Meta-analysis of genome-wide association studies in multiethnic Asians identifies two loci for age-related nuclear cataract.

Age-related cataract is a leading cause of blindness worldwide, especially in developing countries where access to cataract surgery remains limited. Previous linkage and candidate gene studies suggested genetic influences on age-related nuclear cataract but few genetic markers have been identified thus far. We conducted genome-wide association studies on 4569 Asians (including 2369 Malays and 2200 Indians), and replicated our analysis in 2481 Chinese from two independent cohorts (1768 Chinese in Singapore and 803 Chinese in Beijing). We confirmed two genome-wide significant loci for nuclear cataract in the combined meta-analysis of four cohorts (n = 7140). The first locus was at chromosome 3q25.31 in KCNAB1 (rs7615568, fixed-effect Pmeta = 2.30 × 10(-8); random-effect Pmeta = 1.08 × 10(-8)). The second locus was at chromosome 21 in the proximity of CRYAA (rs11911275, fixed-effect Pmeta = 2.77 × 10(-8); random-effect Pmeta = 1.98 × 10(-9)), a major protein component of eye lens. The findings were further supported by up-regulation and down-regulation of KCNAB1 and CRYAA in human lens capsule, respectively, as the severity of nuclear cataract increases. The results offer additional insights into the pathogenesis of nuclear cataract in Asians.

Retinal vessel caliber changes in vasculitis.

BACKGROUND: Retinal vasculitis is a potentially sight-threatening inflammation of the retinal vessels, but little is known about the in vivo vascular changes, which occur in affected eyes. The authors therefore sought to measure vessel caliber in eyes with vasculitis. METHODS: Retrospective case-control study. Vasculitis was confirmed using fluorescein angiography. Vessel calibers were measured using validated semiautomated software. RESULTS: There were 21 eyes from 15 patients with vasculitis and 33 control eyes from 21 control subjects. Most cases were diagnosed with idiopathic vasculitis. All had periphlebitis, and one eye also had arteritis. After adjustment for age and gender, mean arteriolar caliber was 143 µm (95% confidence interval [CI], 134-152) in cases and 158 µm (95% CI, 151-165) in controls (P = 0.01). Venular caliber was similar in cases (229 µm; 95% CI, 215-243) and controls (228 µm; 95% CI, 217-234; P = 0.91), whereas arteriole-to-venule ratio was smaller in cases (0.63; 95% CI, 0.60-0.66) compared with controls (0.70; 95% CI, 0.02-0.11; P = 0.004). CONCLUSION: Retinal vasculitis was associated with narrower arteriolar caliber, whereas venular caliber was similar to controls. This resulted in a smaller arteriole-to-venule ratio in eyes with vasculitis.

Genetic susceptibility, dietary antioxidants, and long-term incidence of age-related macular degeneration in two populations.

OBJECTIVE: To examine effect modification between genetic susceptibility to age-related macular degeneration (AMD) and dietary antioxidant or fish consumption on AMD risk. DESIGN: Pooled data analysis of population-based cohorts. PARTICIPANTS: Participants from the Blue Mountains Eye Study (BMES) and Rotterdam Study (RS). METHODS: Dietary intakes of antioxidants (lutein/zeaxanthin [LZ], ß-carotene, and vitamin C), long-chain omega-3 polyunsaturated fatty acids, and zinc were estimated from food frequency questionnaires. The AMD genetic risk was classified according to the number of risk alleles of CFH (rs1061170) or ARMS2 (rs10490924) as low (no or 1 risk allele) or high (≥ 2 risk alleles). Interactions between dietary intake and genetic risk levels were assessed. Associations between dietary intake and AMD risk were assessed comparing the highest with the 2 lower intake tertiles by genetic risk subgroups using discrete logistic regression, conducted in each study separately and then using pooled data. Participants without AMD lesions at any visit were controls. We adjusted for age and sex in analyses of each cohort sample and for smoking status and study site in pooled-data analyses. MAIN OUTCOME MEASURES: All 15-year incident late AMD cases were confirmed by chief investigators of the Beaver Dam Eye Study, BMES, and RS. Intergrader reproducibility was assessed in an early AMD subsample, with 86.4% agreement between BMES and RS graders, allowing for a 1-step difference on a 5-step AMD severity scale. RESULTS: In pooled data analyses, we found significant interaction between AMD genetic risk status and LZ intake (P=0.0009) but nonsignificant interactions between genetic risk status and weekly fish consumption (P=0.05) for risk of any AMD. Among participants with high genetic risk, the highest intake tertile of LZ was associated with a >20% reduced risk of early AMD, and weekly consumption of fish was associated with a 40% reduced risk of late AMD. No similar association was evident among participants with low genetic risk. No interaction was detected between ß-carotene or vitamin C and genetic risk status. CONCLUSIONS: Protection against AMD from greater LZ and fish consumption in persons with high genetic risk based on 2 major AMD genes raises the possibility of personalized preventive interventions.

