Jong, P.T.V.M. de

Cholesterol-lowering drugs and incident open-angle glaucoma: A population-based cohort study (Article)

2012-01-04T00:00:00Z

Background: Open-angle glaucoma (OAG) is a progressive neurodegenerative disease that may lead to blindness. An elevated intraocular pressure (IOP) is its major risk factor. OAG treatment is currently exclusively directed towards the lowering of the IOP. IOP lowering does not prevent disease progression in all patients and thus other treatment modalities are needed. Earlier studies reported cholesterol-lowering drugs to have neuroprotective properties. The aim of this study was to determine the associations between the use of cholesterol-lowering drugs and incident OAG. Methodology/Principal Findings: Participants in a prospective population-based cohort study underwent ophthalmic examinations, including IOP measurements and perimetry, at baseline and follow-up. The use of statins and non-statin cholesterol-lowering drugs was monitored continuously during the study. Associations between the use of cholesterol-lowering drugs and incident OAG were analyzed with Cox regression; associations between cholesterol-lowering drugs and IOP at follow-up were analyzed with multiple linear regression. During a mean follow-up of 9.8 years, 108 of 3939 eligible participants (2.7%) developed OAG. The hazard ratio for statin use was 0.54 (95% confidence interval 0.31-0.96; P = 0.034) and for non-statin cholesterol-lowering drugs 2.07 (0.81-5.33; P = 0.13). The effect of statins was more pronounced with prolonged use (hazard ratio 0.89 [0.41-1.94; P = 0.77] for use two years or less; 0.46 [0.23-0.94; P = 0.033] for use more than two years; P-value for trend 0.10). The analyzes were adjusted for age and gender, baseline IOP and IOP-lowering treatment, the family history of glaucoma, and myopia. There was no effect of statins on the IOP. Conclusions/Significance: Long-term use of statins appears to be associated with a reduced risk of OAG. The observed effect was independent of the IOP. These findings are in line with the idea that statins have neuroprotective properties and may open a way to a new OAG treatment modality.

Associations between aspirin use and aging macula disorder: The European eye study (Article)

2012-01-01T00:00:00Z

Objective: To study associations between aspirin use and early and late aging macula disorder (AMD). Design: Population-based cross-sectional European Eye Study in 7 centers from northern to southern Europe. Participants: In total, 4691 participants 65 years of age and older, collected by random sampling. Methods: Aspirin intake and possible confounders for AMD were ascertained by a structured questionnaire. Ophthalmic and basic systemic measurements were performed in a standardized way. The study classified AMD according to the modified International Classification System on digitized fundus images at 1 grading center. Nonfasting blood samples were analyzed in a single laboratory. Associations were analyzed by logistic regression. Main Outcome Measures: Odds ratios (ORs) for AMD in aspirin users. Results: Early AMD was present in 36.4% of the participants and late AMD was present in 3.3% of participants. Monthly aspirin use was reported by 1931 (41.2%), at least once weekly by 7%, and daily use by 17.3%. For daily aspirin users, the ORs, adjusted for potential confounders, showed a steady increase with increasing severity of AMD grades. These were: grade 1, 1.26 (95% confidence interval [CI], 1.08-1.46; P<0.001); grade 2, 1.42 (95% CI, 1.18-1.70), and wet late AMD, 2.22 (95% CI, 1.61-3.05). Conclusions: Frequent aspirin use was associated with early AMD and wet late AMD, and the ORs rose with increasing frequency of consumption. This interesting observation warrants further evaluation of the associations between aspirin use and AMD. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Clinical implications of old and new genes for open-angle glaucoma (Article)

2011-12-01T00:00:00Z

Objective: Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG. Design: Population-based setting, family-based setting, and a case-control study. Participants: The Rotterdam Study I cohort (N = 5312; mean age±standard deviation [SD], 68.0±8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age±SD, 48.3±15.2 years), and a cohort from Southampton (N = 702; mean age±SD, 72.5±10.7 years). Methods: After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles. Main Outcome Measures: Odds ratios and AUCs of individual and combined risk alleles. Results: No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027). Conclusions: A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles.

Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies (Article)

2011-12-01T00:00:00Z

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10-11) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10-15) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10-5) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.

Age-related macular degeneration and the risk of stroke: The rotterdam study (Article)

2011-08-01T00:00:00Z

Background and Purpose-Age-related macular degeneration (AMD) and stroke are both frequent diseases in the elderly. A link between AMD and stroke has been suggested, because both disorders have many risk factors in common. The aim of this study was to investigate the association between AMD and stroke and the subtypes cerebral infarction and intracerebral hemorrhage in the general elderly population. Methods-This study was part of the population-based Rotterdam Study and included 6207 participants aged 55 years who were stroke-free at baseline (1990 to 1993). Signs of AMD were assessed on fundus photographs at baseline and at regular follow-up examinations and were categorized in 5 stages (0 to 4) representing an increasing severity. Late AMD (Stage 4) was subdivided into dry and wet AMD. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed using time-dependent Cox regression models adjusted for age, sex, and potential confounders. Results-During a median follow-up of 13.6 years, 726 participants developed a stroke (397 cerebral infarction, 59 intracerebral hemorrhage, 270 unspecified). Late AMD was associated with an increased risk of any stroke (hazard ratio, 1.56; 95% CI, 1.08 to 2.26) due to a strong association with intracerebral hemorrhage (hazard ratio, 6.11; 95% CI, 2.34 to 15.98). In contrast, late AMD was not associated with cerebral infarction. Earlier AMD stages were not associated with risk of stroke or any of its subtypes. Conclusions-We found that late AMD is strongly associated with intracerebral hemorrhage, but not with cerebral infarction, in the general elderly population.

Lifestyle and risk of developing open-angle glaucoma: The Rotterdam study (Article)

2011-06-01T00:00:00Z

Objective: To determine whether lifestyle-related risk factors, such as socioeconomic status, smoking, alcohol consumption, and obesity, are associated with open-angle glaucoma (OAG). Methods: Participants from the Rotterdam Study, a prospective population-based cohort study, were considered eligible if they participated at both baseline and follow-up and if they had no OAG at baseline. All participants underwent an identical ophthalmologic examination at all visits, including intraocular pressure measurements, optic nerve head assessment, and perimetry. Lifestyle-related factors were assessed by questionnaires by trained research assistants or measured during the examinations (body mass index and waist to hip ratio). Cox proportional hazard regression analysis was applied to calculate hazard ratios. Results: Of 3939 eligible participants, 108 (2.7%) developed OAG during 9.7 years' mean follow-up. No statistically significant effect of socioeconomic status, smoking, or alcohol intake was found. In women, each unit increase in body mass index resulted in a 7% decrease in the risk of developing OAG (P = .04). There was a significant increasing effect of body mass index on intraocular pressure (P < .001) in women. Conclusions: Obesity appears to be associated with a higher intraocular pressure and a lower risk of developing OAG. These associations were only present in women. Other lifestyle-related factors, such as socioeconomic status, smoking, and alcohol consumption, were not associated with OAG.

Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and ω-3 fatty acids: The Rotterdam Study (Article)

2011-06-01T00:00:00Z

Objective: To investigate whether dietary nutrients can reduce the genetic risk of early age-related macular degeneration (AMD) conferred by the genetic variants CFH Y402H and LOC387715 A69S in a nested case-control study. Methods: For 2167 individuals (≥55 years) from the population-based Rotterdam Study at risk of AMD, dietary intake was assessed at baseline using a semiquantitative food frequency questionnaire and genetic variants were determined using TaqMan assay. Incident early AMD was determined on fundus photographs at 3 follow-up visits (median follow-up, 8.6 years). The synergy index was used to evaluate biological interaction between risk factors; hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake and genotypes. Results: Five hundred seventeen participants developed early AMD. Significant synergy indices supported the possibility of biological interaction between CFH Y402H and zinc, β-carotene, lutein/zeaxanthin, and eicosapentaenoic/ docosahexaenoic acid (EPA/DHA) and between LOC387715 A69S and zinc and EPA/DHA (all P < .05). Homozygotes of CFH Y402H with dietary intake of zinc in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of β-carotene, lutein/zeaxanthin, and EPA/DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. Carriers of LOC387715 A69S with the highest intake of zinc and EPA/DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all P trends <.05). Conclusions: High dietary intake of nutrients with antioxidant properties reduces the risk of early AMD in those at high genetic risk. Therefore, clinicians should provide dietary advice to young susceptible individuals to postpone or prevent the vision-disabling consequences of AMD.

