Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.

Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study ('Cooperative Health Research in the Region of Augsburg'); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10(-9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.

Incidence and progression of reticular drusen in age-related macular degeneration: findings from an older Australian cohort.

PURPOSE: To assess the 15-year incidence and progression of reticular drusen and associations of this lesion with age-related macular degeneration (AMD) risk factors. DESIGN: Population-based cohort. PARTICIPANTS: Blue Mountains Eye Study participants (n = 3654) 49 years of age and older attended baseline examinations; of these, 75.8%, 76.7%, and 56.1% of survivors attended 5-year, 10-year, and 15-year follow-up examinations, respectively. METHODS: Color retinal photographs were obtained and comprehensive questionnaires were administered at each visit, and DNA samples were genotyped. Fundus autofluorescence images were not available. Reticular drusen identified from photographs were confirmed with side-by-side grading using the Wisconsin AMD grading protocol. Incidence was assessed using Kaplan-Meier product limit survival methods, controlling for competing risk of death. Associations between smoking, fish consumption, serum lipids, systemic and dietary factors, the CFH single nucleotide polymorphism (SNP) rs1061170 and ARMS2 SNP rs10490924, and the 15-year incidence of reticular drusen were analyzed in discrete logistic regression models. Generalized estimating equation models were used to analyze eye-specific relationships between these risk factors and 5-year progression from reticular drusen to late AMD. MAIN OUTCOME MEASURES: Incidence and progression of reticular drusen. RESULTS: The 15-year cumulative incidence of reticular drusen was 4.0% (n = 95). Increasing age (per decade increase; odds ratio [OR], 3.4; 95% confidence interval [CI], 2.6-4.4), female sex (OR, 2.0; 95% CI, 1.3-3.2), and presence of risk alleles of CFH-rs1061170 (OR, 1.8; 95% CI, 1.3-2.4) or ARMS2-rs10490924 (OR, 3.0; 95% CI, 2.1-4.4) were associated with higher reticular drusen incidence. Current smoking at baseline predicted higher reticular drusen incidence (OR 2.1, 95% CI 1.0-4.5) after adjusting for age, sex, CFH-rs1061170 and ARMS2-rs10490924 polymorphisms. Of 118 eyes with reticular drusen, 40 (33.9%) developed late AMD over 5 years. A higher proportion of eyes with reticular drusen located outside versus within the macular area progressed to late AMD (50.0% vs. 37.8%). Dietary lutein-zeaxanthin intake was associated with decreased likelihood of progression from reticular drusen to late AMD (adjusted OR, 0.5; 95% CI, 0.3-1.0). CONCLUSIONS: Known AMD risk factors were associated with greater long-term risk of reticular drusen. Neither total area nor central location of reticular drusen predicted 5-year progression to late AMD. Increased consumption of lutein-zeaxanthin predicted a lower risk of progression.

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.

Fluid intake and all-cause mortality, cardiovascular mortality and kidney function: a population-based longitudinal cohort study.

BACKGROUND: Drinking eight glasses of fluid or water each day is widely believed to improve health, but evidence is sparse and conflicting. We aimed to investigate the association between fluid consumption and long-term mortality and kidney function. METHODS: We conducted a longitudinal analysis within a prospective, population-based cohort study of 3858 men and women aged 49 years or older residing in Australia. Daily fluid intake from food and beverages not including water was measured using a food frequency questionnaire. We did multivariable adjusted Cox proportional hazard models for all-cause and cardiovascular mortality and a boot-strapping procedure for estimated glomerular filtration rate (eGFR). RESULTS: Upper and lower quartiles of daily fluid intake corresponded to >3 L and <2 L, respectively. During a median follow-up of 13.1 years (total 43 093 years at risk), 1127 deaths (26.1 per 1000 years at risk) including 580 cardiovascular deaths (13.5 per 1000 years at risk) occurred. Daily fluid intake (per 250 mL increase) was not associated with all-cause [adjusted hazard ratio (HR) 0.99 (95% CI 0.98-1.01)] or cardiovascular mortality [HR 0.98 (95% CI 0.95-1.01)]. Overall, eGFR reduced by 2.2 mL/min per 1.73 m(2) (SD 10.9) in the 1207 (31%) participants who had repeat creatinine measurements and this was not associated with fluid intake [adjusted regression coefficient 0.06 mL/min/1.73 m(2) per 250 mL increase (95% CI -0.03 to 0.14)]. CONCLUSIONS: Fluid intake from food and beverages excluding water is not associated with improved kidney function or reduced mortality.