Prediction of age-related macular degeneration in the general population: the Three Continent AMD Consortium.

PURPOSE: Prediction models for age-related macular degeneration (AMD) based on case-control studies have a tendency to overestimate risks. The aim of this study is to develop a prediction model for late AMD based on data from population-based studies. DESIGN: Three population-based studies: the Rotterdam Study (RS), the Beaver Dam Eye Study (BDES), and the Blue Mountains Eye Study (BMES) from the Three Continent AMD Consortium (3CC). PARTICIPANTS: People (n = 10,106) with gradable fundus photographs, genotype data, and follow-up data without late AMD at baseline. METHODS: Features of AMD were graded on fundus photographs using the 3CC AMD severity scale. Associations with known genetic and environmental AMD risk factors were tested using Cox proportional hazard analysis. In the RS, the prediction of AMD was estimated for multivariate models by area under receiver operating characteristic curves (AUCs). The best model was validated in the BDES and BMES, and associations of variables were re-estimated in the pooled data set. Beta coefficients were used to construct a risk score, and risk of incident late AMD was calculated using Cox proportional hazard analysis. Cumulative incident risks were estimated using Kaplan-Meier product-limit analysis. MAIN OUTCOME MEASURES: Incident late AMD determined per visit during a median follow-up period of 11.1 years with a total of 4 to 5 visits. RESULTS: Overall, 363 participants developed incident late AMD, 3378 participants developed early AMD, and 6365 participants remained free of any AMD. The highest AUC was achieved with a model including age, sex, 26 single nucleotide polymorphisms in AMD risk genes, smoking, body mass index, and baseline AMD phenotype. The AUC of this model was 0.88 in the RS, 0.85 in the BDES and BMES at validation, and 0.87 in the pooled analysis. Individuals with low-risk scores had a hazard ratio (HR) of 0.02 (95% confidence interval [CI], 0.01-0.04) to develop late AMD, and individuals with high-risk scores had an HR of 22.0 (95% CI, 15.2-31.8). Cumulative risk of incident late AMD ranged from virtually 0 to more than 65% for those with the highest risk scores. CONCLUSIONS: Our prediction model is robust and distinguishes well between those who will develop late AMD and those who will not. Estimated risks were lower in these population-based studies than in previous case-control studies.

Exploring Factors Underlying Ethnic Difference in Age-related Macular Degeneration Prevalence.

