Paulus T. V. M. de Jong

Risk factors for age-related macular degeneration: Pooled findings from three continents.

OBJECTIVE To assess the prevalence and potential risk factors for late age-related macular degeneration (AMD) in three racially similar populations from North America, Europe, and AUSTRALIA: DESIGN Combined analysis of population-based eye disease prevalence data. PARTICIPANTS There were 14,752 participants with gradable photographs from the Beaver Dam Eye Study (n = 4756), Rotterdam Study (n = 6411), and Blue Mountains Eye Study (n = 3585). MAIN OUTCOME MEASURES AMD diagnosis was made from masked grading of stereo macular photographs. Final classification of AMD cases was agreed by consensus between study investigators. RESULTS AMD prevalence was strongly age related. Overall, AMD was present in 0.2% of the combined population aged 55 to 64 years, rising to 13% of the population older than 85 years. Prevalence of neovascular AMD (NV) increased from 0.17% among subjects aged 55 to 64 years to 5.8% for those older than 85 years. Prevalence of pure geographic atrophy (GA) increased from 0.04% to 4.2% for these age groups. There were no significant gender differences in the prevalence of NV or GA. Subjects in the Rotterdam population had a significantly lower age-adjusted and smoking-adjusted risk of NV than subjects in the Beaver Dam and Blue Mountains populations. Apart from age, tobacco smoking was the only risk factor consistently associated with any form of AMD in all sites separately and in pooled analyses over the three sites. CONCLUSIONS These combined data from racially similar communities across three continents provide strong and consistent evidence that tobacco smoking is the principal known preventable exposure associated with any form of AMD.

The Prevalence of Age-related Maculopathy in the Rotterdam Study

PURPOSE To determine the prevalence of age-related maculopathy in an elderly population in The Netherlands. METHODS Fundus photographs of 6251 participants of the Rotterdam Study, a single-center prospective follow-up study in persons 55 to 98 years of age, were reviewed for the presence of drusen, pigmentary abnormalities, and atrophic or neovascular age-related macular degeneration. RESULTS The prevalence of at least one drusen of 63 microns or larger increased from 40.8% in persons 55 to 64 years of age to 52.6% in those 85 years of age or older. Similarly, the prevalence of the following abnormalities increased significantly in these age categories: drusen of 125 microns or larger from 4.8% to 17.5%, retinal pigment epithelial hypopigmentations from 3.5% to 9.0%, and increased retinal pigment from 3.7% to 15.3%. Atrophic or neovascular age-related macular degeneration was present in 1.7% of the total population. Atrophic age-related macular degeneration increased from 0.1% in persons 55 to 64 years of age to 3.7% in those 85 years of age or older. Neovascular age-related macular degeneration increased from 0.1% to 7.4% in these age groups. No sex differences were observed for these lesions. CONCLUSIONS The prevalence of atrophic or neovascular age-related macular degeneration is 1.7%. In those 55 years of age or older, the prevalence increases strongly with age and it is similar in men and women. Neovascular age-related macular degeneration was twice as common as atrophic age-related macular degeneration. These findings suggest that age-related maculopathy may be less common in this European population than in similar populations in the United States.

Genetic loci for retinal arteriolar microcirculation

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

The prevalence of primary open angle glaucoma in a population-based study in the Netherlands: The Rotterdam Study

PURPOSE The objective of this study is to assess the prevalence of primary open-angle glaucoma (POAG) in a defined population in Rotterdam, The Netherlands. METHODS The Rotterdam Study is a single-center prospective cohort study of a total population of more than 10,000 people, 55 years of age or older. For the current analysis, the first 3062 consecutive, unselected, noninstitutionalized participants were examined according to standard protocols, including perimetry. The diagnosis of POAG was based on the presence of a glaucomatous visual field defect combined with either a vertical cup: disc ratio of 0.5 or more or a cup:disc ratio asymmetry of 0.2 or more, or an intraocular pressure (IOP) more than 21 mmHg, with open and normal anterior chamber angles. RESULTS The overall prevalence of POAG in the current study was 1.10% (95% confidence interval [CI]: 1.09, 1.11). Age-specific prevalence figures increased from 0.2% (95% CI: 0.16, 0.24) in the age group of 55 to 59 years to 3.3% (95% CI: 2.57, 4.04) in the age group of 85 to 89 years. Men had a more than three times higher risk of having POAG than women (odds ratio, 3.6). In 52.9% of the patients, POAG had not been diagnosed previously. Of these patients, 38.9% had IOPs of 21 mmHg or lower. In 8.8% of the eyes (2.9% of patients), visual acuity was 20/200 or less due to POAG. CONCLUSION The overall prevalence of POAG in the current study was 1.1%. The prevalence of POAG was higher in men than in women. Of the untreated patients, 38.9% had IOPs of 21 mmHg or lower.