Consumption of dairy products and the 15-year incidence of age-related macular degeneration.

Habitual consumption of dairy products has been shown to play an important role in the prevention of several chronic diseases. We aimed to prospectively assess the relationship between the change in dairy product consumption (both regular fat and low/reduced fat) and the 15-year incidence of age-related macular degeneration (AMD). In the Blue Mountains Eye Study, 2037 participants aged 49 years or above at baseline were re-examined at follow-up in 1997-9, 2002-4 and/or 2007-9. AMD was assessed from retinal photographs. Dietary data were collected using a semi-quantitative FFQ, and servings of dairy product consumption calculated. Over the 15-year follow-up, there were 352, 268 and eighty-four incident cases of any, early and late AMD, respectively. After adjusting for age, sex, current smoking, white cell count and fish consumption, a significant linear trend (P for trend = 0·003) was observed with decreasing consumption of total dairy foods and the 15-year incidence of late AMD, comparing the lowest v. highest quintile of intake (OR 2·80, 95 % CI 1·21, 3·04). Over the 15 years, decreased consumption of reduced-fat dairy foods was associated with an increased risk of incident late AMD, comparing the lowest to highest quintile of intake (OR 3·10, 95 % CI 1·18, 8·14, P for trend = 0·04). Decreasing total dietary Ca intake over the 15 years was also associated with an increased risk of developing incident late AMD (multivariable-adjusted P for trend = 0·03). A lower consumption of dairy products (regular and low fat) and Ca was independently associated with a higher risk of developing incident late AMD in the long term. Additional cohort studies are needed to confirm these findings.

Myopia and the long-term incidence of cataract and cataract surgery: the Blue Mountains Eye Study.

BACKGROUND: To assess the association between refractive errors and the 10-year incidence of cataract and cataract surgery. DESIGN: Population-based prospective study. PARTICIPANTS: Three thousand six hundred fifty-four persons aged 49+ years living in a well-defined geographical region were examined at baseline; 2564 were re-examined after 5 and/or 10 years. METHODS: Baseline refractive error was measured using autorefraction with subjective refinement. Lens photographs were taken at each visit and assessed using the Wisconsin Cataract Grading System. MAIN OUTCOME MEASURES: Long-term incidence of cataract and cataract surgery. RESULTS: Compared with emmetropia, high myopia was associated with increased incidence of nuclear cataract (adjusted odds ratio 3.01, 95% confidence intervals 1.35-6.71). Low (odds ratio 1.86, confidence interval 1.03-3.35) and high myopia (odds ratio 7.80, confidence interval 3.51-17.35) were significantly associated with higher incidence of posterior subcapsular cataract. Low, moderate and high myopia were associated with increased incidence of cataract surgery (odds ratio 2.54, confidence interval 1.76-3.68; odds ratio 2.61, confidence interval 1.45-4.69; and odds ratio 4.81, confidence interval 2.33-9.93, respectively). Either any (odds ratio 1.35, confidence interval 1.08-1.69) or moderate hyperopia (odds ratio 1.76, confidence interval 1.32-2.34) was associated with increased incidence of nuclear cataract. CONCLUSION: Our longitudinal study confirms the association between myopia and an increased risk of nuclear and posterior subcapsular cataract. It also suggests that hyperopia may increase the risk of nuclear cataract.

Retinal vessel caliber is associated with the 10-year incidence of glaucoma: the Blue Mountains Eye Study.