AIMS: To assess contributions of dietary and genetic factors to ethnic differences in AMD prevalence. DESIGN: Population-based analytical study. METHODS: In the Blue Mountains Eye Study, Australia (European ancestry n = 2826) and Multi-Ethnic Cohort Study, Singapore (Asian ancestry, n = 1900), AMD was assessed from retinal photographs. Patterns of dietary composition and scores of the Alternative Healthy Eating Index were computed using food frequency questionnaire data. Genetic susceptibility to AMD was determined using either single nucleotide polymorphisms (SNPs) of the complement factor H and age-related maculopathy susceptibility 2 genes, or combined odds-weighted genetic risk scores of 24 AMD-associated SNPs. Associations of AMD with ethnicity, diet, and genetics were assessed using logistic regression. Six potential mediators covering genetic, diet and lifestyle factors were assessed for their contributions to AMD risk difference between the two samples using mediation analyses. RESULTS: Age-standardized prevalence of any (early or late) AMD was higher in the European (16%) compared to Asian samples (9%, p < .01). Mean AMD-related genetic risk scores were also higher in European (33.3 ± 4.4) than Asian (Chinese) samples (31.7 ± 3.7, p < .001). In a model simultaneously adjusting for age, ethnicity, genetic susceptibility and Alternative Healthy Eating Index scores, only age and genetic susceptibility were significantly associated with AMD. Genetic risk scores contributed 19% of AMD risk difference between the two samples while intake of polyunsaturated fatty acids contributed 7.2%. CONCLUSION: Genetic susceptibility to AMD was higher in European compared to Chinese samples and explained more of the AMD risk difference between the two samples than the dietary factors investigated.

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract.

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10-16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10-19), TMPRSS5 (rs4936279, P = 2.5 × 10-10), LINC01412 (rs16823886, P = 1.3 × 10-9), GLTSCR1 (rs1005911, P = 9.8 × 10-9), and COMMD1 (rs62149908, P = 1.2 × 10-8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.

The long-term relation among retinal arteriolar narrowing, blood pressure, and incident severe hypertension.

The authors assessed associations between retinal vascular signs and incident severe hypertension in an older population-based cohort. At baseline (1992-1994), 3,654 residents aged 49-97 years living in the Blue Mountains area west of Sydney, Australia, were examined; respectively, 2,335 (75.1%) and 1,952 (76%) survivors were reexamined 5 and 10 years later. Retinal arteriolar and venular calibers were measured, and average central retinal artery and central retinal vein equivalents for that eye were estimated. Severe hypertension was defined by previous diagnosis of hypertension plus antihypertensive medication use or by systolic blood pressure > or =160 mmHg and/or diastolic blood pressure > or =100 mmHg at examinations. Of the 1,424 participants at risk, 618 developed severe hypertension over 10 years (cumulative incidence = 47.7%, 95% confidence interval: 44.9, 50.5). Participants who subsequently developed severe hypertension had significantly narrower mean central retinal artery equivalents than those who did not (187.0 vs. 191.9 mum, p < 0.0001). After adjusting for age, sex, body mass index, smoking, mean arterial blood pressure, and plasma glucose and triglyceride levels, baseline narrowing central retinal artery equivalent was associated with increased risk of severe hypertension (per standard deviation reduction, odds ratio = 1.1, 95% confidence interval: 1.1, 1.2; narrowest vs. widest quintile, odds ratio = 1.6, 95% confidence interval: 1.2, 2.1). These findings support structural narrowing in small arteries and arterioles antecedent to clinical onset of severe hypertension.

The LOC387715 polymorphism, inflammatory markers, smoking, and age-related macular degeneration. A population-based case-control study.