Common genetic variants associated with open-angle glaucoma (Article)

2011-06-01T00:00:00Z

Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a metaanalysis using data from six independent studies including: the Rotterdam Study (n = 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n = 1750), Amsterdam Glaucoma Study (n = 296) and cohorts from Erlangen and Tü bingen (n = 1363), Southampton (n = 702) and deCODE (n = 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P = 1.41 3 10-8) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3.

Genetic architecture of open angle glaucoma and related determinants (Article)

2011-01-01T00:00:00Z

Background: Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG. Methods: Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean±SD age: 64.6±9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean±SD age: 46.8614.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control. Results: The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG Conclusions: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.

Genetic architecture of open angle glaucoma and related determinants (Article)

2010-11-07T00:00:00Z

Background: Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG. Methods: Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean±SD age: 64.6±9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean±SD age: 46.8±14.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control. Results: The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG Conclusions: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.

Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo (Article)

2010-10-01T00:00:00Z

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10-8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10-25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10-16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10-13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10-16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

Incidence of Glaucomatous Visual Field Loss: A Ten-Year Follow-up from the Rotterdam Study (Article)

2010-09-01T00:00:00Z

Purpose: To determine the 10-year incidence of glaucomatous visual field loss (GVFL) and to investigate the influence of risk factors for open-angle glaucoma on this incidence. Design: Population-based cohort study. Participants: Participants aged ≥55 years from the Rotterdam Study. Methods: Of the 7983 participants in the Rotterdam Study, 6806 underwent ophthalmic examinations at baseline (1990-1993). In 6723 of these 6806 participants (99%), both visual field screening and an assessment of the optic disc were performed. After exclusion of 93 participants with GVFL at baseline, 6630 participants at risk of developing GVFL remained. These participants underwent similar ophthalmic examinations during 2 follow-up visits (1997-1999 and 2002-2006). The incidence of GVFL was determined as an incidence rate and recalculated to a 10-year risk. Risk factors for open-angle glaucoma (age, gender, positive family history of glaucoma, baseline intraocular pressure (IOP), myopia, and baseline vertical cup-to-disc ratio [VCDR]) were assessed using Cox regression. The dependent variable was the development of GVFL. Main Outcome Measures: Ten-year risk and incidence rates of GVFL. Hazard ratios of the above-mentioned risk factors. Results: Of 6630 participants, 3939 (59%) completed at least 1 follow-up examination and 2571 (39%) completed both; 108 participants developed GVFL. The overall incidence rate and 10-year risk of GVFL were 2.9 per 1000 person-years (95% confidence interval [CI], 2.4-3.5) and 2.8% (2.3-3.4), respectively. The 10-year risk increased from 1.9% at age 55 to 59 years to 6.4% at age ≥80 years (P<0.001). The incidence increased by 11% per millimeter of mercury increase in IOP (hazard ratio 1.11; 95% CI, 1.06-1.15). Male gender (1.62; 1.10-2.38), high myopia (spherical equivalent ≤-4 D myopic; 2.31; 1.19-4.49), and a baseline VCDR above the 97.5th percentile (4.64; 2.72-7.91) were associated with the development of GVFL. A positive family history was only significantly associated with the development of GVFL if IOP was removed from the model (2.0; 1.2-3.3; P = 0.012). Conclusions: These data provide an estimate of the incidence of GVFL in a white population. The development of GVFL was related to higher IOP, older age, high myopia, male gender, a positive family history of glaucoma, and a larger baseline VCDR. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article

A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14 (Letter To Editor)

2010-09-01T00:00:00Z

Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10−14). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16–1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42–2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14 (Letter To Editor)

2010-09-01T00:00:00Z

Course of visual decline in relation to the best1 genotype in vitelliform macular dystrophy (Article)

2010-07-01T00:00:00Z

Purpose: To describe the disease course in patients with vitelliform macular dystrophy (VMD) with a Best1 mutation and to determine the association between Best1 genotype and visual prognosis. Design: Consecutive case series. Participants: Fifty-three patients with VMD with Best1 mutations from 27 Dutch families, aged 11 to 87 years. Methods: Best-corrected visual acuity (VA), fundus appearance, and Arden ratio on the electro-oculogram (EOG) during clinical follow-up were assessed from medical records. Mutation analysis of the Best1 gene was performed on DNA samples using denaturing high-pressure liquid chromatography and direct sequencing. Main Outcome Measures: Cumulative lifetime risk of visual decline below 0.5, 0.3, and 0.1 for the entire group and stratified for genotype. Results: Median age of onset of visual symptoms was 33 years (range: 278). The cumulative risk of VA below 0.5 (20/40) was 50% at 55 years and 75% at 66 years. The cumulative risk of decline less than 0.3 (20/63) was 50% by age 66 years and 75% by age 74 years. Two patients progressed to VA less than 0.1 (20/200). Fourteen different mutations were found. Most patients (96%) had missense mutations; the Thr6Pro, Ala10Val, and Tyr227Asn mutations were most common. Visual decline was significantly faster in patients with an Ala10Val mutation than either the Thr6Pro or the Tyr227Asn mutation (P=0.001). Conclusions: Age of onset of visual symptoms varies greatly among patients with VMD. All patients show a gradual decrease in VA, and most progress to visual impairment at a relatively late age. Our data suggest a phenotypegenotype correlation, because the Ala10Val mutation has a more rapid disease progression than other common mutations. © 2010 by the American Academy of Ophthalmology.

A genome-wide association study of optic disc parameters (Article)

2010-06-01T00:00:00Z

The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p =6.72*10-19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p=2.67*10-33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p =6.15*10-11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p=2.93*10-10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N=3,612), and the TwinsUK cohort (N=843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin. © 2010 Ramdas et al.

Retinal vascular calibers and risk of late-life depression: The rotterdam study (Article)

2010-05-01T00:00:00Z

Objectives: To test the "vascular depression" hypothesis, the authors investigated whether smaller retinal arteriolar or larger venular calibers, which are markers of cerebral microvascular disease, were associated with incident late-life depression. Methods: The authors included 3,605 participants (age ≥55 years) from the population-based Rotterdam Study with no depression at baseline (1993-1995) and fundus photographs gradable for retinal vascular caliber measurements. The authors identified persons with incident depressive symptoms and syndromes using psychiatric interviews during follow-up visits and continuous monitoring. The follow-up was complete until October 2005. Results: After a mean follow-up of 9.0 years, 555 participants developed incident depression, including 312 with depressive syndrome. Neither smaller arteriolar (age-and sex-adjusted hazard ratio: 1.01; 95% confidence interval: 0.93-1.10), nor larger venular calibers (hazard ratio: 1.02; 95% confidence interval: 0.94-1.12) were associated with incident depressive syndromes. Conclusions: Our data showed no evidence of an association between retinal vascular calibers and incident late-life depression.

The Complement Component 5 Gene and Age-Related Macular Degeneration (Article)

2010-03-01T00:00:00Z

Objective: To investigate the association between variants in the complement component 5 (C5) gene and age-related macular degeneration (AMD). Design: Separate and combined data from 3 large AMD case-control studies and a prospective population-based study (The Rotterdam Study). Participants: A total of 2599 AMD cases and 3458 ethnically matched controls. Methods: Fifteen single nucleotide polymorphisms (SNPs) spanning the C5 gene were initially genotyped in 375 cases and 199 controls from The Netherlands (The Amsterdam/Rotterdam-Netherlands [AMRO-NL] study population). Replication testing of selected SNPs was performed in the Rotterdam Study (NL) and study populations from Southampton, United Kingdom (UK), and New York, United States (US). Main Outcome Measures: Early and late stages of prevalent and incident AMD, graded according to (a modification of) the international grading and classification system of AMD. Results: Significant allelic or genotypic associations between 8 C5 SNPs and AMD were found in the AMRO-NL study and this risk seemed to be independent of CFH Y402H, LOC387715 A69S, age, and gender. None of these findings could be confirmed consistently in 3 replication populations. Conclusions: Although the complement pathway, including C5, plays a crucial role in AMD, and the C5 protein is present in drusen, no consistent significant associations between C5 SNPs and AMD were found in any of these studies. The implications for genetic screening of AMD are discussed. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Prediction of incident stroke events based on retinal vessel caliber: A systematic review and individual-participant meta-analysis (Article)

2009-12-04T00:00:00Z

The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5-12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio=1.15, 95% confidence interval: 1.05, 1.25 per 20-μm increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio=1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.