Genetic association of apolipoprotein E with age-related macular degeneration

Age-related macular degeneration (AMD) is the most common geriatric eye disorder leading to blindness and is characterized by degeneration of the neuroepithelium in the macular area of the eye. Apolipoprotein E (apoE), the major apolipoprotein of the CNS and an important regulator of cholesterol and lipid transport, appears to be associated with neurodegeneration. The apoE gene (APOE) polymorphism is a strong risk factor for various neurodegenerative diseases, and the apoE protein has been demonstrated in disease-associated lesions of these disorders. Hypothesizing that variants of APOE act as a potential risk factor for AMD, we performed a genetic-association study among 88 AMD cases and 901 controls derived from the population-based Rotterdam Study in the Netherlands. The APOE polymorphism showed a significant association with the risk for AMD; the APOE epsilon4 allele was associated with a decreased risk (odds ratio 0.43 [95% confidence interval 0.21-0. 88]), and the epsilon2 allele was associated with a slightly increased risk of AMD (odds ratio 1.5 [95% confidence interval 0.8-2. 82]). To investigate whether apoE is directly involved in the pathogenesis of AMD, we studied apoE immunoreactivity in 15 AMD and 10 control maculae and found that apoE staining was consistently present in the disease-associated deposits in AMD-maculae-that is, drusen and basal laminar deposit. Our results suggest that APOE is a susceptibility gene for AMD.

Distribution of central corneal thickness and its association with intraocular pressure : The Rotterdam study

PURPOSE To perform a cross-sectional study on the distribution of central corneal thickness and its association with intraocular pressure in an elderly population. METHODS We measured central corneal thickness and intraocular pressure in 395 subjects (352 control subjects, 13 patients with ocular hypertension, and 30 patients with primary open-angle glaucoma) aged 55 years or more. RESULTS Mean central corneal thickness in the 352 control subjects was 537.4 microm (95% confidence interval [CI], 533.8 to 540.9 microm; range, 427 to 620 microm), with a maximal difference between eyes of 42 microm. There were no differences between sexes and no significant association with age. Linear regression analysis showed an increase of 0.19 mm Hg in intraocular pressure with each 10-microm increase in central corneal thickness (95% CI, 0.09 to 0.28 mm Hg). This association was similar in both eyes and in both sexes. The 13 patients with ocular hypertension had corneas a mean of 16.0 microm thicker (95% CI, -2.6 to +34.6 microm) compared with control subjects (P = .093); the 30 patients with primary open-angle glaucoma had corneas a mean of 21.5 microm thinner (95% CI, 8.8 to 34.1 microm) compared with control subjects (P = .001). CONCLUSION Mean central corneal thickness was similar to that found in clinical studies, was slightly higher in patients with ocular hypertension, and was significantly lower in patients with primary open-angle glaucoma. Intraocular pressure was positively related with central corneal thickness. Central corneal thickness may influence the division between normal and increased intraocular pressure at a simple cutoff point of 21 mm Hg.

Primary Open-angle Glaucoma, Intraocular Pressure, and Diabetes Mellitus in the General Elderly Population: The Rotterdam Study