OBJECTIVE: To assess combined effects on the risk of age-related macular degeneration (AMD) by the LOC387715 polymorphism, smoking, and inflammatory or hemostatic factors. DESIGN: Population-based case-control study. PARTICIPANTS: Two hundred seventy-eight AMD cases (224 early, 54 late) and 557 controls matched for age, gender, and smoking, drawn from the Blue Mountains Eye Study cohort. METHODS: Subjects were genotyped for the LOC387715 Ala69Ser polymorphism (rs# 10490924). Smoking was self-reported. Serum high-sensitivity C-reactive protein (CRP), interleukin 6 (IL-6), soluble intercellular adhesion molecule 1 (sICAM-1), fibrinogen, homocysteine, plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor, and white cell count (WCC) were measured. Combined effects of this genetic variant plus any of these study factors on AMD risk were assessed using logistic regression models, adjusted for age and smoking. We defined interaction if the influence of 2 factors departed from the multiplicative scale, confirmed by a statistically significant interaction term. Otherwise, the combined effect was used. MAIN OUTCOME MEASURES: Age-related macular degeneration was graded using the Wisconsin grading system. RESULTS: Combined effects on the likelihood of early or late AMD were demonstrated for the LOC387715 Ala69Ser G/T and T/T genotypes with the markers high-sensitivity CRP (odds ratios [ORs], 1.2 for the highest tertile alone, 1.6 for G/T and T/T genotypes alone, and 2.2 for both G/T and T/T genotypes plus the highest tertile, compared with the G/G genotype with the 2 lower tertiles), IL-6 (corresponding ORs, 1.1, 1.6, and 2.2), sICAM-1 (ORs, 1.0, 1.5, and 2.3, respectively), and PAI-1 (ORs, 1.3, 1.7, and 2.3, respectively), but not with WCC, fibrinogen, homocysteine, and von Willebrand factor. Findings were similar for early and late AMD separately. Current smokers with G/T and T/T genotypes had strong combined effects on late AMD risk compared with those who never smoked or past smokers with the G/G genotype (ORs, 1.2 for current smokers alone, 1.8 for G/T and T/T genotypes alone, and 6.1 for current smokers plus G/T and T/T genotypes). CONCLUSIONS: We found no significant interaction but combined effects for the LOC387715 genotypes with 3 inflammatory markers and PAI-1 on the risk of early or late AMD, and with current smoking on the risk of late AMD.

Pupil Dilation May Affect Retinal Vessel Caliber Measures.

PURPOSE: To assess the effect of pupil dilation on measures of retinal vessel caliber. DESIGN: Observational study with self-comparisons Methods: Retinal photographs were taken for both eyes of 25 subjects before and after pupil dilation. Three photographic graders, masked to pupil dilation status, measured the same set of images using a computer-assisted, semi-automatic method. We compared means (standard deviations) of retinal arteriolar caliber equivalent (CRAE) and retinal venular caliber equivalent (CRVE) of the same eyes between pre- and post-dilation images. We assessed concordance correlation coefficients (CC), Bland Altman limits-of-agreements, and used linear mixed models to assess CRAE and CRVE measures associated with pupil dilation (influencing image quality), graders (observers) and right-left eye variation. RESULTS: We found high CCs for CRAE (0.82-0.94) and CRVE (0.87-0.94) between pre- and post-dilation images of the same eyes across the graders. Bland Altman plots showed that mean differences ranged from 0.55-3.42µm for CRAE and 1.56-2.29µm for CRVE. After adjusting for right-left eye random variation, a significant fixed effect of dilation was evident in mean CRAE in two of the three graders. There was no significant fixed effect of dilation in mean CRVE across all graders. In models including data of both eyes' measures from pre- and post-dilation images by three graders, the fixed effect for dilation status contributed significantly to CRAE and CRVE variances whereas random effects for graders and dilation status contributed minimally. CONCLUSIONS: Contrary to our hypothesis, we found a systematic effect of pupil dilation on retinal vessel caliber measures.

Joint Contribution of Genetic Susceptibility and Modifiable Factors to the Progression of Age-Related Macular Degeneration over 10 Years: The Three Continent AMD Consortium Report.

