Publications by authors named "Fotis Topouzis"

84 Publications

Emerging Treatment Modalities for Neovascular Age-Related Macular Degeneration: A Systematic Overview.

Adv Ther 2021 Nov 1. Epub 2021 Nov 1.

1st University Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Introduction: Neovascular age-related macular degeneration (nAMD) represents a leading cause of irreversible visual loss affecting the quality of life of millions of elderly patients worldwide. Although the introduction of intravitreal injections with anti-vascular endothelial growth factors (anti-VEGF) agents has revolutionized the management of nAMD, their effectiveness and ultimate success are limited by several therapeutic challenges. Consequently, real-world efficacy appears significantly inferior to that reported by randomized controlled trials. Therefore, further innovative, long-term treatment options are essential to improve the prognosis and outcome of nAMD therapy.

Methods: Emerging pharmacological therapies for nAMD and those currently in clinical trials are reviewed and their mechanism of action, safety, and efficacy are discussed. The evidence presented herein has been collected from online databases PubMed, Cochrane library, and the ClinicalTrials.gov site.

Results: A number of promising technologies and novel anti-VEGF therapies are currently being tested and some have already reached phase III trials. Anti-VEGF agents with enhanced durability and possibly efficacy, gene therapy, angiogenic targets, alternative drug delivery routes such as sustained delivery implants, drug carriers, and encapsulated cell technology are currently being explored. We briefly discuss the potential value of these options.

Conclusion: Several options may optimize future nAMD management. On the basis of current, albeit limited evidence, the most promising technology to reach clinical practice soon appears to be the sustained drug delivery options, which may improve visual outcome and reduce the socioeconomic burden of nAMD.
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http://dx.doi.org/10.1007/s12325-021-01949-7DOI Listing
November 2021

An interpretable multiple-instance approach for the detection of referable diabetic retinopathy in fundus images.

Sci Rep 2021 07 12;11(1):14326. Epub 2021 Jul 12.

Multimedia Understanding Group, Information Processing Laboratory, Department of Electrical and Computer Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Diabetic retinopathy (DR) is one of the leading causes of vision loss across the world. Yet despite its wide prevalence, the majority of affected people lack access to the specialized ophthalmologists and equipment required for monitoring their condition. This can lead to delays in the start of treatment, thereby lowering their chances for a successful outcome. Machine learning systems that automatically detect the disease in eye fundus images have been proposed as a means of facilitating access to retinopathy severity estimates for patients in remote regions or even for complementing the human expert's diagnosis. Here we propose a machine learning system for the detection of referable diabetic retinopathy in fundus images, which is based on the paradigm of multiple-instance learning. Our method extracts local information independently from multiple rectangular image patches and combines it efficiently through an attention mechanism that focuses on the abnormal regions of the eye (i.e. those that contain DR-induced lesions), thus resulting in a final image representation that is suitable for classification. Furthermore, by leveraging the attention mechanism our algorithm can seamlessly produce informative heatmaps that highlight the regions where the lesions are located. We evaluate our approach on the publicly available Kaggle, Messidor-2 and IDRiD retinal image datasets, in which it exhibits near state-of-the-art classification performance (AUC of 0.961 in Kaggle and 0.976 in Messidor-2), while also producing valid lesion heatmaps (AUPRC of 0.869 in the 81 images of IDRiD that contain pixel-level lesion annotations). Our results suggest that the proposed approach provides an efficient and interpretable solution against the problem of automated diabetic retinopathy grading.
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http://dx.doi.org/10.1038/s41598-021-93632-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275626PMC
July 2021

Twelve-Year Incidence of Open-angle Glaucoma: The Thessaloniki Eye Study.

J Glaucoma 2021 09;30(9):851-858

Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Objective: The objective of this study was to determine the 12-year incidence of open-angle glaucoma (OAG), with further classification into primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG), in an elderly White population.

Design: A longitudinal, population-based study in urban Northern Greece.

Participant: Surviving cohort of the 2554 Thessaloniki Eye Study subjects 60 years and above who had the baseline examination.

Methods: The surviving cohort was re-examined 12 years after baseline, using the same methodology and the same standard operating procedures as in the baseline examination. The definitions of glaucoma and pseudoexfoliation were consistent throughout the study. The 12-year incidences of OAG, POAG, and PEXG with corresponding 95% confidence intervals (CIs) were calculated for the whole study population, consisting of clinic-visit and home-visit participants. The population at risk was defined as those who did not meet the study criteria for the diagnosis of glaucoma in either eye at baseline.

Main Outcome Measures: Twelve-year incidence of OAG, with further classification into POAG and PEXG.

Results: Of 1468 eligible subjects in the surviving cohort, 1092 were examined (participation rate 74%). Mean age at baseline was 68.9±4.6 years. Mean follow-up time was 11.6±1.6 years. The 12-year incidence of OAG was 4.4% (95% CI: 3.3-5.8); 0.37% per year. In the overall population the incidence of POAG and PEXG was 2.1% (95% CI: 1.3-3.2) and 2.3% (95% CI: 1.5-3.4), respectively. The corresponding incidence proportions were 2.9 (95% CI: 1.8-4.3) in those without PEX and 8.9 (95% CI: 5.8-12.9) in those with PEX at baseline and/or incidence. The latter was strongly associated with higher odds for incident glaucoma (odds ratio=3.34, 95% CI: 1.83-6.08, P<0.001). Of all incident OAG cases, 11.1% (95% CI: 4.4-24) had baseline intraocular pressure >21 mm Hg.

Conclusions: The incidence of OAG was similar or higher compared with other White populations. The incidence of glaucoma in those with PEX was higher compared with the incidence of glaucoma in those without PEX.
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http://dx.doi.org/10.1097/IJG.0000000000001899DOI Listing
September 2021

Ocular biomarkers and their role in the early diagnosis of neurocognitive disorders.

Eur J Ophthalmol 2021 Nov 17;31(6):2808-2817. Epub 2021 May 17.

1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia Thraki, Greece.