PURPOSE To investigate the association of primary open-angle glaucoma and intraocular pressure (IOP) with newly diagnosed diabetes mellitus. METHODS Subjects participating in the Rotterdam Study (n = 4178; ages, 55 years and older) were examined according to standard protocols, including a medical history interview, perimetry, applanation tonometry, funduscopy, and a nonfasting glucose tolerance test. Glaucoma was defined by the presence of a glaucomatous visual field defect. A distinction was made between high-tension glaucoma and normal-tension glaucoma. The relation of glaucoma and IOP with newly diagnosed diabetes mellitus and blood glucose was analyzed using regression analysis. RESULTS The presence of diabetes mellitus was associated with an overall rise in mean IOP of both eyes of 0.31 mmHg (95% confidence interval, 0.12-0.50), and with a threefold increased presence of high-tension glaucoma (odds ratio, 3.11; 95% confidence interval, 1.12-8.66). A 10-mmol/l higher random serum glucose level was borderline significantly associated with a mean IOP that was, on average, 0.41 mmHg (95% confidence interval, -0.02-0.84) higher and with an odds ratio of 2.82 (95% confidence interval, 0.92-8.58) for high-tension glaucoma. A 10-mmol/l rise in serum glucose on a glucose tolerance test was associated with an overall rise of mean IOP of 0.59 mmHg (95% confidence interval, 0.26-0.92) and with an odds ratio of 1.88 (95% confidence interval, 0.81-4.32) for high-tension glaucoma. CONCLUSION Newly diagnosed diabetes mellitus and high levels of blood glucose are associated with elevated IOP and high-tension glaucoma.

Primary Open-angle Glaucoma, Intraocular Pressure, and Systemic Blood Pressure in the General Elderly Population: The Rotterdam Study

PURPOSE The purpose of this study is to investigate the association of primary open-angle glaucoma (POAG), intraocular pressure (IOP), and systemic blood pressure. METHODS Subjects participating in the Rotterdam Study (n = 4187, 55 years of age and older) were examined according to standard protocols, including a medical history interview, IOP measurement, perimetry, funduscopy, and blood pressure measurement. Primary open-angle glaucoma was defined by the presence of a glaucomatous visual field defect. Additionally, the distinction was made between high-tension glaucoma, defined as POAG with an IOP of more than 21 mmHg, and normal-tension glaucoma, defined as POAG with an IOP of 21 mmHg or less. The relation between blood pressure and hypertension with IOP, POAG, high-tension glaucoma, and normal-tension glaucoma was studied by means of regression analysis. RESULTS A systolic blood pressure or diastolic blood pressure that was 10 mmHg higher was associated with an IOP that was, on average, 0.23 mmHg (95% confidence interval [CI], 0.19-0.27) or 0.24 mmHg (95% CI, 0.16-0.32) higher, respectively. The presence of hypertension was associated with a higher mean IOP of 0.66 mmHg (95% CI, 0.39-0.93). A higher systolic blood pressure of 10 mmHg was associated with an odds ratio of 1.22 (95% CI, 1.03-1.46) for high-tension glaucoma and 0.90 (95% CI, 0.72-1.12) for normal-tension glaucoma. Hypertension was associated with an odds ratio of 2.33 (95% CI, 0.99-5.47) for high-tension glaucoma and 0.77 (95% CI, 0.22-2.72) for normal-tension glaucoma. CONCLUSION Systemic blood pressure and hypertension are associated with IOP and high-tension glaucoma. No association was found between blood pressure or hypertension and normal-tension glaucoma.

Retinitis pigmentosa: defined from a molecular point of view.

Retinitis pigmentosa (RP) denotes a group of hereditary retinal dystrophies, characterized by the early onset of night blindness followed by a progressive loss of the visual field. The primary defect underlying RP affects the function of the rod photoreceptor cell, and, subsequently, mostly unknown molecular and cellular mechanisms trigger the apoptotic degeneration of these photoreceptor cells. Retinitis pigmentosa is very heterogeneous, both phenotypically and genetically. In this review we propose a tentative classification of RP based on the functional systems affected by the mutated proteins. This classification connects the variety of phenotypes to the mutations and segregation patterns observed in RP. Current progress in the identification of the molecular defects underlying RP reveals that at least three distinct functional mechanisms may be affected: 1) the daily renewal and shedding of the photoreceptor outer segments, 2) the visual transduction cascade, and 3) the retinol (vitamin A) metabolism. The first group includes the rhodopsin and peripherin/RDS genes, and mutations in these genes often result in a dominant phenotype. The second group is predominantly associated with a recessive phenotype that results, as we argue, from continuous inactivation of the transduction pathway. Disturbances in the retinal metabolism seem to be associated with equal rod and cone involvement and the presence of deposits in the retinal pigment epithelium.

C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3′-5′ exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.