PURPOSE: To examine associations between quantitatively measured retinal vessel caliber and the 10-year incidence of primary open-angle glaucoma (OAG). DESIGN: Population-based cohort study. PARTICIPANTS: The Blue Mountains Eye Study examined 3654 persons at baseline and 2461 persons at either 5 years, 10 years, or both times. After excluding 44 subjects with OAG at baseline, 2417 participants at risk of OAG at the 5- or 10-year examinations were included. METHODS: Retinal vessel calibers of baseline retinal photographs were measured using a computer-based program and summarized as central retinal artery and vein equivalents (CRAE, CRVE). Incident OAG was defined as the development of typical glaucomatous visual field loss combined with matching optic disc rim thinning and an enlarged cup-to-disc (C:D) ratio of >0.7 or C:D asymmetry between the 2 eyes (≥0.3) at either the 5- or 10-year examination. Generalized estimating equation models were used to account for correlation between eyes while adjusting for glaucoma risk characteristics including intraocular pressure (IOP) or ocular perfusion pressure (OPP). MAIN OUTCOME MEASURES: We assessed the 10-year incidence of OAG. RESULTS: There were 82 persons (104 eyes) who developed incident OAG over the 10-year follow-up. After adjusting for age, sex, family history of glaucoma, smoking, diabetes, hypertension, hypercholesterolemia, body mass index, spherical equivalent refraction, and C:D ratio, narrower CRAE was associated with higher risk of incident OAG (adjusted odds ratio [OR], 1.77; 95% confidence interval [CI], 1.12-2.79, per standard deviation decrease in CRAE). This association persisted after further adjustment for IOP (adjusted OR, 1.87; 95% CI, 1.14-3.05) or OPP (adjusted OR, 1.76; 95% CI, 1.11-2.78), and remained significant when analyses were confined to eyes with IOP<20 mmHg and C:D ratio<0.6 at baseline. There were no independent associations between CRVE and incident OAG. CONCLUSIONS: Retinal arteriolar narrowing, quantitatively measured from retinal photographs, was associated with long-term risk of OAG. These data support the concept that early vascular changes are involved in the pathogenesis of OAG and suggest that computer-based measurements of retinal vessel caliber may be useful to identify people with an increased risk of developing the clinical stage of glaucoma. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Incidence and progression of geographic atrophy: observations from a population-based cohort.

PURPOSE: To examine early age-related macular degeneration (AMD) lesion characteristics and risk factors associated with the long-term development and progression of geographic atrophy (GA). DESIGN: Population-based cohort. PARTICIPANTS: Of 3654 participants aged ≥49 years in the Blue Mountains Eye Study, 75.8%, 76.7%, and 56.1% of survivors attended the 5-, 10-, and 15-year follow-up examinations, respectively. METHODS: Retinal photographs were taken at each visit. Incident GA was confirmed using a side-by-side grading method. Computer planimetry was used to measure the area involved by GA. Fast and slow/normal progression rates were defined as GA area enlargement by ≥2 and <2 mm(2)/year, respectively. Incident GA was estimated using the Kaplan-Meier product-limit method. Early AMD lesion characteristics were assessed for association with GA incidence using eye-specific data and generalized estimating equation models adjusting for age, current smoking, and presence of risk alleles of the complement factor H (CFH) or age-related maculopathy susceptibility 2 (ARMS2) genes, genotyped or imputed using genome-wide scan data. MAIN OUTCOME MEASURES: Incidence and progression of GA. RESULTS: By excluding 41 subjects with GA at baseline, of 2503 participants at risk of GA, incident pure GA (without coexisting neovascular AMD lesions) was confirmed in 57 participants, with a 15-year incidence of 3.6%. Baseline early AMD lesion characteristics associated with GA incidence included drusen type (soft indistinct: odds ratio [OR], 59.0; 95% confidence interval [CI], 20.4-171.0; reticular drusen: OR, 13.9; 95% CI, 4.0-47.6); drusen location within a 500-µm radius of the fovea (OR, 15.1; 95% CI, 7.4-30.8); drusen area greater than 375 µm in diameter (OR, 10.1; 95% CI, 4.0-25.6); presence of retinal pigment epithelial depigmentation (OR, 9.0; 95% CI, 4.1-19.8); or hyperpigmentation (OR, 12.0; 95% CI, 6.1-23.5), referenced to subjects with no or hard drusen only. Fast progression was more frequent among current smokers at baseline, subjects with the CFH or ARMS2 risk genotypes, and pseudophakic eyes. CONCLUSIONS: Early AMD lesion characteristics (type, location, area involved) were strongly associated with higher long-term risk of developing GA independent of age, smoking, and AMD genetic susceptibility from the CFH or ARMS2 genes. Known AMD risk factors also were more frequently present among quickly progressing GA cases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Long-term changes in visual acuity in an older population over a 15-year period: the Blue Mountains Eye Study.