PURPOSE: To assess joint effects of genetic and modifiable factors on the 10-year progression of age-related macular degeneration (AMD). DESIGN: Individual and pooled data analyses of 2 population-based cohorts. PARTICIPANTS: Blue Mountains Eye Study (BMES) and Rotterdam Study (RS) participants (n = 835). METHODS: Participants of the BMES and RS were followed up over 10 years or more. At baseline and follow-up visits, interviews using questionnaires and eye examinations with retinal photography were performed. Age-related macular degeneration was assessed by trained photographic graders and verified by retinal specialists. Genetic susceptibility to AMD meant carrying 2 or more risk alleles of the CFH or ARMS2 SNPs, or both (rs1061170 and rs10490924), relative to 0 or 1 risk allele. Discrete logistic regression models were used to investigate the joint associations of genetic susceptibility and either smoking, fish consumption, dietary intake of lutein-zeaxanthin, or combined environmental risk scores from the 3 modifiable factors with the risk of AMD progression. Odds ratios (ORs) with 95% confidence intervals (CIs) and synergy indexes are reported. MAIN OUTCOME MEASURE: Ten-year progression of AMD, categorized as any (≥1 step) or 2-step (≥2 steps) progression on the Three Continent AMD Consortium 5-step severity scale. RESULTS: Older age, the presence of AMD genetic susceptibility, and baseline AMD status were associated strongly with AMD progression (P < 0.0001). In analyses of pooled data, each additional score from the combined environmental risk scores was associated with an increased risk of 2-step progression over 10 years (OR, 1.26; 95% CI, 1.02-1.56). The copresence of AMD genetic susceptibility and combined risk score of 3 or more was associated with a substantially higher risk of 2-step progression compared with the presence of either factor alone. There was a significant synergistic effect (OR, 4.14; 95% CI, 1.07-15.95) and interaction (P = 0.025) between genetic susceptibility and environmental risk score of 3 or more. CONCLUSIONS: Among persons with AMD genetic susceptibility and pre-existing early AMD lesions, presenting with high environmental risk scores from 3 modifiable factors (smoking, infrequent consumption of fish, low lutein-zeaxanthin intake) were associated with an increased risk of 2-step progression over 10 years.

Nuclear cataract and myopic shift in refraction.

PURPOSE: Nuclear cataract is thought to cause a myopic shift in refraction in older persons. The authors tested this hypothesis by assessing the correlation of nuclear opacity with spherical equivalent refraction (SER) in an older population. DESIGN: Population-based cross-sectional study. METHODS: Three thousand six hundred and fifty-four participants aged 49 years or older were examined in the Blue Mountains Eye Study [BMES] (1992 to 1994). Eye examinations included subjective refraction and lens photographs. Nuclear opacity was assessed against four standard slit-lamp lens photographs using the Wisconsin Cataract Grading System. Nuclear cataract was defined as opacity level 4 or higher. RESULTS: Participants without nuclear cataract had an annual mean hyperopic shift of 0.05 diopters (P < .0001). In persons with nuclear cataract, this hyperopic shift disappeared. A myopic refractive shift occurred only in persons with nuclear opacity levels of 4 or higher. CONCLUSION: This study documents the contribution of nuclear cataract to the mild myopic shift that neutralizes the age-related hyperopic shift occurring in older persons.

Five-year progression of unilateral age-related macular degeneration to bilateral involvement: the Three Continent AMD Consortium report.

PURPOSE: To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. DESIGN: Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study. METHODS: Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any (early and late) or late AMD was assessed among participants with unilateral involvement only. Factors associated with the progression were assessed using logistic regression models while simultaneously adjusting for other significant risk factors. RESULTS: In any 5-year duration, 19-28% of unilateral any AMD cases became bilateral and 27-68% of unilateral late AMD became bilateral. Factors associated with the progression to bilateral involvement of any AMD were age (per year increase, adjusted OR 1.07), carrying risk alleles of the complement factor H and age-related maculopathy susceptibility 2 genes (compared with none, OR 1.76 for 1 risk allele and OR 3.34 for 2+ risk alleles), smoking (compared with non-smokers, OR 1.64 for past and OR 1.67 for current smokers), and the presence of large drusen area or retinal pigmentary abnormalities in the first eye. CONCLUSION: One in four to one in five unilateral any AMD cases, and up to one in two unilateral late AMD cases, progressed to bilateral in 5 years. Known AMD risk factors, including smoking, are significantly associated with the progression to bilateral involvement.

Cataract surgery and the 10-year incidence of age-related maculopathy: the Blue Mountains Eye Study.