Lipoprotein-associated phospholipase A2 and risk of age-related macular degeneration: The Rotterdam study (Article)

2009-03-01T00:00:00Z

Cataract surgery and the risk of aging macula disorder: The Rotterdam study (Article)

2008-11-01T00:00:00Z

PURPOSE. To investigate still-controversial associations between prior cataract surgery and aging macula disorder (AMD) in a general population. METHODS. Baseline lens status and risk of incident AMD (iAMD) were examined in participants of the prospective population-based Rotterdam Study at risk for AMD (n = 6032). Slit lamp examination was used to determine lens status and stereoscopic color fundus photography to determine the presence of AMD. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated with generalized estimating equation (GEE) models. Stratified analyses were also performed for CFH Y402H genotype. RESULTS. After adjusting for age, sex, follow-up time, and the correlation between eyes, a history of cataract surgery was associated with incident dry late AMD (OR, 3.43; 95% CI, 1.82- 6.49). This association remained significant after additional adjustment for smoking status and AMD stage at baseline (OR, 3.44; 95% CI, 1.68-7.08). No statistically significant association was found between prior cataract surgery and the incidence of wet late AMD or early AMD. Homozygous CFH Y402H carriers had higher risks for all types of AMD compared to heterozygotes and noncarriers after cataract surgery, particularly for dry AMD. CONCLUSIONS. The findings imply that cataract surgery increases the risk of dry AMD, particularly in homozygous CFH Y402H carriers. The risk of AMD progression should be considered before recommending cataract surgery to patients with cataract and early AMD. Copyright

Topical β-Blockers and Mortality (Article)

2008-11-01T00:00:00Z

Purpose: To study the associations between long-term and short-term use of topical β-blockers and mortality. Design: Prospective population-based cohort study. Participants: To examine long-term effects, 3842 participants aged 55 years and older were recruited. To examine short-term effects, 484 incident β-blocker users and 4700 age-matched controls were recruited. All participants were recruited as part of the Rotterdam Study. Methods: To examine long-term effects, associations between topical β-blocker use before and at baseline, between 1990 and 1997, and mortality between 1997 and 2005 were studied. Data were analyzed using Cox regression, and hazard ratios were adjusted for age, gender, smoking, systemic hypertension, diabetes mellitus, and angina pectoris. Short-term effects were defined as death within 3 months after the first prescription of a topical β-blocker. Mortality was compared between incident β-blocker users, that is, participants who started using a topical β-blocker between the onset of the Rotterdam Study in 1990 and October 1, 2004, and age-matched controls. Short-term effects were examined using a chi-square test. Confounding by smoking was analyzed by stratification. Main Outcome Measures: For long-term effects, hazard ratios of topical β-blocker use for all-cause mortality and cardiovascular mortality; for short-term effects, chi-square statistics between mortality of incident topical β-blocker users and age-matched controls. Results: With regard to long-term effects, mean age at baseline was 72 years (standard deviation, 7 years). Topical β-blockers were used by 228 participants. Seven hundred nine participants died during the follow-up (18%); 135 (3.5%) died of a cardiovascular cause. The hazard ratio of topical β-blocker use was 0.94 (95% confidence interval [CI], 0.71-1.25; P = 0.69) for all-cause mortality and 1.02 (95% CI, 0.56-1.86; P = 0.95) for cardiovascular mortality. With regard to short-term effects, 4 (0.8%) of the 484 incident topical β-blocker users died within 3 months after their first prescription; 65 (1.4%; P = 0.31) of the 4700 aged-matched controls died within a similar period. Conclusions: Use of topical β-blockers seems not to be associated with excess mortality. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.

Polymorphisms in the Vascular Endothelial Growth Factor Gene and Risk of Age-related Macular Degeneration. The Rotterdam Study (Article)

2008-11-01T00:00:00Z

Purpose: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and a target for inhibition therapy in wet age-related macular degeneration (AMD). The purpose of this study was to examine whether genetic variation in the VEGF gene is associated with AMD and, especially, with its wet end stage. Design: Prospective population-based cohort study. Participants: Four thousand two hundred twenty-eight participants aged 55 years and older. Methods: AMD was classified according to a modified International Classification System using fundus color images. Genotypes and haplotypes were determined for 3 functional VEGF single nucleotide polymorphisms (SNPs): C-2578A, G-1154A, and G-634C. Cox proportional hazards regression analyses were used to investigate possible associations between the individual SNPs and incident AMD. The Haplo.Stats program was used to test the associations between VEGF gene haplotypes and incident AMD. Main Outcome Measure: AMD. Results: Of 4228 participants at risk for incident early and late AMD for whom blood specimens were available for VEGF genotyping, incident early AMD developed in 514 and incident late AMD developed in 89 (35 dry and 54 wet) after a mean follow-up of 7.4 years. None of the SNPs showed a significant association with incident early or late AMD, especially not with incident wet AMD. Haplotype analyses also detected no associations. Conclusions: The a priori hypothesis that 3 common SNPs in the VEGF gene would be a risk factor for AMD, especially the wet form, could not be confirmed. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Sunlight exposure, antioxidants, and age-related macular degeneration (Article)

2008-10-01T00:00:00Z

Objective: To examine the association of sunlight exposure and antioxidant level with age-related macular degeneration (AMD). Methods: Four thousand seven hundred fifty-three participants aged 65 years or older in the European Eye Study underwent fundus photography, were interviewed for adult lifetime sunlight exposure, and gave blood for antioxidant analysis. Blue light exposure was estimated by combining meteorologic and questionnaire data. Results: Data on sunlight exposure and antioxidants were available in 101 individuals with neovascular AMD, 2182 with early AMD, and 2117 controls. No association was found between blue light exposure and neovascular or early AMD. Significant associations were found between blue light exposure and neovascular AMD in individuals in the quartile of lowest antioxidant level - vitamin C, zeaxanthin, vitamin E, and dietary zinc - with an odds ratio of about 1.4 for 1 standard deviation unit increase in blue light exposure. Higher odds ratios for blue light were observed with combined low antioxidant levels, especially vitamin C, zeaxanthin, and vitamin E (odds ratio, 3.7; 95% confidence interval, 1.6-8.9), which were also associated with early stages of AMD. Conclusions: Although it is not possible to establish causality between sunlight exposure and neovascular AMD, our results suggest that people in the general population should use ocular protection and follow dietary recommendations for the key antioxidant nutrients.

The additional yield of a periodic screening programme for open-angle glaucoma: A population-based comparison of incident glaucoma cases detected in regular ophthalmic care with cases detected during screening (Article)

2008-09-01T00:00:00Z

Aim: To study the additional yield of a periodic screening programme for open-angle glaucoma (OAG) by comparing, in a population-based setting, incident OAG (iOAG) cases detected in regular ophthalmic care with those detected during screening. Methods: Participants aged 55 and over from the population-based Rotterdam Study underwent the same ophthalmic examination at baseline (1991-3) and follow-up (1997-9), including visual field testing and simultaneous stereo optic disc photography. Of 3842 participants, 87 (2.3%) developed iOAG during a mean follow-up time of 6.5 years. Of these 87 iOAG cases, 78 (90%) were included in this study. Results: Of the 78 iOAG cases detected at follow-up, 23 (29%) had already been detected before during regular ophthalmic care. The remaining 55 (71%) undetected iOAG cases more often showed glaucomatous optic neuropathy without glaucomatous visual field loss (29 of 55 (53%)) as compared with the detected cases (four of 23 (17%); p = 0.009). Of the undetected iOAG cases, only four had developed significant visual field loss in their better eye. Conclusion: The additional yield of a periodic OAG screening programme is lower than expected from published prevalence data. In the discussion, the authors estimate that-in a white population with a low prevalence of pseudoexfoliation-about one in 1000 screened persons could be saved from bilateral end-stage OAG.

Alcohol consumption and risk of aging macula disorder in a general population: The Rotterdam study (Article)

2008-06-01T00:00:00Z

Objective: To investigate the possible relationship between overall or specific alcohol consumption and risk of aging macula disorder (AMD), a synonym for age-related macular degeneration, in a general population. Methods: Alcohol consumption and risk of early or late incident AMD (iAMD) were examined among all participants in the prospective population-based Rotterdam Study, with complete data on alcohol consumption among 4229 subjects at risk of AMD. Aging macula disorder was graded according to the International Classification and Grading System for AMD by 2 trained professionals who were masked for all other determinants. We used Cox proportional hazards regression models to estimate hazard ratios and corresponding 95% confidence intervals. Results: During a mean follow-up period of 8.0 years, 600 cases of iAMD were identified, of which 519 were early iAMD and 81 were late iAMD. After correction for age, sex, smoking, complement factor H genotype status, and other potential confounders, we did not find an association between overall or specific alcohol consumption and development of early iAMD or dry or wet late iAMD. Conclusion: Our findings suggest that overall or specific alcohol consumption is not a risk factor for AMD.