PURPOSE: To describe the change in visual acuity (VA) and incidence of visual impairment (VI) in an older population over a 15-year period. DESIGN: Population-based cohort. PARTICIPANTS: Of the 3654 participants of the Blue Mountains Eye Study (BMES) baseline examination from 1992 through 1994, 1149 were re-examined during the 15-year follow-up between 2007 and 2010. METHODS: Best-corrected VA by means of subjective refraction was measured with a logarithm of the minimum angle of resolution chart using Early Treatment Diabetic Retinopathy Study methods at each examination. MAIN OUTCOME MEASURES: Unilateral VI was defined as VA worse than 20/40 and blindness was defined as VA worse than 20/200 in the worse eye. Incident bilateral VI and blindness were determined according to VA in the better eye at the 15-year visit. Doubling of the visual angle was defined as a loss of 15 letters or more from baseline to the 15-year visit. Halving of the visual angle was defined as a VA improvement of 15 letters or more over the same period. Causes of VI were determined at examination, by photographic grading, and from medical records. RESULTS: Cumulative 15-year incidence of unilateral and bilateral VI was 12.3% (95% confidence interval [CI], 11.0-13.6) and 5.2% (95% CI, 4.3-6.1), respectively, and for unilateral and bilateral blindness, the cumulative incidence was 3.7% (95% CI, 3.0-4.4) and 0.9% (95% CI, 0.5-1.3), respectively. These incidence rates increased significantly with increasing age (P<0.01 for trend). Doubling and halving of the visual angle occurred in 6.9% (95% CI, 5.9-7.9) and 1.6% (95% CI, 1.0-2.2) of participants, respectively. Cataract accounted for 48.5% of unilateral and bilateral incident VI, followed by age-related macular degeneration (26.9%). Age-related macular degeneration accounted for 56.9% of unilateral and bilateral incident blindness cases, followed by cataract (20.7%). CONCLUSIONS: These data provide population-based estimates of long-term incidence of visual impairment among older persons. Our estimate for cumulative incidence of blindness, accounting for competing risk of death, was similar to that of the Beaver Dam Eye Study (BDES) after age standardization. However, our estimate for cumulative incidence of VI was lower compared with that observed in the BDES population. This difference may be explained in part by a higher mortality rate among our population. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Correction of visual impairment by cataract surgery and improved survival in older persons: the Blue Mountains Eye Study cohort.

OBJECTIVE: We assessed whether correction of visual impairment (VI) by cataract surgery was associated with improved long-term survival in an older Australian population. DESIGN: Population-based cohort study. PARTICIPANTS: In the Blue Mountains Eye Study, 354 participants, aged ≥ 49 years, had both cataract and VI or had undergone cataract surgery before baseline examinations. They were subsequently examined after 5- and 10-year follow-ups. METHODS: Associations between the mortality risk and the surgical correction of VI (visual acuity [VA] <20/40, attributable to cataract) were assessed in Cox proportional hazard regression models, after multivariate adjustment, using time-dependent variables for the study factor. MAIN OUTCOME MEASURES: All-cause mortality. RESULTS: The 15-year crude mortality of participants who had undergone cataract surgery at baseline with no subsequent VI (71.8%) was relatively similar to that in participants with cataract-related VI who had not yet undergone surgery (79.4%). However, after adjusting for age and sex, participants who underwent cataract surgery before baseline or during follow-up and no longer had VI had significantly lower long-term mortality risk (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.46-0.77) than participants with VI due to cataract who had not undergone cataract surgery. This lower mortality risk in the group with surgically corrected VI (HR, 0.54; 95% CI, 0.41-0.73) persisted after further adjustment for smoking, body mass index, home ownership, qualifications, poor self-rated health, the presence of poor mobility, hypertension, diabetes, self-reported history of angina, myocardial infarction, stroke, cancer, asthma, and arthritis. This finding remained significant (HR, 0.55; 95% CI, 0.41-0.73) after additional adjustment for the number of medications taken (continuous variable) and the number (≥ 5 vs. <5) of comorbid conditions (poor mobility, hypertension, diabetes, angina, myocardial infarction, stroke, cancer, asthma, or arthritis) as indicators of frailty. CONCLUSIONS: Surgical correction of VI due to cataract was associated with significantly better long-term survival of older persons after accounting for known cataract and mortality risk factors, and indicators of general health. Whether some uncontrolled factors (frailty or general health) could have influenced decisions not to perform cataract surgery in some participants is unknown. However, this finding strongly supports many previous reports linking VI with poor survival. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Genetic association of refractive error and axial length with 15q14 but not 15q25 in the Blue Mountains Eye Study cohort.