PURPOSE: To assess the long-term (10-year) risk of late age-related maculopathy (ARM) in eyes that had previously undergone cataract surgery (before the baseline examination). DESIGN: Population-based cohort study. PARTICIPANTS: In the Blue Mountains Eye Study (BMES) cohort, 2335 of 3654 baseline participants > or =49 years old (75% of survivors) were reexamined after 5 years and 1952 (76% of survivors) were reexamined after 10 years. METHODS: At the baseline examination, nonphakic (aphakic or pseudophakic) eyes were identified at slit-lamp examination and confirmed at lens photographic grading. Side-by-side grading of baseline and follow-up stereoretinal photographs was performed using the Wisconsin ARM grading system. Eye-specific data were analyzed using Kaplan-Meier estimates and generalized estimating equation models, adjusting for correlation between the 2 eyes. MAIN OUTCOME MEASURES: Incident late ARM was defined if either neovascular ARM or geographic atrophy developed in eyes without either lesion at baseline. RESULTS: After excluding eyes with either late ARM lesion at baseline or that had missing photographs at either examination, 4763 eyes were considered at risk of incident late ARM, including 132 eyes that had cataract surgery before the baseline examination. Late ARM developed in 10 of 132 nonphakic eyes (7.6%) compared to 96 of 4631 phakic eyes (2.1%). After adjusting for baseline age, gender, smoking, and presence of early ARM lesions, nonphakic (cataract surgical) eyes had a 3-fold risk of developing late-stage ARM (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.1-9.9) or neovascular ARM (OR, 3.4; 95% CI, 1.1-10.9) compared to phakic eyes. CONCLUSIONS: Our findings support the hypothesis that the long-term risk of developing late ARM is higher in cataract surgical eyes, consistent with findings from the Beaver Dam Eye Study.

Retinal vessel signs and 10-year incident age-related maculopathy: the Blue Mountains Eye Study.

OBJECTIVE: To examine whether retinal vessel signs are independent predictors of the long-term development of age-related maculopathy (ARM). DESIGN: Prospective population-based cohort study. PARTICIPANTS: Blue Mountains Eye Study participants aged > or =49 years (n = 3654) were examined during 1992 through 1994; 2335 (75% of survivors) were reexamined after 5 years and 1952 (76% of survivors) were reexamined after 10 years. METHODS: Baseline focal arteriolar narrowing and arteriovenous (AV) nicking were assessed and vessel calibers were measured from retinal photographs. A side-by-side grading method was used to assess ARM incidence. Eye-specific data were analyzed using generalized estimating equation models, adjusting for age, gender, smoking, and blood pressure. MAIN OUTCOME MEASURES: Incident early ARM (soft indistinct or reticular drusen or combined soft distinct drusen and retinal pigment abnormality) was defined in eyes free of both early and late ARM at baseline. Incident late ARM (either geographic atrophy or neovascular macular degeneration) was defined in eyes free of these 2 lesions at baseline. RESULTS: Over a 10-year period, incident late ARM developed in 106/4745 eyes at risk of late ARM (2.2%). Eyes with mild (2.7%) or severe (4.6 %) AV nicking were more likely to develop late ARM than eyes without this sign (1.5%). The adjusted odds ratio (OR) was 1.4, 95% confidence interval (CI) 0.8 to 2.4 for mild and OR 2.6, 95% CI 1.2 to 5.5 for severe AV nicking. Eyes with focal narrowing were also more likely to develop late ARM (7.6% vs. 1.8%), adjusted OR 2.2, 95% CI 1.1 to 4.1. Incident early ARM developed in 398/4490 eyes at risk of early ARM (8.9%). Severe AV nicking, but not focal arteriolar narrowing, was associated with an increased long-term risk of early ARM (13.6% vs. 8.2%; OR 1.5; 95% CI 1.0-2.3). Neither arteriolar nor venular caliber was significantly associated with the incidence of either early or late ARM. CONCLUSIONS: These 10-year incidence data confirm our previous observation that structural retinal arteriolar changes may either contribute to ARM progression or share common pathologic pathways with ARM, independent of traditional vascular risk factors.

