Increased High Density Lipoprotein-levels associated with Age-related Macular degeneration. Evidence from the EYE-RISK and E3 Consortia

Purpose Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. Design Pooled analysis of cross-sectional data. Participants Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. Methods AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. Main Outcome Measures AMD features and stage; lipid measurements. Results HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14–1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91–0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10–1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10–7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10–6 and P = 1.6 × 10–4). Conclusions Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.</p

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

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

Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium.

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 (E3) 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/m2; 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.Medical Research Council (G1000143), Cancer Research UK (C864/A14136), Research into Ageing (262), Wellcome Trust, Richard Desmond Charitable Trust (via Fight for Sight), National Institute for Health Research, Stichting Lijf en Leven, Krimpen aan de Lek, MD Fonds, Utrecht, Rotterdamse Vereniging Blindenbelangen, Rotterdam, Stichting Oogfonds Nederland, Utrecht, Blindenpenning, Amsterdam, Blindenhulp, The Hague, Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn, Landelijke Stichting voor Blinden en Slechtzienden, Utrecht, Swart van Essen, Rotterdam, Stichting Winckel-Sweep, Utrecht, Henkes Stichting, Rotterdam, Lameris Ootech BV, Nieuwegein, Medical Workshop, de Meern, NWO (Graduate Programme 2010 BOO (022.002.023)), Laboratoires Thea (Clermont-Ferrand, France), inter regional grant (PHRC) and the regional Council of Burgundy, European Community’s Seventh Framework Programme (FP7/2007-2013), Rheinland-Pfalz AZ 961-386261/733), Johannes Gutenberg-University of Mainz, Boehringer Ingelheim, PHILIPS Medical Systems, Novartis Pharma, Novartis European Union (European Social Fund—ESF), Greek National Strategic Reference Framework (NSRF) (Research Funding Program: THALES), European Social FundThis is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10654-016-0191-

Association of systemic medication use with glaucoma and intraocular pressure: the E3 Consortium

PURPOSE: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. DESIGN: Meta-analysis of eleven population-based cohort studies of the European Eye Epidemiology (E3) consortium. PARTICIPANTS: A total of 143240 participants were included in the glaucoma analyses and 47177 participants in the IOP analyses. METHODS: We examined associations of four categories of systemic medications (antihypertensive medications: beta-blockers, diuretics, calcium channel blockers [CCBs], alpha-agonists, angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers; lipid-lowering medications; antidepressants; antidiabetic medications) with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Multivariable regression analyses were carried out in each study and results were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in diabetic participants only. MAIN OUTCOME MEASURES: Glaucoma prevalence and IOP. RESULTS: In the meta-analyses of our maximally-adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR] with corresponding 95% confidence interval [95% CI]: 1.23 [1.08 to 1.39]). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR [95% CI]: 1.96 [1.23 to 3.12]). The use of other antihypertensive medications, lipid-lowering medications, antidepressants or antidiabetic medications were not clearly associated with glaucoma. Use of systemic beta-blockers was associated with a lower IOP (Beta [95% CI]: -0.33 [-0.57 to -0.08] mmHg). Monotherapy of both selective (Beta [95% CI]: -0.45 [-0.74 to -0.16] mmHg) and non-selective (Beta [95% CI]: -0.54 [-0.94 to -0.15] mmHg) systemic beta-blockers was associated with lower IOP. There was a suggestive association between use of high-ceiling diuretics and lower IOP (Beta [95% CI]: -0.30 [-0.47; -0.14] mmHg), but not when used as monotherapy. Use of other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were not associated with IOP. CONCLUSIONS: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic beta-blocker use. Both findings are potentially important given that glaucoma patients frequently use systemic antihypertensive medications. Determining whether the CCB association is causal should be a research priority

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

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

The European Eye Epidemiology Spectral-domain Optical Coherence Tomography Classification of Macular Diseases for Epidemiological Studies

PURPOSE: The aim of the European Eye Epidemiology (E3) consortium was to develop a spectral-domain optical coherence tomography (SD-OCT)-based classification for macular diseases to standardize epidemiological studies. METHODS: A European panel of vitreoretinal disease experts and epidemiologists belonging to the E3 consortium was assembled to define a classification for SD-OCT imaging of the macula. A series of meeting was organized, to develop, test and finalize the classification. First, grading methods used by the different research groups were presented and discussed, and a first version of classification was proposed. This first version was then tested on a set of 50 SD-OCT images in the Bordeaux and Rotterdam centres. Agreements were analysed and discussed with the panel of experts and a final version of the classification was produced. RESULTS: Definitions and classifications are proposed for the structure assessment of the vitreomacular interface (visibility of vitreous interface, vitreomacular adhesion, vitreomacular traction, epiretinal membrane, full-thickness macular hole, lamellar macular hole, macular pseudo-hole) and of the retina (retinoschisis, drusen, pigment epithelium detachment, hyper-reflective clumps, retinal pigment epithelium atrophy, intraretinal cystoid spaces, intraretinal tubular changes, subretinal fluid, subretinal material). Classifications according to size and location are defined. Illustrations of each item are provided, as well as the grading form. CONCLUSION: The E3 SD-OCT classification has been developed to harmonize epidemiological studies. This homogenization will allow comparing and sharing data collection between European and international studies