Host polymorphisms in interleukin 4, complement factor H, and C-reactive protein associated with nasal carriage of Staphylococcus aureus and occurrence of boils (Article)

2008-05-01T00:00:00Z

Background. Staphylococcus aureus is capable of persistently colonizing the vestibulum nasi. We hypothesized that polymorphisms in host inflammatory response genes and genetic variation in S. aureus contribute to susceptibility to S. aureus carriage and infection. Methods. The prevalence of persistent nasal carriage of S. aureus in 3851 participants aged 61-101 years was 18% (678 of 3851 participants), whereas 73% of volunteers (2804 of 3851) were not colonized. A total of 1270 individuals had boils. Polymorphisms in TNFA (C -863T), IL4 (C -542T), CFH (Tyr402His), and CRP (C1184T, C2042T, and C2911G) were determined. Genetic similarity among 428 S. aureus isolates was determined by use of amplified fragment length polymorphism analysis (AFLP)-mediated genotyping. Results. The IL4 -524 C/C host genotype was associated with an increased risk of persistent S. aureus carriage, irrespective of S. aureus AFLP genotype. The CRP haplotype 1184C; 2042C; 2911C was overrepresented in individuals who were not colonized . In individuals with boils, carriers of the CFH Tyr402 variant, and the CRP 2911 C/C genotype were overrepresented. Conclusion. Persistent carriage of S. aureus is influenced by genetic variation in host inflammatory response genes. As would be expected in multifactorial host-microbe interactions, these effects are limited. Interestingly, host genotype was associated with the carriage of certain S. aureus genotypes. Apparently, a close interaction between host and bacterial determinants are prerequisites for long-term colonization.

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

2008-02-08T00:00:00Z

Human iris color was one of the first traits for which Mendelian segregation was established. To date, the genetics of iris color is still not fully understood and is of interest, particularly in view of forensic applications. In three independent genome-wide association (GWA) studies of a total of 1406 persons and a genome-wide linkage study of 1292 relatives, all from the Netherlands, we found that the 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genome-wide evidence for association and linkage to iris color. Single nucleotide polymorphisms (SNPs) in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene were independently associated to iris color variation. OCA2 has been implicated in iris color previously. A replication study within two populations confirmed that the HERC2 gene is a new and significant determinant of human iris color variation, in addition to OCA2. Furthermore, HERC2 rs916977 showed a clinal allele distribution across 23 European populations, which was significantly correlated to iris color variation. We suggest that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, within the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those two genes. Testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin.

Estrogen receptors alpha and beta and the risk of open-angle glaucoma: The rotterdam study (Article)

2008-01-01T00:00:00Z

Objective: To investigate whether polymorphisms in the estrogen receptor alpha (ESR1) and beta (ESR2) genes were a risk factor for open-angle glaucoma (OAG). Methods: Participants 55 years and older from the population-based Rotterdam Study underwent, at baseline and at follow-up, the same ophthalmic examination, including visual field screening and stereo optic disc photography. A diagnosis of OAG was based on an algorithm using optic disc measures and visual field loss. Haplotypes of the ESR1 and ESR2 genes were determined. Results: We diagnosed incident OAG in 87 of 3842 participants (2.3%) at risk after a mean follow-up of 6.5 years. We could not detect any association with ESR1 haplotypes. Haplotype 1 of ESR2 showed a 3.6-fold (95% confidence interval, 1.4-9.2) higher risk of incident OAG in men. In women, no association was found between ESR2 and incident OAG. Conclusion: Polymorphisms in the ESR1 gene are unrelated to OAG, but ESR2 polymorphisms seem to lead to increased risk of OAG in men.

Comprehensive analysis of the candidate genes CCL2, CCR2, and TLR4 in age-related macular degeneration (Article)

2008-01-01T00:00:00Z

PURPOSE. To determine whether variants in the candidate genes TLR4, CCL2, and CCR2 are associated with age-related macular degeneration (AMD). METHODS. This study was performed in two independent Caucasian populations that included 357 cases and 173 controls from the Netherlands and 368 cases and 368 controls from the United States. Exon 4 of the TLR4 gene and the promoter, all exons, and flanking intronic regions of the CCL2 and CCR2 genes were analyzed in the Dutch study and common variants were validated in the U.S. study. Quantitative (q)PCR reactions were performed to evaluate expression of these genes in laser-dissected retinal pigment epithelium from 13 donor AMD and 13 control eyes. RESULTS. Analysis of single nucleotide polymorphisms (SNPs) in the TLR4 gene did not show a significant association between D299G or T399I and AMD, nor did haplotypes containing these variants. Univariate analyses of the SNPs in CCL2 and CCR2 did not demonstrate an association with AMD. For CCR2, haplotype frequencies were not significantly different between cases and controls. For CCL2, one haplotype containing the minor allele of C35C was significantly associated with AMD (P = 0.03), but this did not sustain after adjustment for multiple testing (q = 0.30). Expression analysis did not demonstrate altered RNA expression of CCL2 and CCR2 in the retinal pigment epithelium from AMD eyes (for CCL2 P = 0.62; for CCR2 P = 0.97). CONCLUSIONS. No evidence was found of an association between TLR4, CCR2, and CCL2 and AMD, which implies that the common genetic variation in these genes does not play a significant role in the etiology of AMD. Copyright

Systemic Antihypertensive Medication and Incident Open-angle Glaucoma (Article)

2007-12-01T00:00:00Z

Purpose: To determine the association between systemic antihypertensive medication and incident open-angle glaucoma. Design: Prospective population-based cohort study. Participants: The study population consisted of a subset of 3842 participants of the Rotterdam Study for whom data from identical ophthalmologic examinations at baseline and follow-up were available. Methods: Use of antihypertensive medication was registered over an average follow-up period of 6.5 years. Associations between incident open-angle glaucoma and antihypertensive medication were assessed using multivariate logistic regression models adjusted for age, gender, duration of follow-up, intraocular pressure, intraocular pressure-lowering medication, and cardiovascular disease. Main Outcome Measures: Odds ratios of associations between incident open-angle glaucoma and use of antihypertensive medication. Results: During follow-up, there were 87 incident cases of open-angle glaucoma. Participants using calcium channel antagonists had a 1.8-fold (95% confidence interval [CI], 1.04-3.2; P = 0.037) higher risk of developing incident open-angle glaucoma. β-Blockers were associated with a nonsignificant risk reduction (odds ratio, 0.6; 95% CI, 0.3-1.02; P = 0.060). None of the other classes of antihypertensives was significantly associated with incident open-angle glaucoma. Conclusions: These data suggest that use of calcium channel antagonists is associated with open-angle glaucoma, but this requires confirmation. These results do not support the use of calcium channel antagonists for the treatment of normal-tension glaucoma.

Risk of bilateral visual impairment in individuals with amblyopia: The Rotterdam study (Article)

2007-11-01T00:00:00Z

Background: The excess risk of bilateral visual impairment (BVI; bilateral visual acuity <0.5) among individuals with amblyopia is an argument for screening for amblyopia, but data are scarce. Methods: The risk was estimated by determining the incidence of BVI in the Rotterdam Study, a population-based cohort of subjects aged 55 years or over (n = 5220), including 192 individuals with amblyopia (3.7%). Using a multistate lifetable, the lifetime risk and excess period spent with BVI were determined. Results: The relative risk of BVI for amblyopes was 2.6 (95% confidence interval 1.4-4.5). For individuals with amblyopia, the lifetime risk of BVI was 18%, whereas they lived on average 7.2 years with BVI. For non-amblyopic individuals, these figures were 10% and 6.7 years, respectively. Conclusion: Amblyopia nearly doubles the lifetime risk of BVI and affected individuals spent an extra six months with BVI. This study provides data for future cost-effectiveness analyses.

