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1.  Evaluation of MMP1 and MMP3 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma 
Molecular Vision  2009;15:2890-2895.
Purpose
To investigate possible genetic associations of matrix metalloproteinase-1 (MMP1) and MMP3 gene polymorphisms with exfoliation syndrome (XFS) with (XFS/+G) and without (XFS/-G) glaucoma in a cohort of Greek patients.
Methods
A total of 182 unrelated Greek patients with XFS, including 92 patients with XFS/+G, and 214 unrelated age- and gender-matched controls were enrolled in the study. MMP1 -1607 1G/2G (rs1799750) and MMP3 -1171 5A/6A (rs3025058) polymorphisms were determined using standard PCR/restriction fragment length polymorphism methods. Differences in allele and genotype distributions were analyzed using logistic regression.
Results
The distribution of genotypes and alleles in MMP1 and MMP3 polymorphisms was not significantly different between cases with exfoliation syndrome, with or without glaucoma, and controls. However, the allele contrast for the MMP1 variant showed a trend for a significant association with XFS/-G (Odds Ratio=1.47 [1.03–2.10]), since after correction for multiple comparisons, this association was no longer statistically significant.
Conclusions
Our study provided some evidence of a possible role of the MMP1 variant in the development of exfoliation syndrome in Greek patients.
PMCID: PMC2797043  PMID: 20038976
2.  FLT1 Genetic Variation Predisposes to Neovascular AMD in Ethnically Diverse Populations and Alters Systemic FLT1 Expression 
Purpose.
Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway.
Methods.
Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis.
Results.
The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway.
Conclusions.
Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.
Significance of VEGF pathway genetic variation within AMD is unclear. We demonstrate genetic risk for neovascular AMD present in FLT1, but not KDR, VASH1, or VEGFA using multiple, ethnically diverse cohorts. The association was more significant in meta-analysis than in any single cohort.
doi:10.1167/iovs.14-14047
PMCID: PMC4073997  PMID: 24812550
age-related macular degeneration; angiogenesis; FLT1; VEGF
3.  Plasma homocysteine and genetic variants of homocysteine metabolism enzymes in patients from central Greece with primary open-angle glaucoma and pseudoexfoliation glaucoma 
Background
The purpose of this study was to investigate plasma homocysteine levels and polymorphisms in genes encoding enzymes in the metabolic pathway of homocysteine in association with primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXFG).
Methods
A total of 156 glaucoma patients (76 with POAG and 80 with PXFG) and 135 controls matched for age and sex were enrolled in this study. Plasma homocysteine levels were measured using a commercially available enzyme-linked immunosorbent assay kit. DNA was extracted from peripheral blood leukocytes and real-time polymerase chain reaction was performed for genotyping of the samples. Patients were genotyped using predesigned TaqMan® single nucleotide polymorphism genotyping assays for two exon variations (rs1801131, rs1801133) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and one intron variation (rs8006686) in the methylenetetrahydrofolate dehydrogenase (MTHFD1) gene.
Results
Homocysteine levels were slightly higher in the patient group (POAG and PXFG) compared with controls, but the difference did not reach statistical significance. The minor alleles of the MTHFR single nucleotide polymorphisms showed a protective effect for POAG and showed an increased risk for PXFG, but none of these associations reached statistical significance (P>0.05). The minor allele of MTHFD1 rs8006686 showed a trend for increased risk of both POAG and PXFG (P>0.05). No statistically significant interaction was seen between the genetic variants and homocysteine levels (P>0.05).
Conclusion
Our results show that neither the examined single nucleotide polymorphisms from genes involved in the pathway of homocysteine metabolism nor the measured homocysteine levels were associated with POAG or PXFG in our study cohort.
doi:10.2147/OPTH.S64904
PMCID: PMC4166342  PMID: 25246760
homocysteine; glaucoma; polymorphisms
4.  Perimetric and retinal nerve fiber layer findings in patients with Parkinson’s disease 
BMC Ophthalmology  2012;12:54.
Background
Visual dysfunction is common in Parkinson’s disease (PD). It remains, however, unknown whether it is related to structural alterations of the retina. The aim of this study is to compare visual field (VF) findings and circumpapillary retinal nerve fiber layer (RNFL) thickness in a series of PD patients and normal controls, in order to assess possible retinal anatomical changes and/or functional damage associated with PD.
Methods
PD patients and controls were recruited and underwent VF testing with static automated perimetry and RNFL examination with optical coherence tomography (OCT). Cognitive performance using Mini Mental State Examination (MMSE), PD staging using modified Hoehn and Yahr (H-Y) scale and duration of the disease was recorded in PD patients.
Results
One randomly selected eye from each of 24 patients and 24 age-matched controls was included. OCT RNFL thickness analysis revealed no difference in the inferior, superior, nasal or temporal sectors between the groups. The average peripapillary RNFL was also similar in the two groups. However, perimetric indices of generalized sensitivity loss (mean deviation) and localized scotomas (pattern standard deviation) were worse in patients with PD compared to controls (p < 0.01). 73% of eyes of PD patients had glaucomatous-like asymmetrical hemifield defects with abnormal Glaucoma Hemifield Test and various combinations of arcuate defects (n = 12), nasal steps (n = 11) and paracentral scotomas (n = 16). Bilateral defects were found in 14 patients (58%). No correlation was found between VF indices and MMSE or H-Y scores.