Given the fact that different types of dementia can be diagnosed only postmortem or when the disease has progressed enough to cause irreversible damage to certain brain areas, there has been an increasing need for the development of sensitive and reliable methods that can detect early preclinical forms of dementia, before the symptoms have even appeared. Ideally, such a method would have the following characteristics: to be inexpensive, sensitive and specific, Non-invasive, fast and easily accessible. The ophthalmologic examination and especially the study of the retina, has caught the attention of many researchers, as it can provide a lot of information about the CNS and it fulfills many of the aforementioned criteria. Since the introduction of the non-invasive optical coherence tomography (OCT) and the newly developed modality OCT-angiography (OCT-A) that can demonstrate the structure and the microvasculature of the retina and choroid, respectively, there have been promising results regarding the value of the ophthalmologic examination in the early diagnosis of Alzheimer's disease. In this review paper, we summarize and discuss the ocular findings in patients with cognitive impairment disorders and we highlight the importance of the ophthalmologic examination to the diagnosis of these disorders.
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http://dx.doi.org/10.1177/11206721211016311DOI Listing
November 2021

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

JAMA 2021 02;325(8):753-764

Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

The Contribution of Ocular Biomarkers in the Differential Diagnosis of Alzheimer's Disease versus Other Types of Dementia and Future Prospects.

J Alzheimers Dis 2021 ;80(2):493-504

1st Neurology Department, AHEPA University Hospital, Thessaloniki, Greece.

With dementia becoming increasingly prevalent, there is a pressing need to become better equipped with accurate diagnostic tools that will favorably influence its course via prompt and specific intervention. The overlap in clinical manifestation, imaging, and even pathological findings between different dementia syndromes is one of the most prominent challenges today even for expert physicians. Since cerebral microvasculature and the retina share common characteristics, the idea of identifying potential ocular biomarkers to facilitate diagnosis is not a novel one. Initial efforts included studying less quantifiable parameters such as aspects of visual function, extraocular movements, and funduscopic findings. However, the really exciting prospect of a non-invasive, safe, fast, reproducible, and quantifiable method of pinpointing novel biomarkers has emerged with the advent of optical coherence tomography (OCT) and, more recently, OCT angiography (OCTA). The possibility of analyzing multiple parameters of retinal as well as retinal microvasculature variables in vivo represents a promising opportunity to investigate whether specific findings can be linked to certain subtypes of dementia and aid in their earlier diagnosis. The existing literature on the contribution of the eye in characterizing dementia, with a special interest in OCT and OCTA parameters will be reviewed and compared, and we will explicitly focus our effort in advancing our understanding and knowledge of relevant biomarkers to facilitate future research in the differential diagnosis between Alzheimer's disease and common forms of cognitive impairment, including vascular dementia, frontotemporal dementia, and dementia with Lewy bodies.
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http://dx.doi.org/10.3233/JAD-201516DOI Listing
September 2021

Factors associated with non-active retinal capillary density as measured with Confocal Scanning Laser Doppler Flowmetry in an elderly population: the Thessaloniki Eye Study (TES).

Br J Ophthalmol 2020 09 29;104(9):1246-1253. Epub 2019 Nov 29.

Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece

Purpose: To identify factors associated with retinal capillary density as measured with Confocal Scanning Laser Doppler Flowmetry (Heidelberg retina flowmeter (HRF)) in the Thessaloniki Eye Study (TES).

Methods: Participants of the TES (age ≥60 years, cross-sectional population-based study) were assessed for active capillary density in the superior and inferior peripapillary retina using the HRF. Pixel-by-pixel analysis was performed to quantify the percentage of zero flow pixels (ZFPs; surrogate for % retinal area with non-active capillaries). Multivariable regression analyses were performed to assess the association of non-active vascular density with ophthalmic and systemic variables. Glaucoma, late age-related macular degeneration and diabetic retinopathy subjects were excluded.

Results: 1189 subjects were included in the analysis. Older age (per year) was associated with higher percentage of ZFP in both the superior (slope estimate (SE)=0.0020) and the inferior (SE=0.0019) peripapillary retina (p<0.0001). History of migraine was associated with lower percentage of ZFP (SE=-0.0166) compared with no history of migraine in the superior peripapillary retina only (p<0.05). Higher intraocular pressure ((IOP) per mm Hg) and height (per cm) were associated with higher percentage of ZFP in the inferior peripapillary retina only (SE=0.0012, p<0.05 and SE=0.0005, p<0.05, respectively). The group consuming vegetables one to three times per week compared with the group consuming vegetables at least once a day had higher percentage of ZFP only in the inferior peripapillary retina (SE=0.0080, p<0.05).

Conclusion: At a population level, our study revealed associations of older age, higher IOP and taller height with lower active retinal capillary density and of migraine with higher capillary density. Looking further into these associations may provide insight into disease mechanisms.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315212DOI Listing
September 2020

Brinzolamide/brimonidine fixed-dose combination bid as an adjunct to a prostaglandin analog for open-angle glaucoma/ocular hypertension.

Eur J Ophthalmol 2021 Jan 9;31(1):103-111. Epub 2019 Oct 9.

Consultorio Oftalmologico Dr. Fabian Lerner and Facultad de Ciencias Medicas, Universidad Favaloro, Buenos Aires, Argentina.

Purpose: To evaluate the additive intraocular pressure-lowering effect of twice-daily brinzolamide 1%/brimonidine 0.2% fixed-dose combination (BBFC) as an adjunct to a prostaglandin analog (PGA) in patients with open-angle glaucoma or ocular hypertension insufficiently controlled with PGA monotherapy.

Methods: In this Phase 4, double-masked trial, patients aged ⩾18 years, with a mean intraocular pressure of ⩾19 and <32 mm Hg in at least one eye were randomized (1:1) to receive BBFC + PGA ( = 96) or vehicle + PGA ( = 92) for 6 weeks. The primary endpoint was the mean change in diurnal intraocular pressure from baseline (averaged over 09:00 and 11:00 h) at Week 6.