Diabetic macular ischaemia is associated with narrower retinal arterioles in patients with type 2 diabetes.

PURPOSE: Diabetic macular ischaemia (DMI) is an important cause of visual loss in patients with diabetes, but its relationship to the larger retinal vessels is unknown. We examined whether retinal vessel calibre is related to DMI. METHODS: Clinic-based case-control study of patients with type 2 diabetes. The presence and severity of DMI was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) protocols from fundus fluorescein angiographic (FFA) images. Custom software was used to quantify the greatest linear dimension and area of the foveal avascular zone (FAZ). Retinal vessel calibre was measured using a semi-automated software on fundus fluorescein images. RESULTS: Of 53 patients examined, 18 (34%), 18 (34%) and 17 (32%) had no/mild, moderate and severe DMI, respectively. Persons with moderate or severe DMI had narrower mean retinal arteriolar calibre than persons with no/mild DMI (140.6 µm 95% confidence interval (CI) 134.7, 146.4 versus 150.7 µm, 95% CI 142.5, 158, p = 0.04). The association remained after multivariate adjustment for age, gender, previous panretinal photocoagulation, neovascularization at the disc and elsewhere and diabetic retinopathy severity. Increased FAZ size was also associated with narrower arteriolar calibre. Retinal venular calibre and arteriole to venule ratio (AVR) were not associated with DMI. CONCLUSIONS: Retinal arteriolar narrowing was associated with moderate-to-severe macular ischaemia in eyes with diabetic retinopathy. This suggests that larger vessels other than capillaries may also be associated with DMI.

Relationships between age, blood pressure, and retinal vessel diameters in an older population.

PURPOSE: To describe the cross-sectional relationships between age, blood pressure (BP), and quantitative measures of retinal vessel diameters in an older Australian population. METHODS: Retinal photographs from right eyes of participants (n = 3654, aged 49+ years) in the Blue Mountains Eye study taken during baseline examinations (1992-1994) were digitized. The width of all retinal vessels located 0.5 to 1.0 disc diameters from the disc margin was measured by a computer-assisted method. Summarized estimates for central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) represent average retinal vessel diameters. The arteriole-to-venule ratio (AVR) was calculated. Associations between age and BP and CRAE, CRVE, and AVR were assessed with generalized linear models. RESULTS: Retinal vessel diameters decreased with increasing age in both men and women. CRAE and CRVE decreased by 4.8 microm and 4.1 microm, respectively, per decade increase in age, after adjusting for sex and mean arterial blood pressure. Mean AVR declined by 0.01 for each increasing decade of age, until 79 years. After adjustment for age, sex, smoking, and body mass index, CRAE, CRVE and AVR were all significantly and inversely associated with BP. For every 10-mm Hg increase in mean arterial blood pressure, AVR decreased by 0.012 and CRAE and CRVE decreased by 3.5 microm and 0.96 microm, respectively. CONCLUSIONS: Retinal arteriolar and venular diameters narrow with increasing age, and these parameters are inversely related to BP, independent of age, gender, and smoking. The findings are consistent with those from the Atherosclerosis Risk in Communities Study suggesting that decreased retinal vessel diameters may reflect microvascular damage from elevated blood pressure.

The association between ocular biometry and retinal vascular caliber is comparable from early childhood to adolescence.