C-reactive protein level and risk of aging macula disorder: The Rotterdam study (Article)

2007-10-01T00:00:00Z

Objective: To examine whether C-reactive protein (CRP) level is a risk factor for aging macula disorder (AMD) in a general population. Methods: We examined serum high-sensitivity CRP (HsCRP) levels in 4914 participants of the population-based Rotterdam Study at risk for AMD. After a mean follow-up of 7.7 years, 561 cases of early and 97 cases of late incident AMD (iAMD) were identified. We used Cox proportional hazards regression models to estimate hazard ratios and corresponding 95% confidence intervals (CIs). Results: After adjustment for age and sex, hazard ratios were 1.11 (95% CI, 1.02-1.21) per standard deviation increase in HsCRP level for early iAMD and 1.28 (95% CI, 1.02-1.60) for late iAMD. Hazard ratios for early iAMD increased per quartile increase in HsCRP level as follows: second quartile, 1.19 (95% CI, 0.94-1.52); third quartile, 1.29 (95% CI, 1.01-1.64); and fourth quartile, 1.33 (95% CI, 1.05-1.70). The risk of late iAMD was higher in all upper quartiles of HsCRP. Conclusion: Elevated baseline levels of HsCRP were associated with the development of early and late AMD in this large population-based cohort.

C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy (Article)

2007-09-01T00:00:00Z

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.

Usefulness of Combining Complement Factor H and C-Reactive Protein Genetic Profiles for Predicting Myocardial Infarction (from the Rotterdam Study) (Article)

2007-08-15T00:00:00Z

Complement factor H (CFH) is an important regulator of the complement cascade. Binding of C-reactive protein (CRP) to CFH augments the ability of CFH to downregulate the effect of complement in atherosclerotic lesions. The CFH Tyr402His polymorphism has been suggested to influence the ability of CFH to bind CRP. We hypothesized that the combined presence of unfavorable CRP and CFH genetic profiles is associated with risk of myocardial infarction (MI). The Rotterdam Study is a population-based cohort study in 7,983 men and women aged ≥55 years. The CFH Tyr402His (rs1061170) polymorphism was determined (His402allele 37%), and using 3 tagging polymorphisms (rs1130864, rs1205, and rs3093068), CRP haplotypes were inferred (1 = CTC, 2 = TCC, 3 = CCC, 4 = CCG; frequencies of 33%, 32%, 30%, and 6%, respectively). Participants were grouped by CFH genotype (TyrTyr [reference], TyrHis, and HisHis) and CRP haplotype (haplotype 1 homozygotes [reference], haplotype 2 carriers, haplotype 3 carriers, and haplotype 4 carriers), which resulted in a total of 12 groups. CFH His402homozygotes who were also CRP haplotype 3 carriers had an age- and gender-adjusted hazard ratio of 5.9 (95% confidence interval 2.1 to 16.5) to develop MI compared with the reference group. In conclusion, this population-based study suggests that the combined presence of unfavorable CFH and CRP genetic profiles is associated with risk of MI.

Complement factor H polymorphism, inflammatory mediators, and retinal vessel diameters: The Rotterdam study (Article)

2007-07-01T00:00:00Z

PURPOSE. Retinal venular dilatation is associated with systemic inflammation. The hypothesis for the current study was that larger retinal venular diameters are related to the His allele of the Tyr402His polymorphism in the complement factor H (CFH) gene, a major inhibitor of the complement pathway. Possible effect modification by smoking and inflammatory markers was examined. METHODS. This cross-sectional study was performed within the Rotterdam Study, a population-based study among elderly persons aged 55 years and older. The Tyr402His polymorphism of the CFH gene was genotyped in 5066 participants and retinal arteriolar and venular diameters were graded on digitized fundus transparencies. RESULTS. Genotype frequencies were 41% in TyrTyr, 45% in TyrHis, and 14% in HisHis carriers. The His402allele was associated with smaller rather than larger venular diameters (age-and sex-adjusted means and standard errors [in micrometers] were 222.5 ± 0.45 for TyrTyr, 221.9 ± 0.43 for TyrHis, and 220.6 ± 0.78 for HisHis carriers; P-trend = 0.03). This association was apparent only in never-smokers and was not modified by the inflammatory markers erythrocyte sedimentation rate, leukocyte count, C-reactive protein, or fibrinogen. Adjustment for cardiovascular risk factors did not change results. No associations were found with arteriolar diameters. CONCLUSIONS. The findings do not support the hypothesis that the His402allele is related to larger retinal venular diameters. The association with smaller retinal venular diameters most likely is a chance finding, because it was present only among never-smokers and was not modified by inflammatory mediators of complement. These results suggest that the Tyr402His variant is not related to retinal venular diameters. Copyright

L1 retrotransposition can occur early in human embryonic development (Article)

2007-07-01T00:00:00Z

L1 elements are autonomous retrotransposons that can cause hereditary diseases. We have previously identified a full-length L1 insertion in the CHM (choroideremia) gene of a patient with choroideremia, an X-linked progressive eye disease. Because this L1 element, designated L1CHM, contains two 3′-transductions, we were able to delineate a retrotransposition path in which a precursor L1 on chromosome 10p15 or 18p11 retrotransposed to chromosome 6p21 and subsequently to the CHM gene on chromosome Xq21. A cell culture retrotransposition assay showed that L1CHM is one of the most active L1 elements in the human genome. Most importantly, analysis of genomic DNA from the CHM patient's relatives indicated somatic and germ-line mosaicism for the L1 insertion in his mother. These findings provide evidence that L1 retrotransposition can occur very early in human embryonic development.

Blood pressure, arterial stiffness, and open-angle glaucoma: The Rotterdam Study (Article)

2007-06-01T00:00:00Z

Objective: To investigate cross-sectional associations among blood pressures (BPs), arterial stiffness, and open-angle glaucoma (OAG). Methods: Study participants came from the population-based Rotterdam Study. The baseline examination phase took place after an extensive home interview from March 20, 1990, to June 17, 1993, and the third phase between March 19, 1997, and December 16, 1999. Cases were classified into high-tension OAG (htOAG) and normal-tension OAG (ntOAG), according to an intraocular pressure greater than 21 mm Hg or 21 mm Hg or less. Pulse pressure was the difference between systolic and diastolic BP. Diastolic perfusion pressure was the difference between diastolic BP and the intraocular pressure; indicators of arterial stiffness were carotid-femoral pulse wave velocity and carotid distensibility. Associations were evaluated with logistic regression analysis, adjusted for age, sex, body mass index, smoking, diabetes mellitus, serum cholesterol level, and BP-lowering treatment. Results: A total of 5317 participants were included in this study. In participants with a higher pulse pressure, the prevalence of htOAG was elevated (odds ratio [OR] per standard deviation, 1.32; 95% confidence interval [CI], 1.03-1.69). In persons treated for systemic hypertension, low diastolic perfusion pressure (<50 mm Hg) was inversely associated with ntOAG (OR, 0.25; 95% CI, 0.10-0.63) and positively associated with htOAG (OR, 4.68; 95% CI, 1.29-17.01). The lowest tertile of carotid distensibility compared with the highest had an OR for htOAG of 2.84 (95% CI, 0.99-8.10; P=.05). Conclusions: We found that htOAG was associated with high pulse pressure, possibly with increased carotid arterial stiffness, and, only in persons treated for systemic hypertension, with low diastolic perfusion pressure. In these persons, ntOAG was associated with high diastolic BP, whereas the association between ntOAG and low diastolic perfusion pressure was inverted.

Cigarette Smoking and Age-Related Macular Degeneration in the EUREYE Study (Article)

2007-06-01T00:00:00Z

Objective: To examine the association between cigarette smoking and age-related maculopathy (ARM) including age-related macular degeneration (AMD) in the European population. Design: Cross-sectional study. Participants: Four thousand seven hundred fifty randomly sampled ≥65-year-olds from 7 study centers across Europe (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain). Methods: Participants underwent an eye examination and digital retinal photography. The images were graded at a single center. Smoking history was ascertained by a structured questionnaire administered by trained fieldworkers. Multinomial and binary logistic regressions were used to examine the association between smoking history and ARM grade and type of AMD, taking account of potential confounders and the multicenter study design. Main Outcome Measures: Photographic images were graded according to the International Classification System for ARM and stratified using the Rotterdam staging system into 5 exclusive stages (ARM 0-3 and ARM 4, also known as AMD). Age-related macular degeneration also was classified as neovascular AMD or geographic atrophy (GA). Results: One hundred fifty-eight cases were categorized as AMD (109 neovascular AMD and 49 GA); 2260 had no signs of ARM (ARM 0). Current smokers had increased odds of neovascular AMD (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.4-4.8) or GA (OR, 4.8; 95% CI, 2.1-11.1), whereas for ex-smokers the odds were around 1.7. Compared with people with unilateral AMD, those with bilateral AMD were more likely to have a history of heavy smoking in the previous 25 years (OR, 5.1; 95% CI, 1.3-20.0). The attributable fraction for AMD due to smoking was 27% (95% CI, 19%-33%). There was no consistent association with ARM grades 1 to 3 and smoking. Conclusions: These findings highlight the need for increasing public awareness of the risks associated with smoking and the benefit of quitting smoking. Patients with unilateral disease who are current smokers should be advised of the risk of second-eye disease.

