an Adjuvant Treatment for Tectonic Corneal Lamellar Graft Preparation 
Purpose:
To describe a new surgical approach for the tectonic reconstruction of the anterior ocular segment and the management of scleral and conjuctival melting.
Methods:
Case series of patients demonstrating anterior segment anomalies, such as scleral and conjunctival melting. The anterior stromal part of a pre-cut corneal graft for Descemet’s stripping automated endothelial keratoplasty (DSAEK) was cross-linked with riboflavin and ultraviolet A irradiation and was used to cover scleral (scleral melting in a patient with necrotizing scleritis, one case) and conjuctival (dehiscence of the conjunctiva in patients with anti-glaucomatous valve exposure, two cases) areas. The endothelial part of all corneal grafts was used for DSAEK in patients with need of corneal endothelial transplantation.
Results:
Repair of scleral and conjuctival melting was successful in all cases. No intra- or post- operative complications occured. Visual acuity of all patients remained stable during the follow up period. One year postoperatively the corneal graft remained in place and no signs of inflammation were evident, while all grafts were epithelialized.
Conclusions:
The use of cross-linked corneal graft for the tectonic reconstruction of the anterior ocular segment represents an adequate surgical approach for the management of scleral and conjuctival melting; while, at the same time it offers the advantage of using one corneal graft for two recipients.
doi:10.2174/1874364101307010079
PMCID: PMC3837367  PMID: 24278090
Corneal collagen cross-linking; scleral melting; conjuctival melting; corneal transplantation.
13.  Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies 
Human mutation  2011;32(12):1407-1416.
Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status, has been reported. We present a pooled analysis (n=21,160) demonstrating associations between late AMD and APOε4 (OR=0.72 per haplotype; CI: 0.65–0.74; P=4.41×10−11) and APOε2 (OR=1.83 for homozygote carriers; CI: 1.04–3.23; P=0.04), following adjustment for age-group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR=1.54; CI: 1.38–1.72; P=2.8×10−15) and atrophic (OR=1.38; CI: 1.18–1.61; P=3.37×10−5) AMD but not early AMD (OR=0.94; CI: 0.86–1.03; P=0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyondε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.
doi:10.1002/humu.21577
PMCID: PMC3217135  PMID: 21882290
age-related macular degeneration; AMD; apolipoprotein E; APOE; case-control association study
14.  Variations in Apolipoprotein E Frequency With Age in a Pooled Analysis of a Large Group of Older People 
American Journal of Epidemiology  2011;173(12):1357-1364.
Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ2 for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ2 for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
doi:10.1093/aje/kwr015
PMCID: PMC3145394  PMID: 21498624
aged; apolipoprotein E2; apolipoprotein E3; apolipoprotein E4; apolipoproteins E; longevity; meta-analysis; multicenter study
15.  Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma 
PLoS Genetics  2012;8(5):e1002611.
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4×10−8), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6×10−8). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4×10−2 for rs11656696 and p = 9.1×10−4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
Author Summary
Glaucoma is a major eye disease in the elderly and is the second leading cause of blindness worldwide. The numerous familial glaucoma cases, as well as evidence from epidemiological and twin studies, strongly support a genetic component in developing glaucoma. However, it has proven difficult to identify the specific genes involved. Intraocular pressure (IOP) is the major risk factor for glaucoma and the only target for the current glaucoma therapy. IOP has been shown to be highly heritable. We investigated the role of common genetic variants in IOP by performing a genome-wide association study. Discovery analyses in 11,972 participants and subsequent replication analyses in a further 7,482 participants yielded two common genetic variants that were associated with IOP. The first (rs11656696) is located in GAS7 at chromosome 17, the second (rs7555523) in TMCO1 at chromosome 1. Both variants were associated with glaucoma in a meta-analysis of 4 case-control studies. GAS7 and TMCO1 are expressed in the ocular tissues that are involved in glaucoma. Both genes functionally interact with the known glaucoma disease genes. These data suggest that we have identified two genes involved in IOP regulation and glaucomatous neuropathy.
doi:10.1371/journal.pgen.1002611
PMCID: PMC3342933  PMID: 22570627
16.  Weighing in Ocular Perfusion Pressure in Managing Glaucoma 
The role of vascular risk factors in glaucoma is increasingly being supported by the literature, with the association between low ocular perfusion pressure (PP) and glaucoma being the most consistent result. However, we need to be cautious when interpreting these results and consider all possible confounders in the observed associations. While we assess PP through its principal components, the weight of intraocular pressure (IOP) and blood pressure (BP) in the PP equation remains unknown. Also, the role of PP in glaucoma needs to be elucidated with regards to IOP and BP fluctuation during the 24hour period and the effect of IOP-lowering and BP-lowering treatment. The complexity of the interaction of PP with other potential risk factors for glaucoma means that PP cannot be currently considered in the assessment of an individual patient. The role of PP in glaucoma warrants further research and randomized clinical trials assessing PP should include vision and/or structure preservation as end-points and ideally address all of the above issues.
doi:10.2174/1874364100903010043
PMCID: PMC2759119  PMID: 19816588

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