PURPOSE: We aimed to establish whether the change in retinal microvascular structure observed cross-sectionally with axial elongation and larger corneal curvature is comparable from early childhood to adolescence. METHODS: In all, 1077 Sydney Paediatric Eye Study participants (36 to <72 months of age) and 1740, 2353, and 1216 from the Sydney Childhood Eye Study (6, 12, and 17 years of age), respectively, were examined. Quantifiable retinal vascular caliber measurements were obtained using validated computer-based methods. Ocular biometry measurements were performed according to standardized protocols. RESULTS: After multivariable adjustment, in children 36 to <72 months of age, each 1.0-mm increase in axial length was associated with a 3.67- and 6.53-µm narrowing of mean retinal arteriolar caliber (P = 0.005) and venular caliber (P < 0.0001), respectively. Each 1.0-mm increase in axial length in children 6, 12, and 17 years of age was associated with a 5.30-, 3.96-, and 4.03-µm decrease in mean retinal arteriolar caliber, respectively. Each 1.0-mm increase in axial length in children 6, 12, and 17 years of age was associated with a 7.12-, 6.72-, and 6.85-µm decrease in retinal venular caliber, respectively. Corneal curvature was inversely associated with retinal vascular caliber among all age groups (P < 0.001). Among those without significant refractive error (>0.00 and <2.00 diopters), significant inverse associations were observed between axial length and corneal curvature with retinal vessel caliber among all age groups. CONCLUSIONS: We demonstrate a similar magnitude of retinal vessel narrowing with axial length elongation and increasing corneal curvature from childhood through to adolescence. These data confirm the robustness of the associations between ocular biometric traits and retinal microvascular structural changes during childhood development.

Smoking, socioeconomic factors, and age-related cataract: The Singapore Malay Eye study.

OBJECTIVE: To describe the relationship of smoking, sex, and socioeconomic factors with age-related cataract in Malay adults in Singapore. METHODS: In a population-based study, 3280 Malay individuals aged 40 to 80 years participated (78.7% response rate). All had interviews, systemic examination, and laboratory investigations. Lens opacity was graded from slitlamp and retroillumination photographs using the Wisconsin Cataract Grading System. Smoking-cataract associations were compared with the Blue Mountains Eye Study in Australia. RESULTS: Of 2927 participants (89.2%) with gradable lens photographs, 1338 (45.7%) had cataract. After adjusting for age, sex, body mass index, hypertension, and diabetes, current smokers had a higher prevalence of nuclear cataract (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.46-2.98), cortical cataract (OR, 1.33; 95% CI, 1.02-1.74), posterior subcapsular cataract (OR, 1.39; 95% CI, 1.02-1.91), or any cataract (OR, 1.48; 95% CI, 1.10-1.99). These associations were not seen in the Blue Mountains Eye Study. Primary or lower education (OR, 1.67; 95% CI, 1.06-2.64) and low monthly income (OR, 1.43; 95% CI, 1.09-1.87) were both associated with nuclear cataract, while small-sized public housing was associated with posterior subcapsular cataract (OR, 1.70; 95% CI, 1.28-2.25). Among men, 43.5% currently smoked compared with only 3.2% of women. The population attributable risk of nuclear cataract due to smoking was estimated to be 17.6% in men. CONCLUSIONS: Smoking and indicators of low socioeconomic status were associated with cataract in Malay persons, with 1 in 6 nuclear cataract cases in men attributable to smoking. Smoking-cataract associations were stronger in Malay than in white persons.

Correlation between generalized and focal retinal arteriolar narrowing in an older population.

This study aimed to assess the associations between generalized and focal retinal arteriolar narrowing in the Blue Mountains Eye Study population (n = 3654 persons aged 49+ years). Summarized estimates of the average retinal arteriolar diameter, the central retinal arteriolar equivalent (CRAE) and arteriole-to-venule ratio were obtained from right eye photographs of each participant using a computer-assisted method. Focal retinal arteriolar narrowing was graded from retinal photographs of both eyes using a 'light-box' method. The proportion of subjects with focal arteriolar narrowing increased as CRAE decreased from the widest (2.2%) to the narrowest (7.8%) quintile (P for trend = 0.001). A receiver operating characteristic curve was constructed using CRAE to detect focal arteriolar narrowing. With the diagnostic cut point set at the 4th decile of CRAE, the sensitivity and specificity in detecting focal arteriolar narrowing were 64% and 61%,respectively. These data suggest a moderate correlation between generalized (CRAE) and focal arteriolar narrowing. However, no significant association was found between arteriole-to-venule ratio and focal arteriolar narrowing.