Results: The mean diurnal intraocular pressure at baseline was similar in the BBFC + PGA (22.8 mm Hg) and vehicle + PGA (22.9 mm Hg) groups. The least squares mean change in diurnal intraocular pressure from baseline at Week 6 was greater with BBFC + PGA (-5.59 mm Hg (95% confidence interval: -6.2 to -5.0)) than with vehicle + PGA (-2.15 mm Hg (95% confidence interval: -2.7 to -1.6)); the treatment difference was statistically significant in favor of BBFC + PGA (-3.44 mm Hg, (95% confidence interval: -4.2 to -2.7); < 0.001). Ocular adverse events were reported in 21.1% and 8.7% of patients in the BBFC + PGA and vehicle + PGA groups, respectively. The most frequent ocular adverse event was ocular hyperemia (5.3%) in the BBFC + PGA group and blurred vision (2.2%) in the vehicle + PGA group.

Conclusion: BBFC + PGA significantly reduced mean diurnal intraocular pressure than PGA alone in patients with open-angle glaucoma or ocular hypertension. The safety findings with BBFC + PGA were consistent with the known safety profile of the individual medications.
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http://dx.doi.org/10.1177/1120672119878044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859663PMC
January 2021

Factors Associated With Retinal Vessel Diameters in an Elderly Population: the Thessaloniki Eye Study.

Invest Ophthalmol Vis Sci 2019 05;60(6):2208-2217

Laboratory of Research and Clinical Applications in Ophthalmology (LARCAO), Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Purpose: To identify the factors associated with retinal vessel diameters in the population of the Thessaloniki Eye Study.

Methods: Cross-sectional population-based study (age ≥ 60 years). Subjects with glaucoma, late age-related macular degeneration, and diabetic retinopathy were excluded from the analyses. Retinal vessel diameters were measured using the IVAN software, and measurements were summarized to central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole to venule ratio (AVR).

Results: The analysis included 1614 subjects. The hypertensive group showed lower values of CRAE (P = 0.033) and AVR (P = 0.0351) compared to the normal blood pressure (BP) group. On the contrary, the group having normal BP under antihypertensive treatment did not have different values compared to the normal BP group. Diastolic BP (per mm Hg) was negatively associated with CRAE (P < 0.0001) and AVR (P < 0.0001), while systolic BP (per mm Hg) was positively associated with CRAE (P = 0.001) and AVR (P = 0.0096). Other factors significantly associated included age, sex, alcohol, smoking, cardiovascular disease history, ophthalmic medication, weight, and IOP; differences were observed in a stratified analysis based on BP medication use.

Conclusions: Our study confirms previous reports about the association of age and BP with vessel diameters. The negative correlation between BP and CRAE seems to be guided by the effect of diastolic BP as higher systolic BP is independently associated with higher values of CRAE. The association of BP status with retinal vessel diameters is determined by diastolic BP status in our population. Multiple other factors are also independently associated with retinal vessel diameters.
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http://dx.doi.org/10.1167/iovs.18-26276DOI Listing
May 2019

Twelve-Year Incidence and Baseline Risk Factors for Pseudoexfoliation: The Thessaloniki Eye Study (An American Ophthalmological Society Thesis).

Am J Ophthalmol 2019 10 13;206:192-214. Epub 2019 May 13.

UCLA Stein Eye Institute, David Geffen School of Medicine at UCLA, University of California Los Angeles, CA, USA.

Purpose: To determine the 12-year incidence of pseudoexfoliation (PEX), baseline risk factors for incident PEX and risk factors for incident pseudoexfoliative glaucoma (PEXG) among those with PEX in an elderly white population.

Methods: Longitudinal, population-based study in Thessaloniki, the major urban center in Northern Greece. The baseline cohort included 2554 participants ≥60 years old. The surviving cohort was re-examined 12 years later using the same methodology. PEX was defined as typical fibrillar material at the pupil margin and/or on the lens capsule. Glaucoma was defined as both structural and functional damage, irrespective of intraocular pressure (IOP).

Results: Of 1468 eligible subjects in the surviving cohort, 1092 (74%) participated in the follow-up study. The mean age ± standard deviation (SD) at baseline was 68.9 ± 4.6 years. The mean follow-up time was 11.6 ± 1.6 years. The 12-year incidence of PEX was 19.6% (95% confidence interval (CI), 17.1-22.2), with women more likely to be affected than men (Fisher's exact test, P = .0197). Higher axial length was associated with lower odds of incident PEX (odds ratio [OR], 0.72 per mm; 95% CI, 0.57-0.92). PEX at baseline was not associated with an increased likelihood of major vascular disease (P = .9038). Higher baseline IOP (OR, 1.26 per mm Hg; 95% CI, 1.07-1.48) and history of heart attack at baseline (OR, 13.49; 95% CI, 2.85-63.87) were associated with a greater likelihood of developing PEXG among those with PEX. A history of alcohol consumption at baseline was protective of individuals developing PEXG if they had PEX at baseline.

Conclusion: This is one of the very few longitudinal population-based studies that has specifically assessed the incidence of PEX. The association with axial length was previously found only in a cross-sectional study. The associations with heart attack and alcohol consumption are new findings. In individuals with baseline PEX, higher IOP at baseline, history of heart attack at baseline, and no alcohol consumption were associated with a greater likelihood of developing glaucomatous damage approximately 12 years later. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
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http://dx.doi.org/10.1016/j.ajo.2019.05.005DOI Listing
October 2019

The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome.

Hum Mol Genet 2019 08;28(15):2531-2548

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.
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http://dx.doi.org/10.1093/hmg/ddz075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644155PMC
August 2019

Factors associated with serum 25-hydroxyvitamin D concentrations in older people in Europe: the EUREYE study.

Eur J Clin Nutr 2019 02 26;73(2):319-328. Epub 2018 Oct 26.

Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.

Background/objectives: We aimed to describe serum 25-hydroxyvitamin D (25OHD) concentrations in older Europeans and to investigate associations between 25OHD and lifestyle factors, including dietary intake and supplement use.

Subjects/methods: Men and women aged ≥ 65 years were recruited from seven centres across north to south Europe. Serum 25OHD and 25OHD concentrations were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 4495 samples and total 25OHD (25OHD + 25OHD) was adjusted for season of blood collection.