Increased High Density Lipoprotein-levels associated with Age-related Macular degeneration. Evidence from the EYE-RISK and E3 Consortia

Purpose Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. Design Pooled analysis of cross-sectional data. Participants Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. Methods AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. Main Outcome Measures AMD features and stage; lipid measurements. Results HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14–1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91–0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10–1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10–7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10–6 and P = 1.6 × 10–4). Conclusions Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.</p

Increased high-density lipoprotein levels associated with age-related macular degeneration: evidence from the EYE-RISK and European Eye Epidemiology Consortia

Purpose Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. Design Pooled analysis of cross-sectional data. Participants Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. Methods AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. Main Outcome Measures AMD features and stage; lipid measurements. Results HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14–1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91–0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10–1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10–7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10–6 and P = 1.6 × 10–4). Conclusions Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.</p

Physical activity, incidence and progression of age-related macular degeneration: A multi-cohort study.

PURPOSE: To investigate the impact of physical activity (PA) on the incidence or progression of age-related macular degeneration (AMD) in the general population. DESIGN: Meta-analysis of longitudinal cohort studies. METHODS: We included a total of 14,630 adults with no or early AMD at baseline from seven population-based studies and examined associations of PA with AMD incidence and progression using multi-state models (MSM) per study and subsequent random effects meta-analysis. Age effects were assessed using meta-regression. MAIN OUTCOME MEASURE: Hazard ratio (HR) for incident early or progression to late AMD. RESULTS: At baseline, mean age ranged from 60.7± 6.9 to 76.4 ± 4.3 years and prevalence of early AMD was 7.7%, ranging from 3.6 to 16.9% between cohorts. During follow-up, 1461 and 189 events occurred for early and late AMD, respectively. In meta-analyses, no or low to moderate PA (high PA as reference) was associated with an increased risk for incident early AMD (HR 1.19; 95%CI=[1.01, 1.40]; p=0.04), but not for late AMD. In subsequent meta-regression, we found no association of age with the effect of PA on incident AMD. CONCLUSIONS: Our study suggests high levels of PA to be protective for the development of early AMD across several population-based cohort studies. Our results establish PA as a modifiable risk factor for AMD and inform further AMD prevention strategies to reduce its public health impact

Association of systemic medication use with glaucoma and intraocular pressure: the E3 Consortium

PURPOSE: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. DESIGN: Meta-analysis of eleven population-based cohort studies of the European Eye Epidemiology (E3) consortium. PARTICIPANTS: A total of 143240 participants were included in the glaucoma analyses and 47177 participants in the IOP analyses. METHODS: We examined associations of four categories of systemic medications (antihypertensive medications: beta-blockers, diuretics, calcium channel blockers [CCBs], alpha-agonists, angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers; lipid-lowering medications; antidepressants; antidiabetic medications) with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Multivariable regression analyses were carried out in each study and results were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in diabetic participants only. MAIN OUTCOME MEASURES: Glaucoma prevalence and IOP. RESULTS: In the meta-analyses of our maximally-adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR] with corresponding 95% confidence interval [95% CI]: 1.23 [1.08 to 1.39]). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR [95% CI]: 1.96 [1.23 to 3.12]). The use of other antihypertensive medications, lipid-lowering medications, antidepressants or antidiabetic medications were not clearly associated with glaucoma. Use of systemic beta-blockers was associated with a lower IOP (Beta [95% CI]: -0.33 [-0.57 to -0.08] mmHg). Monotherapy of both selective (Beta [95% CI]: -0.45 [-0.74 to -0.16] mmHg) and non-selective (Beta [95% CI]: -0.54 [-0.94 to -0.15] mmHg) systemic beta-blockers was associated with lower IOP. There was a suggestive association between use of high-ceiling diuretics and lower IOP (Beta [95% CI]: -0.30 [-0.47; -0.14] mmHg), but not when used as monotherapy. Use of other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were not associated with IOP. CONCLUSIONS: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic beta-blocker use. Both findings are potentially important given that glaucoma patients frequently use systemic antihypertensive medications. Determining whether the CCB association is causal should be a research priority