Conclusion
PD patients may demonstrate glaucomatous-like perimetric defects even in the absence of decreased RNFL thickness.
doi:10.1186/1471-2415-12-54
PMCID: PMC3515471  PMID: 23031247
Visual loss; Visual fields; Parkinson's disease; Retina; Visual processing
5.  The Floppy Eyelid Syndrome: Evaluating Lid Laxity and Its Correlation to Sleep Apnea Syndrome and Body Mass Index 
ISRN Ophthalmology  2012;2012:650892.
Background. The aim of this study is to present a method of lid laxity evaluation and investigate whether there is an association between floppy eyelid syndrome (FES) and body mass index (BMI) in sleep apnea syndrome (SAS) patients compared to normal subjects. Method. A total of 135 participants (81 patients with SAS and 54 normal subjects) had a full ophthalmologic examination. The presence of FES was estimated in relation to SAS and BMI. Results. The floppy eyelid was characterized “hyperelastic,” “FES stage 1 (asymptomatic),” or “FES stage 2 (symptomatic)” depending on its laxity capacity. Hyperelastic floppy eyelid in SAS patients was statistically significant (P < 0.05) when compared to normals. Similarly, the presence of hyperelasticity in high-BMI SAS patients was also statistically significant (P < 0.05) when compared to low-BMI SAS patients. Floppy eyelid syndrome was more frequent in SAS patients than in normal subjects (P < 0.05), but no association was found between FES and obesity (P > 0.05). Conclusion. A classification of FES is proposed based on lid laxity. In addition to this, our data suggests a clear association of hyperelasticity and FES to SAS patients but no association between obesity and FES.
doi:10.5402/2012/650892
PMCID: PMC3914272  PMID: 24558590
6.  European ST80 community-associated methicillin-resistant Staphylococcus aureus orbital cellulitis in a neonate 
BMC Ophthalmology  2012;12:7.
Background
Methicillin-resistant Staphylococcus aureus is a serious cause of morbidity and mortality in hospital environment, but also, lately, in the community. This case report is, to our knowledge, the first detailed description of a community-associated methicillin-resistant S. aureus ST80 orbital cellulitis in a previously healthy neonate. Possible predisposing factors of microbial acquisition and treatment selection are also discussed.
Case presentation
A 28-day-old Caucasian boy was referred to our hospital with the diagnosis of right orbital cellulitis. His symptoms included right eye proptosis, periocular edema and redness. Empirical therapy of intravenous daptomycin, rifampin and ceftriaxone was initiated. The culture of pus yielded a methicillin-resistant S. aureus isolate and the molecular analysis revealed that it was a Panton-Valentine leukocidine-positive ST80 strain. The combination antimicrobial therapy was continued for 42 days and the infection was successfully controlled.
Conclusions
Clinicians should be aware that young infants, even without any predisposing condition, are susceptible to orbital cellulitis caused by community-associated methicillin-resistant S. aureus. Prompt initiation of the appropriate empirical therapy, according to the local epidemiology, should successfully address the infection, preventing ocular and systemic complications.
doi:10.1186/1471-2415-12-7
PMCID: PMC3352026  PMID: 22490061
Neonatal orbital cellulitis; Methicillin-resistant; Staphylococcus aureus; Daptomycin
7.  Influence of ROBO1 and RORA on Risk of Age-Related Macular Degeneration Reveals Genetically Distinct Phenotypes in Disease Pathophysiology 
PLoS ONE  2011;6(10):e25775.
ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD. We evaluated association of 19 single nucleotide polymorphisms (SNPs) in ROBO1 with wet and dry stages of AMD in a sibling cohort and a Greek case-control cohort containing 491 wet AMD cases, 174 dry AMD cases and 411 controls. Association signals and interaction results were replicated in an independent prospective cohort (1070 controls, 164 wet AMD cases, 293 dry AMD cases). The most significantly associated ROBO1 SNPs were rs1387665 under an additive model (meta P = 0.028) for wet AMD and rs9309833 under a recessive model (meta P = 6×10−4) for dry AMD. Further analyses revealed interaction between ROBO1 rs9309833 and RORA rs8034864 for both wet and dry AMD (interaction P<0.05). These studies were further supported by whole transcriptome expression profile studies from 66 human donor eyes and chromatin immunoprecipitation assays from mouse retinas. These findings suggest that distinct ROBO1 variants may influence the risk of wet and dry AMD, and the effects of ROBO1 on AMD risk may be modulated by RORA variants.
doi:10.1371/journal.pone.0025775
PMCID: PMC3188561  PMID: 21998696
8.  Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration 
Human Genomics  2011;5(6):538-568.
Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance.
Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.
doi:10.1186/1479-7364-5-6-538
PMCID: PMC3525248  PMID: 22155603
vitamin D; age-related macular degeneration

Results 1-8 (8)