Results: The mean (25th, 75th quartile) of seasonally adjusted 25OHD was 46 (34, 65) nmol/L, with the highest concentration of 25OHD in Bergen [61 (49, 79) nmol/L], and the lowest in Paris [36 (24, 57) nmol/L)]. Vitamin D deficiency (25-50 nmol/L) and vitamin D insufficiency (50-75 nmol/L) were found in 41 and 33% of the population, respectively. In multivariable analysis controlled for confounders, seasonally adjusted 25OHD concentrations were significantly (p < 0.05) lower in smokers and participants with self-reported diabetes and higher with increasing dietary vitamin D, and supplement use with fish liver oil, omega-3, and vitamin D. Additionally, in further analysis excluding Bergen, 25OHD was associated with higher intakes of oily fish and increasing UVB exposure. We observed low concentrations of 25OHD in older people in Europe.

Conclusions: Our findings of the higher 25OHD concentrations in supplement users (omega-3 fish oil, fish liver oil, vitamin D) add to current recommendations to reduce vitamin D deficiency. We were unable to fully assess the role of dietary vitamin D as we lacked information on vitamin D-fortified foods.
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http://dx.doi.org/10.1038/s41430-018-0353-1DOI Listing
February 2019

Risk factors for Age-related Macular Degeneration in a Greek population: The Thessaloniki Eye Study.

Ophthalmic Epidemiol 2018 Oct - Dec;25(5-6):457-469

a Laboratory of Research and Clinical Applications in Ophthalmology (LARCAO), Department of Ophthalmology, School of Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece.

Purpose: To assess the association of potential risk factors with early and late age-related macular degeneration (AMD) in the Thessaloniki Eye Study (TES) population Design: Population-based, cross-sectional study of subjects over age of 60 living in Thessaloniki, Greece Methods: Subjects without any AMD features and subjects with early and late AMD (neovascular AMD or geographic atrophy) were identified in the TES cohort using standardized procedures and masked grading of stereo color fundus photos. Demographic, lifestyle, systemic and other ophthalmic covariates were also collected during a detailed examination process. Their association with AMD was investigated using univariate and multivariate adjusted logistic regression models.

Results: Among the 2108 participants with gradable photos, the grading process identified 1204 subjects with no AMD, 848 subjects with early AMD, and 56 subjects with late AMD (24 with geographic atrophy and 32 with neovascular AMD). In multivariate analysis, compared to no AMD, late AMD was positively associated with older age (OR:1.16; 95%CI:1.10-1.22 per year of age), current smoking (smoking vs. never smoking, OR:2.34; 95%CI:1.12-4.90), prior cataract surgery (cataract surgery vs. no cataract surgery OR:2.06; 95%CI:0.96-4.40), marital status (divorced/separated vs. married, OR:3.10; 95%CI:1.08-8.93) and with 60% lower odds when sleeping in the afternoon (yes vs. no, OR:0.40; 95%CI:0.22-0.72). Early AMD was positively associated with older age (OR: 1.03; 95%CI:1.01-1.05 per year of age) and negatively with higher pulse pressure (OR:0.99; 95%CI:0.98-0.99 per mmHg).

Conclusions: In TES, apart for well-known risk factors for AMD like age, smoking, and cataract surgery, two novel behavioral risk factors for prevalent late AMD were suggested. Sleeping in the afternoon was associated with 60% decreased odds for late AMD and 67% decreased odds for neovascular AMD. Being divorced/separated compared to married was associated with 3-fold higher odds for late AMD. Large longitudinal population-based studies will be necessary to further establish the potential late AMD risk effects of these two novel factors, to demonstrate potential implications of underlying pathogenetic mechanisms, and to explore preventive measures and therapeutic targets.
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http://dx.doi.org/10.1080/09286586.2018.1512634DOI Listing
March 2019

Overdiagnosis of open-angle glaucoma in the general population: the Thessaloniki Eye Study.

Acta Ophthalmol 2018 Nov 4;96(7):e859-e864. Epub 2018 Sep 4.

1st Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Purpose: To assess the overdiagnosis of open-angle glaucoma (OAG) and to investigate associated factors.

Methods: This was a cross-sectional, population-based study of an urban Caucasian population in northern Greece. Randomly selected subjects ≥60 years (n = 2554) participated in the Thessaloniki Eye Study. The definition of OAG required the presence of structural and functional damage, irrespective of intraocular pressure (IOP). Non-OAG subjects were classified as overdiagnosed with OAG if they had reported at least one of the following (self-reported glaucoma): (i) prior diagnosis of glaucoma, (ii) prior laser for glaucoma, (iii) prior glaucoma surgery. Factors associated with the overdiagnosis of OAG were investigated using a logistic regression model.

Results: Of 57 (2.2%) subjects with self-reported glaucoma, 34 (60%) were overdiagnosed with OAG, corresponding to a prevalence of 1.3% (34/2554). In a logistic regression model among non-OAG subjects, worse visual acuity (VA) (20/200 or worse versus 20/25 or better; odds ratio (OR) = 4.30, 95% Confidence Intervals (CI), 1.13-16.35), family history of glaucoma (OR = 8.69, 95% CI, 2.83-26.67) and history of cataract surgery (OR = 11.50, 95% CI, 3.85-34.36) were statistically significantly associated with the overdiagnosis of OAG. Age, sex, higher IOP, higher vertical cup-to-disc ratio and pseudoexfoliation were not statistically significant.

Conclusion: The overdiagnosis of OAG was substantial in this elderly, Caucasian population. The overdiagnosis of glaucoma has not been previously addressed in population-based studies and needs to be further explored.
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http://dx.doi.org/10.1111/aos.13758DOI Listing
November 2018

MicroRNA-related polymorphisms in pseudoexfoliation syndrome, pseudoexfoliative glaucoma, and primary open-angle glaucoma.

Ophthalmic Genet 2018 10 27;39(5):603-609. Epub 2018 Aug 27.

b Laboratory of Research and Clinical Applications in Ophthalmology, 1st Department of Ophthalmology , School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital , Thessaloniki , Greece.

