Johannes R. Vingerling

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.

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.

Retinal Vessel Diameters and Risk of Hypertension. The Rotterdam Study

Generalized retinal arteriolar narrowing is an important sign of systemic hypertension, and a lower arteriolar:venular diameter ratio predicts the risk of hypertension. We investigated whether this association was based on arteriolar or venular diameters or both. This study was based on the prospective population-based Rotterdam Study (1990–1993) and included 1900 participants (≥55 years of age) of whom 739 persons had normal blood pressure (systolic <120 mm Hg and diastolic <80 mm Hg) and 1161 prehypertension (systolic 120 to 139 mm Hg or diastolic 80 to 89 mm Hg). For each participant, retinal arteriolar and venular diameters were measured on digitized images of 1 eye. After a mean follow-up of 6.6 years, 808 persons developed hypertension, defined as either systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or use of antihypertensive medication. Adjusted for age, gender, follow-up time, body mass index, smoking, diabetes mellitus, total and high-density lipoprotein cholesterol, C-reactive protein, and intima-media thickness, arteriolar narrowing was associated with an increased risk of hypertension (odds ratio per SD: 1.38; 95% CI, 1.23 to 1.55); for venular narrowing this was less striking (OR: 1.17; 95% CI, 1.04 to 1.32). Each SD decrease in the arteriolar:venular diameter ratio significantly increased the risk of hypertension by 24%. To examine the effect of baseline blood pressure, we stratified persons into those with “normal blood pressure” or “prehypertension.” Within these strata, arteriolar narrowing was still related to incident hypertension. These data show that both retinal arteriolar and venular narrowing may precede the development of systemic hypertension.

Common Variants near FRK/COL10A1 and VEGFA are Associated with Advanced Age-related Macular Degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10−8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10−9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

Meta-analysis: retinal vessel caliber and risk for coronary heart disease.

Coronary heart disease (CHD) remains the leading cause of death in the United States despite advances in prevention, diagnosis, and therapy. Further improvement in outcomes can be achieved through more accurate identification of persons at risk, enhanced understanding of pathogenesis, novel interventions, and better implementation of existing preventive and therapeutic strategies. Coronary microvascular dysfunction is increasingly recognized as an important contributor to CHD, particularly among women (1), and interest in noninvasive methods of assessing the coronary microcirculation is considerable (2). The coronary and retinal vessels undergo similar changes (such as sclerosis) in hypertension (3, 4), and assessment of retinal vessels may provide an indication of coronary microvascular damage (5). With the advent of computer-assisted methods for measuring retinal vessel caliber from retinal photographs, retinal vascular imaging has been found to independently predict increased risk for CHD in prospective epidemiologic studies (610), which raises the possibility of using retinal vessel assessment as a novel risk marker. However, the results reported thus far have not been consistent. The ARIC (Atherosclerosis Risk in Communities) study (6), the first large epidemiologic study to report associations of retinal vessel caliber with incident CHD, suggested that these associations were only present in middle-age women. Subsequent studies have produced conflicting results. The CHS (Cardiovascular Health Study) (9) reported associations of narrower retinal arterioles and wider venules with incident CHD in both older women and men, but other studies found associations mainly in younger women and men, with weak or no association in older persons (10). Differences in study populations and inclusion criteria may account for the varying findings. For example, participants with diabetes or prevalent CHD were included in some studies (10) but not others (9, 11), and analytic methods and adjustment for traditional cardiovascular risk factors varied considerably among studies. To provide robust evidence to address these discrepancies, we conducted a systematic review and an individual-participant meta-analysis of population-based cohort studies, adjusting for traditional risk factors, to determine the associations between retinal vessel caliber and CHD risk. We particularly examined whether the associations differed between women and men. Methods Data Extraction We reviewed the literature to identify all studies that measured retinal vessel caliber, documented CHD events, and were conducted in general populations. We conducted a search of MEDLINE and EMBASE of all studies published between 1950 and 4 June 2009. We used the MEDLINE search terms (exp Retinal Diseases/, (retina or retinal).tw., retinopathy.tw., Arteriolar narrowing.tw., Arterio-venous nicking.tw., Arteriovenous nicking.tw., venular dilatation.tw., venular dilation.tw., arterio-venular ratio.tw.) and (Cardiovascular Diseases/, exp Heart Diseases/, exp Vascular Diseases/, cardiovascular.tw., coronary.tw., heart.tw., mortality.tw.) and (incidence/, exp Mortality/, exp epidemiologic studies/, prognos

Three Genome-wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene

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