Estrogen receptor α gene polymorphisms associated with incident aging macula disorder (Article)

2007-03-01T00:00:00Z

PURPOSE. It has been suggested that early menopause increases the risk of aging-macula disorder (AMD), the major cause of incurable blindness with a dry and wet late subtype, and that exposure to endogenous or postmenopausal exogenous estrogens reduces this risk. This study was undertaken to investigate whether genetic variations in the estrogen receptor α (ESR1) gene are associated with incident AMD. METHODS. In the Rotterdam Study, a prospective population-based cohort study of participants aged 55 years and older, associations between ESR1 PvuII-XbaI haplotypes and incident early or late AMD were studied in 4571 participants after a mean follow-up time of 7.7 years. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs), with adjustment for the most common confounders. RESULTS. ESR1 PvuII-XbaI haplotype 1 was a risk factor for late AMD. Persons with two copies of haplotype 1 were at 3.20 (95% CI, 1.47-6.99) times higher risk for late AMD than non-carriers of haplotype 1, after adjustment for age and sex. This increase was more pronounced for wet AMD (hazard ratio [HR] 4.29; 95% CI, 1.47-12.49) after adjustment for age, sex, smoking, and complement factor H genotype. Correction for additional confounders, including age at menopause, use of hormone replacement therapy, blood pressure, and body mass index did not essentially alter the findings. CONCLUSIONS. Persons with one or two copies of ESR1 PvuII-XbaI haplotype 1 have an increased risk of late AMD, especially of the wet form. Copyright

ABCC6 and pseudoxanthoma elasticum (Article)

2007-02-01T00:00:00Z

ABCC6 belongs to the adenosine triphosphate-binding cassette (ABC) gene subfamily C. This protein family is involved in a large variety of physiological processes, such as signal transduction, protein secretion, drug and antibiotic resistance, and antigen presentation [Kool et al. (1999) 59:175-182; Borst and Elferink (2002) 71:537-592]. ABCC6 is primarily and highly expressed in the liver and kidney [Kool et al. (1999) 59:175-182; Bergen et al. (2000) 25:228-2231]. The precise physiological function and natural substrate(s) transported by ABCC6 are unknown, but the protein may be involved in active transport of intracellular compounds to the extracellular environment [Kool et al. (1999) 59:175-182] [Scheffer et al. (2002) 82:515-518]. Recently, it was shown that loss of function mutations in ABCC6 cause pseudoxanthoma elasticum (PXE) [Bergen et al. (2000) 25:228-2231; Le Saux et al. (2000) 25:223-227]. PXE is an autosomal recessively inherited multi-organ disorder [Goodman et al. (1963) 42:297-334; Lebwohl et al. (1994) 30:103-107]. PXE is primarily associated with the accumulation of mineralized and fragmented elastic fibers of the connective tissue in the skin [Neldner (1988) 6:1-159], Bruch's membrane in the retina [Hu et al. (2003) 48:424-438], and vessel walls [Kornet et al. (2004) 30:1041-1048]. PXE patients usually have skin lesions and breaks in Bruch's membrane of the retina (angioid streaks). Also, a variety of cardiovascular complications has been observed [Hu et al. (2003) 48:424-438]. Recently, a mouse model for PXE was created by targeted disruption of Abcc6 [Gorgels et al. (2005) 14:1763-1773; Klement et al. (2005) 25:8299-8310], which may be useful to elucidate the precise function of Abcc6 and to develop experimental therapies.

Retinal vessel diameters and risk of impaired fasting glucose or diabetes: the Rotterdam study (Article)

2006-01-01T00:00:00Z

The association between a smaller retinal arteriolar-to-venular ratio (AVR) and incident diabetes may be due to arteriolar narrowing, venular dilatation, or both. We investigated associations between baseline vessel diameters and incident impaired fasting glucose or diabetes in a population-based cohort (aged > or =55 years). Baseline retinal vessel diameters (1990-1993) were measured on digitized images of 2,309 subjects with a normal glucose tolerance test (postload glucose <7.8 mmol/l). At follow-up (1997-1999), impaired fasting glucose was defined as 6.1-7.0 mmol/l and diabetes as > or =7.0 mmol/l and/or antidiabetic medication use. Odds ratios (ORs) per SD increase in venular diameters were 1.13 (95% CI 1.00-1.29) for impaired fasting glucose and 1.09 (0.90-1.33) for diabetes. ORs per SD decrease in arteriolar diameters were 1.12 (0.98-1.27) and 1.08 (0.89-1.31) and per SD decrease in AVR were 1.29 (1.13-1.46) and 1.19 (0.98-1.45). After adjustment for cardiovascular risk factors, the associations were unaltered for venules and disappeared for arterioles. After stratification on age, associations between venular dilatation and impaired fasting glucose (1.23 [1.02-1.47]) or diabetes (1.18 [0.89-1.56]) were mainly present in participants aged <70 years. In conclusion, in our study, the risk of impaired fasting glucose and diabetes with AVR was explained by venular dilatation rather than arteriolar narrowing, warranting more focus on the causes of this dilatation.

Dietary intake of antioxidants and risk of age-related macular degeneration. (Article)

2005-12-28T00:00:00Z

CONTEXT: Age-related macular degeneration (AMD) is the most prevalent cause of irreversible blindness in developed countries. Recently, high-dose supplementation with beta carotene, vitamins C and E, and zinc was shown to slow the progression of AMD. OBJECTIVE: To investigate whether regular dietary intake of antioxidants is associated with a lower risk of incident AMD. DESIGN: Dietary intake was assessed at baseline in the Rotterdam Study (1990-1993) using a semiquantitative food frequency questionnaire. Incident AMD until final follow-up in 2004 was determined by grading fundus color transparencies in a masked way according to the International Classification and Grading System. SETTING: Population-based cohort of all inhabitants aged 55 years or older in a middle-class suburb of Rotterdam, the Netherlands. PARTICIPANTS: Of 5836 persons at risk of AMD at baseline, 4765 had reliable dietary data and 4170 participated in the follow-up. MAIN OUTCOME MEASURE: Incident AMD, defined as soft distinct drusen with pigment alterations, indistinct or reticular drusen, geographic atrophy, or choroidal neovascularization. RESULTS: Incident AMD occurred in 560 participants after a mean follow-up of 8.0 years (range, 0.3-13.9 years). Dietary intake of both vitamin E and zinc was inversely associated with incident AMD. The hazard ratio (HR) per standard deviation increase of intake for vitamin E was 0.92 (95% confidence interval [CI], 0.84-1.00) and for zinc was 0.91 (95% CI, 0.83-0.98). An above-median intake of all 4 nutrients, beta carotene, vitamin C, vitamin E, and zinc, was associated with a 35% reduced risk (HR, 0.65; 95% CI, 0.46-0.92) of AMD. Exclusion of supplement users did not affect the results. CONCLUSION: In this study, a high dietary intake of beta carotene, vitamins C and E, and zinc was associated with a substantially reduced risk of AMD in elderly persons.

Retinal vessel diameters and incident open-angle glaucoma and optic disc changes: the Rotterdam study. (Article)

2005-04-01T00:00:00Z

PURPOSE: It remains unclear whether reduced retinal blood flow and smaller arterioles, reported to exist in patients with open-angle glaucoma (OAG), are a cause or a consequence of ganglion cell loss. We examined whether baseline retinal vessel diameters were related to incident (i)OAG or incident optic disc changes in a population-based sample. METHODS: In the prospective population-based Rotterdam Study, baseline diameters of retinal arterioles and venules (1990-1993) were measured in digitized images of 3469 persons (aged 55 years and older) at risk for OAG. The follow-up examinations took place from 1997 to 1999. iOAG was based on the presence of incident glaucomatous visual field loss and/or incident glaucomatous optic neuropathy. Changes in neuroretinal rim, cup area, or vertical cup-to-disc ratio were calculated with a semiautomated image analyzer in 2782 persons. RESULTS: After a mean follow-up time of 6.5 years, 74 participants had iOAG. At baseline, the mean arteriolar diameter was 147.5 +/- 14.2 microm (SD) and the venular, 222.9 +/- 20.0 microm. Neither arteriolar diameters (odds ratio [OR] per SD decrease: 0.82; 95% confidence interval [CI]: 0.66-1.03) nor venular ones (OR per SD increase: 1.20; 95% CI: 0.95-1.53) were significantly related to iOAG. Baseline retinal vessel diameters did not predict changes in the optic disc. Additional adjustment for cardiovascular risk factors did not alter these results. CONCLUSIONS: The data show that baseline retinal vessel diameters did not influence the risk of iOAG or incident optic disc changes. These data provide no evidence for a retinal vascular role in the pathogenesis of OAG.