Background: Pseudoexfoliation syndrome (PEX) and glaucoma (pseudoexfoliative glaucoma; PEXG, primary open-angle glaucoma; POAG) have mainly been studied for their associations with genes' polymorphisms. The purpose of this exploratory study was to investigate the role of polymorphisms in genes encoding for micro RNAs (miRNAs) and in genes related to miRNA biogenesis.

Material And Methods: In the present genetic association study, ninety-two polymorphisms were investigated for their contribution to PEX (n = 203), PEXG (n = 38), and POAG (n = 40) pathogenesis compared to a control group (n = 188). The next generation sequencing (NGS) genotypic analysis revealed data for additional 28 variants.

Results: A protective association was found between PEX and polymorphism 11382316 (mir-3161) [odds ratio (OR) = 0.64, 95% confidence interval (CI): 0.47-0.86, p = 0.003], rs2155248 (mir-1304) [OR = 0.66, 95%CI: 0.47-0.94, p = 0.019], and rs28635903 (mir-1268a) [OR = 0.30, 95%CI: 0.10-0.94, p = 0.029]. Polymorphism rs113297757 (mir-3196) was associated with an increased risk of POAG [OR = 7.75, 95%CI: 2.13-28.76, p = 3 × 10]. Polymorphism rs1057035 (DICER) and rs55671916 (XPO5) in the 3'-UTR of genes related to miRNA biogenesis was associated with decreased risk of PEX [OR = 0.65, 95%CI: 0.46-0.92, p = 0.014] and increased risk of PEXG [OR = 2.84, 95%CI: 1.02-7.94, p = 0.038], respectively. The aforementioned associations according to the allelic model were further supported by the genotypic models of statistical analyses.

Conclusions: This is the first study to report distinct associations of PEX, PEXG, and POAG in the same population with variants of genes involved in miRNA biogenesis and with miRNA genes' polymorphisms. Further studies in larger groups of patients of various origins are needed to confirm the reported preliminary results.
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http://dx.doi.org/10.1080/13816810.2018.1509352DOI Listing
October 2018

Inter- and intraobserver repeatability and reproducibility of choroidal thickness measurements using two different methods.

Int Ophthalmol 2019 May 31;39(5):1061-1069. Epub 2018 Mar 31.

Department of Ophthalmology, Aristotle University of Thessaloniki, AHEPA Hospital, St. Kiriakidi 1, 54621, Thessaloniki, Greece.

Purpose: To measure the inter- and intraobserver repeatability and reproducibility of choroidal thickness measurements taken by the enhanced depth imaging of spectral-domain optical coherence tomography (EDI-OCT) in randomly selected subjects using two different protocols.

Methods: Twenty subjects of the Thessaloniki Eye Study database were randomly selected. The participants underwent EDI-OCT, and the choroidal thickness was measured on EDI images using two different protocols. All images were assessed by two examiners independently in two sessions in different days.

Results: The interobserver intraclass correlation coefficient (ICC) for average choroidal thickness was 0.944. The average ICC for central, Cmin, and Cmax choroidal thickness was 0.899, 0.863, and 0.955, respectively. The interobserver ICC for average choroidal volume was 0.932. Intraobserver repeatability ICC for grader 1 ranged between 0.925 and 0.9720 and for grader 2 between 0.913 and 0.994.

Conclusion: Choroidal thickness measurements by EDI-OCT showed a high inter- and intraobserver reproducibility.
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http://dx.doi.org/10.1007/s10792-018-0909-zDOI Listing
May 2019

The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data.

Ophthalmology 2018 08 13;125(8):1149-1159. Epub 2018 Mar 13.

Bordeaux Population Health Research Center, Team LEHA, Unité Mixte de Recherche (UMR) 1219, INSERM, Université de Bordeaux, Bordeaux, France; Service d'Ophtalmologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Topic: To estimate the prevalence of nonrefractive visual impairment and blindness in European persons 55 years of age and older.

Clinical Relevance: Few visual impairment and blindness prevalence estimates are available for the European population. In addition, many of the data collected in European population-based studies currently are unpublished and have not been included in previous estimates.

Methods: Fourteen European population-based studies participating in the European Eye Epidemiology Consortium (n = 70 723) were included. Each study provided nonrefractive visual impairment and blindness prevalence estimates stratified by age (10-year strata) and gender. Nonrefractive visual impairment and blindness were defined as best-corrected visual acuity worse than 20/60 and 20/400 in the better eye, respectively. Using random effects meta-analysis, prevalence rates were estimated according to age, gender, geographical area, and period (1991-2006 and 2007-2012). Because no data were available for Central and Eastern Europe, population projections for numbers of affected people were estimated using Eurostat population estimates for European high-income countries in 2000 and 2010.

Results: The age-standardized prevalence of nonrefractive visual impairment in people 55 years of age or older decreased from 2.22% (95% confidence interval [CI], 1.34-3.10) from 1991 through 2006 to 0.92% (95% CI, 0.42-1.42) from 2007 through 2012. It strongly increased with age in both periods (up to 15.69% and 4.39% in participants 85 years of age or older from 1991 through 2006 and from 2007 through 2012, respectively). Age-standardized prevalence of visual impairment tended to be higher in women than men from 1991 through 2006 (2.67% vs. 1.88%), but not from 2007 through 2012 (0.87% vs. 0.88%). No differences were observed between northern, western, and southern regions of Europe. The projected numbers of affected older inhabitants in European high-income countries decreased from 2.5 million affected individuals in 2000 to 1.2 million in 2010. Of those, 584 000 were blind in 2000, in comparison with 170 000 who were blind in 2010.

Conclusions: Despite the increase in the European older population, our study indicated that the number of visually impaired people has decreased in European high-income countries in the last 20 years. This may be the result of major improvements in eye care and prevention, the decreasing prevalence of eye diseases, or both.
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http://dx.doi.org/10.1016/j.ophtha.2018.02.005DOI Listing
August 2018

Tolerable rates of visual field progression in a population-based sample of patients with glaucoma.

Br J Ophthalmol 2018 07 28;102(7):916-921. Epub 2017 Sep 28.

Department of Ophthalmology, Aristotle University of Thessaloniki, School of Medicine, AHEPA Hospital, Thessaloniki, Greece.

Aims: To provide population-based data on the maximum tolerable rate of progression to avoid visual impairment (maxTRoP_VI) and blindness (maxTRoP_BL) from open-angle glaucoma (OAG).

Methods: Participants with OAG in the Thessaloniki Eye Study (cross-sectional, population-based study in a European population) were included in the analysis. Visual impairment was defined as mean deviation (MD) equal to or worse than -12dB and blindness as MD equal to or worse than -24dB. Additional thresholds for visual impairment were tested. For each participant maxTRoP_VI was defined as the rate of progression which would not lead to visual impairment during expected lifetime. MaxTRoP_BL was defined accordingly. Both parameters were calculated for each OAG subject using age, sex, MD and life expectancy data. The eye with the better MD per subject was included in the analysis.

Results: Among 135 subjects with OAG, 123 had reliable visual fields and were included in the analysis. The mean age was 73±6 years and the median MD was -3.65±5.28dB. Among those, 69.1% would have a maxTRoP_VI slower than -1dB/year and 18.7% would have a maxTRoP_VI between -1 and -2dB/year. Also, 72.4% would have a maxTRoP_BL slower than -2dB/year. For all tested thresholds for visual impairment, approximately 86% of the OAG study participants would not be able to tolerate a rate of progression equal to or faster than -2dB/year.

Conclusions: The majority of patients with glaucoma in our study would have a maximum tolerable rate of progression slower than -1dB/year in their better eye. Patient-tailored strategies to monitor the visual field are important, but raise the issue of feasibility with regard to the number of visual field tests needed.
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http://dx.doi.org/10.1136/bjophthalmol-2017-310635DOI Listing
July 2018

Prospective study of glaucoma referrals across Europe: are we using resources wisely?

Br J Ophthalmol 2018 03 3;102(3):329-337. Epub 2017 Aug 3.

NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, University College London, Institute of Ophthalmology, London, UK.

Background: To investigate the outcomes of glaucoma referrals across different European countries.

Methods: 250 patients newly referred to tertiary referral glaucoma specialist practices in the UK, Hungary, Slovenia, Italy and Greece were prospectively enrolled (50 consecutive patients per centre). Referral accuracy and predictive value of referral criteria for an intervention or further monitoring (positive predictive value) were analysed.

Results: Same-day discharges occurred in 43% (95% CI 39% to 75%) (12/28) of optometrist-initiated referrals (UK only), 37% (95% CI 30% to 45%) (59/158) of ophthalmologist-initiated referrals (all centres) and 54% (95% CI 40% to 68%) (26/48) of self-referrals (Hungary, Italy and Greece). The percentages from all referral sources were 46% (95% CI 32% to 60%) in the UK, 56% (95% CI 44% to 70%) in Hungary, 30% (95% CI 17% to 43%) in Slovenia, 22% (95% CI 11% to 34%) in Italy and 60% (95% CI 46% to 74%) in Greece (p<0.001). Overall, the referring criterion was confirmed in 54% (95% CI 45% to 63%) (64/119) for intraocular pressure (IOP) >21 mm Hg, 56% (95% CI 43% to 69%) (33/59) for a suspicious optic disc and 61% (95% CI 45% to 77%) (22/36) for a suspicious visual field, with large between-country differences (p<0.05 for all comparisons). Of all referrals, 32% (95% CI 26% to 37%) were initiated on the basis of IOP >21 mm Hg only. By combining the IOP criterion with any other referring criterion, the positive predictive value increased from 56% (95% CI 45% to 67%) to at least 89% (95% CI 68% to 100%). In the UK, a hypothetical IOP threshold of >26 mm Hg, as a requirement for IOP-only referrals, would reduce IOP-only referrals by 44%, while not missing any definite glaucoma cases.

Conclusion: The accuracy of referrals was poor in the UK and the other countries. Requiring a combination of criteria and raising the IOP threshold for IOP-only referrals are needed to cut waste in clinical care.
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http://dx.doi.org/10.1136/bjophthalmol-2017-310249DOI Listing
March 2018

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future.

Ophthalmology 2017 12 14;124(12):1753-1763. Epub 2017 Jul 14.

Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands. Electronic address:

Purpose: Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future.

Design: Meta-analysis of prevalence data.

Participants: A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe.

Methods: AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV).

Main Outcome Measures: Prevalence of early and late AMD, BCVA, and number of AMD cases.

Results: Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%-5.0%) in those aged 55-59 years to 17.6% (95% CI 13.6%-21.5%) in those aged ≥85 years; for late AMD these figures were 0.1% (95% CI 0.04%-0.3%) and 9.8% (95% CI 6.3%-13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer ≥80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million.

Conclusion: We observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti-vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans.
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http://dx.doi.org/10.1016/j.ophtha.2017.05.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755466PMC
December 2017

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

Nat Genet 2017 07 29;49(7):993-1004. Epub 2017 May 29.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

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) 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). 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.
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http://dx.doi.org/10.1038/ng.3875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685441PMC
July 2017

Achievements and Limits of Current Medical Therapy of Glaucoma.

Dev Ophthalmol 2017 25;59:1-14. Epub 2017 Apr 25.

Prescribing medical therapy for the treatment of glaucoma can be a complex process since many parameters should be taken into consideration regarding its achievements and limits. Today, a variety of options, including multiple drug classes and multiple agents within classes, are available to the clinician, but caution should be given to their side effects and contraindications. Glaucoma patients with preexisting ocular surface disease should be treated with caution, and preferably with preservative-free formulations, as there is an increased risk for symptom deterioration. The development and use of fixed-combination therapies has reduced the preservative-related side effects that threaten patient adherence and has minimized the washout effect of multiple instillations. Adherence to medical treatment is not only crucial to its efficacy but also to its cost-effectiveness. Further factors to consider are that there are patients who are nonresponders to treatment, and also that the target intraocular pressure (IOP) cannot be reached in all patients, regardless of the response to treatment. The progression of damage can occur even under maximum medical treatment or maximally tolerated medical treatment, and regardless of whether low IOP levels are reached. Furthermore, there is some conflict between medical treatment and quality of life due to long-term everyday use and to side effects of treatment. New molecules and new delivery systems are being investigated to open new horizons in glaucoma management. Although the general rule is to initiate glaucoma management with medical treatment, the limits of medical therapy should be considered to identify those patients in need of surgical management.
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http://dx.doi.org/10.1159/000458482DOI Listing
September 2017

Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour.