Cholesterol and age-related macular degeneration: is there a link? (Article)

2004-04-01T00:00:00Z

PURPOSE: To examine the relation among serum cholesterol, apolipoprotein E genotype (APOE), and the risk of early and late age-related macular degeneration (AMD). DESIGN: The Rotterdam Study, a population based prospective cohort study. METHODS: Serum levels of total and high-density lipoprotein (HDL) cholesterol as well as APOE genotype were determined at baseline. Of 3,944 subjects, 400 were diagnosed with incident early and late AMD after a mean follow-up of 5.2 years. RESULTS: Serum HDL, but not total, cholesterol was associated with an increased risk of AMD (odds ratio/SD, 1.20; 95% confidence interval; 1.06-1.35). The association remained unchanged after adjustment for APOE genotype. When stratifying for APOE genotype, the association was strongest in persons with the e 4 allele; an inverse association seemed to be present for e 2 carriers. CONCLUSION: Elevated HDL but not total cholesterol is associated with an increased risk of AMD. Apolipoprotein E genotype does not explain this association but may be an effect modifier.

Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam Study (Article)

2004-01-01T00:00:00Z

PURPOSE: A lower retinal arteriolar-to-venular ratio (AVR) has been suggested to reflect generalized arteriolar narrowing and to predict the risk of cardiovascular diseases. The contribution of the separate arteriolar and venular diameters to this AVR is unknown. Thus, associations between retinal arteriolar and venular diameters, and the AVR on the one hand and blood pressure, atherosclerosis, inflammation markers, and cholesterol levels on the other were examined in the Rotterdam Study. METHODS: In this cross-sectional population-based study, for one eye of each subject (> or =55 years; n = 5674), retinal arteriolar and venular diameters (in micrometers) of the blood columns were summed on digitized images. At baseline blood pressures, cholesterol levels, and markers of atherosclerosis and inflammation were also measured. RESULTS: With increasing blood and pulse pressures, retinal arteriolar and venular diameters and the AVR decreased significantly and linearly. Lower arteriolar diameters were associated with increased carotid intima-media thickness. Larger venular diameters were associated with higher carotid plaque score, more aortic calcifications, lower ankle-arm index, higher leukocyte count, higher erythrocyte sedimentation rate, higher total serum cholesterol, lower HDL, higher waist-to-hip ratio, and smoking. A lower AVR was related to increased carotid intima-media thickness, higher carotid plaque score, higher leukocyte count, lower HDL, higher body mass index, higher waist-to-hip ratio, and smoking. CONCLUSIONS: Because larger venular diameters are associated with atherosclerosis, inflammation, and cholesterol levels, the AVR does not depend only on generalized arteriolar narrowing due to the association between smaller arteriolar diameters and higher blood pressures. These data indicate that retinal venular diameters are variable and may play their own independent role in predicting cardiovascular disorders.

Blood pressure, atherosclerosis, and the incidence of age-related maculopathy: the Rotterdam Study (Article)

2003-01-01T00:00:00Z

PURPOSE: To determine whether blood pressure and subclinical atherosclerosis are associated with incident age-related maculopathy (ARM). METHODS: The study was performed within the Rotterdam Study, a population-based, prospective cohort study in Rotterdam, The Netherlands. A total of 4822 subjects who at baseline were aged 55 years more, were free of ARM, and participated in at least one of two follow-up examinations after a mean of 2 and 6.5 years, were included in the study. At baseline, blood pressure and the presence of atherosclerosis were determined. ARM was assessed according to the International Classification and Grading System and defined as large, soft drusen with pigmentary changes; indistinct drusen; or atrophic or neovascular age-related macular degeneration. RESULTS: After a mean follow-up of 5.2 years, incident ARM was diagnosed in 417 subjects. Increased systolic blood pressure or pulse pressure was associated with a higher risk of ARM. Adjusted for age, gender, smoking, total and high-density lipoprotein cholesterol, body mass index, and diabetes mellitus, odds ratios (OR) per 10-mm Hg increase were 1.08 (95% confidence interval [CI]: 1.03-1.14) and 1.11 (95% CI: 1.04-1.18), respectively. Moreover, different measures of atherosclerosis were associated with the risk of ARM. An increase in carotid wall thickness (OR per 1 SD, 1.15; 95% CI: 1.03-1.28) increased the risk of ARM. The lowest compared with the highest tertile of ankle-arm index had an OR of 1.32 (95% CI: 1.00-1.75). A weak association was found between aortic calcifications and the risk of ARM. CONCLUSIONS: Elevated systolic blood or pulse pressure or the presence of atherosclerosis may increase the risk of development of ARM.

Relationship between refraction and prevalent as well as incident age-related maculopathy: the Rotterdam Study (Article)

2003-01-01T00:00:00Z

PURPOSE: To study the relationship between baseline spherical equivalents (SphE) of refraction and prevalent as well as incident age-related maculopathy (pARM and iARM, respectively). METHODS: The study was performed as part of the Rotterdam Study, a population-based, prospective cohort study. The SphE (in diopters), measured with autorefraction and subjective optimization, was recorded in 6209 subjects aged 55 years or more. Aphakic or pseudophakic eyes at baseline were excluded. Stereoscopic transparencies of the macular region were graded according to the International Classification and Grading System. ARM was defined as large soft drusen with pigmentary changes, or indistinct drusen, or atrophic or neovascular age-related macular degeneration (AMD). For the prevalence analyses, ARM was classified into no, p(early)ARM, or pAMD, and in each subject the eye with the most advanced ARM and the corresponding refraction was selected. After a mean 5.2 years of follow-up, 4935 subjects had complete data for these incidence analyses. In each subject, the eye with iARM was selected. RESULTS: The age- and gender-adjusted odds ratio (OR) of pARM (n = 536) for every diopter of progress toward hyperopia was 1.09 (95% confidence interval [CI]1.04-1.13). For p(early)ARM (n = 440) the OR was 1.09 (1.04-1.14) and for pAMD (n = 96) the OR was 1.09 (1.00-1.19). Baseline refraction was significantly associated with increased risk of iARM (n = 497). For each diopter of progress toward hyperopia the OR was 1.05 (95% CI 1.01-1.10). Additional adjustments for smoking, atherosclerosis, and blood pressure did not alter the relationship. CONCLUSIONS: These population-based incidence data confirm results from prevalence and case-control studies that there is an association between hyperopia and ARM.

Cholesterol lowering drugs and risk of age related maculopathy: prospective cohort study with cumulative exposure measurement (Article)

2003-01-01T00:00:00Z

A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy (Article)

2002-12-01T00:00:00Z

Age-related maculopathy (ARM) is a multifactorial disorder known to have a substantial genetic component. The epsilon4 allele of the apolipoprotein E gene (APOE-4) has previously been reported to have a protective effect on ARM risk, while the APOE-2 allele may increase disease risk. This study combined four independent data sets (three US and one European) of Caucasian ARM patients and controls in order to obtain better statistical power to examine the role of APOE in ARM. APOE genotype and allele frequencies were compared for 617 ARM cases and 1260 controls, adjusting for age and sex differences between the two groups via multiple logistic regression. The protective effect of the APOE-4 allele on ARM risk was confirmed (age- and sex-adjusted odds ratio (OR) for APOE-4 carriers 0.54, 95% confidence interval (CI) 0.41-0.70, p < 0.0001). The effect of APOE-4 did not differ significantly between males and females and was observed consistently for both atrophic and neovascular ARM. Evidence for an increased risk of ARM due to the APOE-2 allele was found for men, but not for women (OR for men 1.54, 95% CI 0.97-2.45; OR for women 0.74, 95% CI 0.52-1.06, p = 0.01 for interaction of sex and APOE-2 carrier status). These data confirm that the APOE-4 allele, or an allele in linkage disequilibrium with it, reduces the risk of ARM. They also suggest that the effect of the APOE-2 allele may vary by gender, and that APOE-2 may confer an increased risk only to males.

Incidence and progression rates of age-related maculopathy: the Rotterdam Study (Article)

2001-01-01T00:00:00Z

PURPOSE: To describe the incidence rate of age-related macular degeneration (AMD) and the progression rates of early stages of age-related maculopathy (ARM), and to study the hierarchy of fundus features that determine progression. METHODS: A group of 4953 subjects aged 55 years and older living in Rotterdam, The Netherlands, was studied at baseline and at 2-year follow-up to determine the incidence of neovascular and atrophic AMD. A subgroup of 1244 subjects was studied for progression of early stages of ARM. Fundus transparencies were graded for features of ARM using the International Classification System. ARM was stratified in four exclusive stages, according to type of drusen and presence of pigmentary irregularities. RESULTS: The overall 2-year cumulative incidence of AMD was 0.2%, increasing to 1.8% in subjects of 85 years and older. Of those in the early stages, one fourth showed progression to a more severe stage. The most important predictors for progression were more than 10% of macular area covered by drusen (odds ratio [OR] 5.7, 95% confidence interval [CI] 2.9-11.3), presence of depigmentation (OR 4.0, 95% CI 2.5-6.4), and hyperpigmentation (OR 3.4, 95% CI 2.1-5.4). CONCLUSIONS: The incidence of AMD appears to be lower in The Netherlands than in the United States. Progression of early ARM stages occurs in a distinct pattern at a stable rate, with a large area of drusen and presence of pigmentary changes as the most important predictors.

The APO(*)E3-Leiden mouse as an animal model for basal laminar deposit (Article)

2000-01-01T00:00:00Z

AIM: To investigate the APO(*)E3-Leiden mouse as an animal model for age related maculopathy (ARM) related extracellular deposits. METHODS: Eyes were obtained from APO(*)E3-Leiden transgenic mice on a high fat/cholesterol (HFC) diet (n=12) or on a normal mouse chow (n=6), for 9 months. As controls, eyes were collected from APO-E knockout mice on the same diets. From each mouse one eye was processed for microscopic evaluation and immunohistochemistry with a polyclonal antibody directed against human apo-E. Electron microscopy was also performed. RESULTS: All 12 eyes of the APO(*)E3-Leiden mice on an HFC diet contained basal laminar deposit (BLD; class 1 to class 3), whereas two of six APO(*)E3-Leiden mice on normal chow showed BLD class 1. The ultrastructural aspects of this BLD were comparable with those seen in early BLD in humans, and BLD showed immunoreaction with anti-human-apo-E antibodies. No BLD was found in any of the control mice. Drusen were not detected in any of the mice. CONCLUSION: These results indicate that APO(*)E3-Leiden mice can be used as animal model for the pathogenesis of BLD, and that a HFC diet enhances the accumulation of this deposit. Furthermore, this study supports the previously suggested involvement of dysfunctional apo-E in the accumulation of extracellular deposits in ARM.

Genetic Risk of age-related maculopathy (Article)

1998-01-01T00:00:00Z

OBJECTIVE: To investigate to what extent age-related maculopathy (ARM) is genetically determined. DESIGN AND SETTING: Familial aggregation study based on probands derived from the population-based Rotterdam Study. PARTICIPANTS: First-degree relatives of 87 patients with late ARM, i.e., atrophic or neovascular macular degeneration, were compared with first-degree relatives of 135 control subjects without ARM. MAIN OUTCOME MEASURES: Presence and stage of ARM as diagnosed on fundus transparencies, odds ratio, lifetime risk, risk ratio, and population-attributable risk. RESULTS: Independent of other risk factors, the prevalence of early (odds ratio = 4.8, 95% confidence interval [CI] = 1.8-12.2) and late (odds ratio = 19.8, 95% CI = 3.1-126.0) ARM was significantly higher in relatives of patients with late ARM. The lifetime risk estimate of late ARM was 50% (95% CI = 26%-73%) for relatives of patients vs 12% (95% CI = 2%-16%) for relatives of controls (P < .001), yielding a risk ratio of 4.2 (95% CI = 2.6-6.8). Relatives of patients expressed the various features of ARM at a younger age. The population-attributable risk related to genetic factors was 23%. CONCLUSIONS: First-degree relatives of patients with late ARM developed ARM at an increased rate at a relatively young age. Our findings indicate that approximately one fourth of all late ARM is genetically determined and suggest that genetic susceptibility may play an important role in determining the onset of disease.

Genetic Risk of primary open-angle glaucoma. A population-based familial aggregation study (Article)

1998-01-01T00:00:00Z

OBJECTIVES: To study familial aggregation of primary open-angle glaucoma in a general population and to determine the absolute and relative risks for first-degree relatives. METHODS: First-degree relatives of patients with glaucoma (n = 48) and control subjects (n = 155) from the population-based Rotterdam Study underwent a standardized examination, including perimetry. MAIN OUTCOME MEASURES: Intraocular pressure, vertical cup-disc ratio; and the presence of glaucoma, defined as a visual field defect with a cup-disc ratio of 0.7 or higher or asymmetry of 0.3 or higher between both eyes. RESULTS: The prevalence of glaucoma was 10.4% in siblings of patients, 1.1% in offspring of patients, 0.7% in siblings of controls, and 0% in offspring of controls. Life-time risk of elevated intraocular pressure in relatives of patients vs relatives of controls was 42.5% vs 6.7%, of enlarged cup-disc ratio was 62.2% vs 16.6%, and of glaucoma was 22.0% vs 2.3%, yielding a risk ratio for glaucoma of 9.2 (95% confidence interval = 1.2-73.9). The population-attributable risk of glaucoma was 16.4%. CONCLUSIONS: In a general population, relatives of patients with glaucoma have a strongly increased risk of glaucoma. Enlarged cup-disc ratio, not intraocular pressure, was the earliest and most prominent feature of familial aggregation. Further studies are needed to disentangle the genetic components of the increased familial risk.

Genetic association of apolipoprotein E with age-related macular degeneration (Article)

1998-01-01T00:00:00Z

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.

Elevated plasma fibrinogen: cause or consequence of cardiovascular disease? (Article)

1998-01-01T00:00:00Z

An association between increased plasma fibrinogen and an increased risk for myocardial infarction (MI) is well established, but the nature of this association is subject to debate. Our aim was to shed light on the potentially causal nature of this association. We examined whether increased plasma fibrinogen, due to a condition that is independent of cardiovascular events, also increases the risk for MI. A case-control study was performed in 139 subjects with a history of MI and 287 control subjects selected from the Rotterdam Study, a population-based cohort of 7983 subjects aged 55 years and older. The genotype of the -455G/A polymorphism in the fibrinogen beta-gene was determined by polymerase chain reaction. Functional plasma fibrinogen levels were determined according to von Clauss. The plasma level of fibrinogen was significantly higher in subjects with one or two A alleles compared with subjects with the GG genotype: 3.8 (95% confidence interval [CI], 3.6 to 3.9) g/L and 3.6 (3.5 to 3.7) g/L, respectively. With increasing plasma fibrinogen level, the risk for MI increased gradually; a rise in fibrinogen of 1 g/L was associated with a 45% increased risk (odds ratio adjusted for age, sex, and smoking, 1.45; 95% CI, 1.12 to 1.88). There was no association between the genotype of the -455G/A polymorphism and the risk for MI. The -455G/A polymorphism is therefore associated with increased plasma fibrinogen levels but not with an increased risk for MI. These findings indicate that an increased plasma fibrinogen level due to this genetic factor does not increase the risk for MI.

Increased expression of angiogenic growth factors in age-related maculopathy (Article)

1997-01-01T00:00:00Z

AIMS/BACKGROUND: The late stages of age-related maculopathy (ARM), especially neovascular macular degeneration (ARMD), can severely affect central vision and are the main cause of blindness in the elderly in the Western world. It has been shown that angiogenic growth factors are present in neovascular membranes in ARMD. However, it is not known if angiogenic growth factors play a role in the onset of neovascularisation. METHODS: In order to elucidate the involvement of angiogenic growth factors in the initiation of neovascularisation in early stages of ARM, the expression patterns of VEGF, TGF-beta, b-FGF, and PDGF-AA on 18 human maculae with ARM, and on 11 control specimens were investigated immunohistochemically. RESULTS: A significantly increased expression of VEGF (p = 0.00001) and TGF-beta (p = 0.019) was found in the retinal pigment epithelium (RPE) of maculae with ARM compared with control maculae. Furthermore, an increased expression of VEGF and PDGF was found in the outer nuclear layer of maculae with ARM. CONCLUSION: These results demonstrate an increased expression of VEGF in the RPE, and in the outer nuclear layer in maculae with ARM, that could be involved in the pathogenesis of neovascular macular degeneration. Furthermore, enhanced TGF-beta expression in the RPE cells of maculae with early stages of ARM was shown.