Sci Rep 2017 02 27;7:43359. Epub 2017 Feb 27.

Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing.
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http://dx.doi.org/10.1038/srep43359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5327401PMC
February 2017

Associations between Serum Vitamin D and Genetic Variants in Vitamin D Pathways and Age-Related Macular Degeneration in the European Eye Study.

Ophthalmology 2017 01 28;124(1):90-96. Epub 2016 Oct 28.

Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom. Electronic address:

Purpose: To study associations between early and late age-related macular degeneration (AMD) and neovascular AMD (nvAMD) with serum 25-hydroxy vitamin D (25(OH)D) and genetic variants in vitamin D pathway genes.

Design: Population-based, cross-sectional study in a random sample aged 65 years or older from 7 European countries.

Participants: Of 4753 participants, 4496 (2028 men and 2468 women), with a mean age of 73 years, provided a blood sample; 2137 had no signs of AMD, 2209 had early AMD, and 150 had late AMD, of whom 104 had nvAMD.

Methods: Participants were interviewed to determine smoking and alcohol use, sunlight exposure, and diet; underwent fundus photography. Fundus images were graded using the International Classification System for Age-Related Maculopathy. The 25(OH)D was measured by liquid chromatography-tandem mass spectrometry and categorized as deficient (<30 nmol/l), insufficient (30-50 nmol/l), or adequate (≥50 nmol/l). Genotyping was performed on a subsample of 1284 AMD cases and controls for 93 single nucleotide polymorphisms (SNPs) from 7 genes. Associations were investigated by linear or logistic regression adjusted for potential confounders.

Main Outcome Measures: Adjusted odds ratio (OR) for 3 outcomes (early AMD, late AMD, nvAMD).

Results: No linear association was found with 25(OH)D and early or late AMD or nvAMD. There was no association between insufficient or deficient status with early or late AMD. Deficient status was associated with nvAMD (adjusted OR, 1.27; 95% confidence interval, 1.1-1.45; P < 0.0001). Significant (P < 0.05) associations with 25(OH)D were found for SNPs in genes GC, VDR, CYP2R1, and CYP27B1. Two SNPs (VDR) were associated with early AMD, 4 SNPs (RXRA) and 1 SNP (VDR) were associated with nvAMD, and 1 SNP (RXRA), 2 SNPs (VDR), and 1 SNP (CYP2R1) were associated with late AMD. After Bonferroni correction, no SNPs were associated with early AMD, late AMD, or nvAMD.

Conclusions: Deficiency in 25(OH)D was associated with nvAMD, but the adjusted OR was small, and we cannot exclude residual confounding. The hypothesis of a causal association of vitamin D with AMD is not supported by clear evidence for an association of vitamin D SNPs with early AMD, late AMD, or nvAMD.
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http://dx.doi.org/10.1016/j.ophtha.2016.09.007DOI Listing
January 2017

Association Between Myopia, Ultraviolet B Radiation Exposure, Serum Vitamin D Concentrations, and Genetic Polymorphisms in Vitamin D Metabolic Pathways in a Multicountry European Study.

JAMA Ophthalmol 2017 Jan;135(1):47-53

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Importance: Myopia is becoming increasingly common globally and is associated with potentially sight-threatening complications. Spending time outdoors is protective, but the mechanism underlying this association is poorly understood.

Objective: To examine the association of myopia with ultraviolet B radiation (UVB; directly associated with time outdoors and sunlight exposure), serum vitamin D concentrations, and vitamin D pathway genetic variants, adjusting for years in education.

Design, Setting, And Participants: A cross-sectional, population-based random sample of participants 65 years and older was chosen from 6 study centers from the European Eye Study between November 6, 2000, to November 15, 2002. Of 4187 participants, 4166 attended an eye examination including refraction, gave a blood sample, and were interviewed by trained fieldworkers using a structured questionnaire. Myopia was defined as a mean spherical equivalent of -0.75 diopters or less. Exclusion criteria included aphakia, pseudophakia, late age-related macular degeneration, and vision impairment due to cataract, resulting in 371 participants with myopia and 2797 without.

Exposures: Exposure to UVB estimated by combining meteorological and questionnaire data at different ages, single-nucleotide polymorphisms in vitamin D metabolic pathway genes, serum vitamin D3 concentrations, and years of education.

Main Outcomes And Measures: Odds ratios (ORs) of UVB, serum vitamin D3 concentrations, vitamin D single-nucleotide polymorphisms, and myopia estimated from logistic regression.

Result: Of the included 3168 participants, the mean (SD) age was 72.4 (5) years, and 1456 (46.0%) were male. An SD increase in UVB exposure at age 14 to 19 years (OR, 0.81; 95% CI, 0.71-0.92) and 20 to 39 years (OR, 0.7; 95% CI, 0.62-0.93) was associated with a reduced adjusted OR of myopia; those in the highest tertile of years of education had twice the OR of myopia (OR, 2.08; 95% CI, 1.41-3.06). No independent associations between myopia and serum vitamin D3 concentrations nor variants in genes associated with vitamin D metabolism were found. An unexpected finding was that the highest quintile of plasma lutein concentrations was associated with a reduced OR of myopia (OR, 0.57; 95% CI, 0.46-0.72).

Conclusions And Relevance: Increased UVB exposure was associated with reduced myopia, particularly in adolescence and young adulthood. The association was not altered by adjusting for education. We found no convincing evidence for a direct role of vitamin D in myopia risk. The relationship between high plasma lutein concentrations and a lower risk of myopia requires replication.
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http://dx.doi.org/10.1001/jamaophthalmol.2016.4752DOI Listing
January 2017

Mediterranean Diet Score and Its Association with Age-Related Macular Degeneration: The European Eye Study.

Ophthalmology 2017 01 5;124(1):82-89. Epub 2016 Nov 5.

Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom.

Purpose: To examine associations between adherence to a Mediterranean diet and prevalence of age-related macular degeneration (AMD) in countries ranging from Southern to Northern Europe.

Design: Cross-sectional, population-based epidemiologic study.

Participants: Of 5060 randomly sampled people aged 65 years or older from 7 study centers across Europe (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain), full dietary data were available in 4753. The mean age of participants was 73.2 years (standard deviation, 5.6), and 55% were women.

Methods: Participants underwent an eye examination and digital retinal color photography. The images were graded at a single center. Dietary intake during the previous 12 months was assessed by using a semiquantitative food-frequency questionnaire (FFQ). A previously published Mediterranean Diet Score (MDS) was used to classify participants according to their responses on the FFQ. Multivariable logistic regression was used to investigate the association of the MDS score and AMD, taking account of potential confounders and the multicenter study design.

Main Outcome Measures: Images were graded according to the International Classification System for age-related maculopathy and stratified using the Rotterdam staging system into 5 exclusive stages (AMD 0-4) and a separate category of large drusen (≥125 μm). Age-related macular degeneration 4 included neovascular AMD (nvAMD) and geographic atrophy (GA).

Results: Increasing MDS was associated with reduced odds of nvAMD in unadjusted and confounder-adjusted analysis. Compared with the lowest MDS adherence (≤4 score), those in the highest category MDS adherence (>6 score) showed lower odds of nvAMD (odds ratio, 0.53; 0.27-1.04; P trend = 0.01). The association with MDS did not differ by Y204H risk allele (P = 0.89). For all early AMD (grade 1-3), there was no relationship with MDS (P trend = 0.9). There was a weak trend (P = 0.1) between MDS and large drusen; those in the highest category of MDS had 20% reduced odds compared with those in the lowest (P = 0.05).

Conclusions: This study adds to the limited evidence of the protective effect of adherence to a Mediterranean dietary pattern in those with late AMD, although it does not support previous reports of a relationship with genetic susceptibility. Interventions to encourage the adoption of the Mediterranean diet should be developed, and methods by which such behavior change can be achieved and maintained investigated.
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http://dx.doi.org/10.1016/j.ophtha.2016.09.019DOI Listing
January 2017

Associations with intraocular pressure across Europe: The European Eye Epidemiology (E) Consortium.

Eur J Epidemiol 2016 11 9;31(11):1101-1111. Epub 2016 Sep 9.

NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m; 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.
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http://dx.doi.org/10.1007/s10654-016-0191-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206267PMC
November 2016

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.

Nat Genet 2016 Feb 11;48(2):189-94. Epub 2016 Jan 11.

Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in 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 new targets for preventative therapies.
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http://dx.doi.org/10.1038/ng.3482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731307PMC
February 2016

Ophthalmic epidemiology in Europe: the "European Eye Epidemiology" (E3) consortium.

Eur J Epidemiol 2016 Feb 19;31(2):197-210. Epub 2015 Dec 19.

Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.

The European Eye Epidemiology (E3) consortium is a recently formed consortium of 29 groups from 12 European countries. It already comprises 21 population-based studies and 20 other studies (case-control, cases only, randomized trials), providing ophthalmological data on approximately 170,000 European participants. The aim of the consortium is to promote and sustain collaboration and sharing of data and knowledge in the field of ophthalmic epidemiology in Europe, with particular focus on the harmonization of methods for future research, estimation and projection of frequency and impact of visual outcomes in European populations (including temporal trends and European subregions), identification of risk factors and pathways for eye diseases (lifestyle, vascular and metabolic factors, genetics, epigenetics and biomarkers) and development and validation of prediction models for eye diseases. Coordinating these existing data will allow a detailed study of the risk factors and consequences of eye diseases and visual impairment, including study of international geographical variation which is not possible in individual studies. It is expected that collaborative work on these existing data will provide additional knowledge, despite the fact that the risk factors and the methods for collecting them differ somewhat among the participating studies. Most studies also include biobanks of various biological samples, which will enable identification of biomarkers to detect and predict occurrence and progression of eye diseases. This article outlines the rationale of the consortium, its design and presents a summary of the methodology.
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http://dx.doi.org/10.1007/s10654-015-0098-2DOI Listing
February 2016

Ethnicity-Based Differences in the Association of LOXL1 Polymorphisms with Pseudoexfoliation/Pseudoexfoliative Glaucoma: A Meta-Analysis.

Ann Hum Genet 2015 Nov 24;79(6):431-50. Epub 2015 Sep 24.

Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Pseudoexfoliation (PEX) is an age-related disorder of the extracellular matrix; it is strongly associated with glaucoma, the leading cause of irreversible blindness worldwide. We conducted an ethnic-based meta-analysis of the association of LOXL1 polymorphisms with PEX/pseudoexfoliative glaucoma (PEXG). Association studies were retrieved systematically from PubMed, EMBASE, and Web of Knowledge. Allelic and genotype frequencies of rs3825942, rs1048661, and rs2165241 were compared between PEX/PEXG and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random effects model. Overall, 39 independent cohorts were included. Rs3825942 (G) was an at risk allele for PEX/PEXG in Caucasians, Japanese, Koreans, Chinese, South Asians, and Middle Easterners, but protective in Black South Africans (OR = 0.10, 95%CI:0.06-0.16). Rs1048661 (G) was an at risk allele for PEX/PEXG in Caucasians, South Asians, Middle Easterners and Black South Africans, but was protective in Japanese (OR = 0.03, 95%CI:0.02-0.06) and Koreans (OR = 0.10, 95%CI:0.05-0.22). These associations we-re confirmed for the genotypic recessive models. Rs2165241 (C) was a protective allele for PEX/PEXG in Caucasians, but was an at risk allele in Japanese (OR = 7.49, 95%CI:3.22-17.41) and Koreans (OR = 6.63, 95%CI:2.60-16.90). This was confirmed for the genotypic dominant model. Other genetic and/or environmental factors may modify the effect of LOXL1 polymorphisms in certain ethnic groups.
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http://dx.doi.org/10.1111/ahg.12128DOI Listing
November 2015
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