PURPOSE: Myopia is a common complex condition influenced by genetic and environmental factors. Two recent genome-wide association studies have identified loci on chromosomes 15q25 and 15q14 associated with refractive error in Caucasian populations. Our study aimed to assess the association of these 2 loci with refractive error and ocular biometric measures in an independent ethnically matched Caucasian cohort. DESIGN: Genetic association study using unrelated individuals. PARTICIPANTS: Blue Mountains Eye Study (BMES) cohort. A total of 1571 individuals were included in this study. METHODS: Single nucleotide polymorphism (SNP) genotype data were collected from the BMES cohort as part of the Wellcome Trust Case Control Consortium 2. Imputation was performed using MACH version 1.1.16, and statistical analysis was conducted using PLINK. Association tests were performed at both loci using refractive error (spherical equivalent), axial length, corneal curvature, and anterior chamber depth as the phenotypes. MAIN OUTCOME MEASURES: Refractive error, axial length, corneal curvature, and anterior chamber depth. RESULTS: A total of 1571 individuals were available from the BMES for analysis. A statistically significant association for refractive error was evident for SNPs at the 15q14 locus, with P values ranging from 1.5 × 10(-2) at rs685352 to 6.4 × 10(-4) at rs560764, whereas association could not be confirmed for SNPs at the 15q25 locus, with P values ranging from 8.0 × 10(-1) to 6.4 × 10(-1). Ocular biometric analysis revealed that axial length was the most likely trait underlying the refractive error association at the 15q14 locus for SNPs rs560766 (P=0.0054), rs634990 (P=0.0086), and rs8032019 (P=0.0081). CONCLUSIONS: Our results confirm the association with refractive error at the 15q14 locus but do not support the association observed at the 15q25 locus. Axial length seemed to be a major parameter at the 15q14 locus, underscoring the importance of this locus in myopia and future clinical treatment.

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.

Adherence to dietary guidelines and 15-year risk of all-cause mortality.

Past investigation of diet in relation to disease or mortality has tended to focus on individual nutrients. However, there has been a recent shift to now focus on overall patterns of food intake. The present study aims to investigate the relationship between diet quality reflecting adherence to dietary guidelines and mortality in a sample of older Australians, and to report on the relationship between core food groups and diet quality. This was a population-based cohort study of persons aged 49 years or older at baseline, living in two postcode areas west of Sydney, Australia. Baseline dietary data were collected during 1992-4, from 2897 people using a 145-item Willett-derived FFQ. A modified version of the Healthy Eating Index for Australians was developed to determine diet quality scores. The Australian National Death Index provided 15-year mortality data using multiple data linkage steps. Hazard risk (HR) ratios and 95 % CI for mortality were assessed for diet quality. Subjects in quintile 5 (highest) of the Total Diet Score had a 21 % reduced risk of all-cause mortality (HR 0·79, 95 % CI 0·63, 0·98, P(trend)=0·04) compared with those in quintile 1 (lowest) after multivariate adjustment. The present study provides longitudinal support for a reduced risk of all-cause mortality in an older population who have greater compliance with published dietary guidelines.

Is quality of diet associated with the microvasculature? An analysis of diet quality and retinal vascular calibre in older adults.

It is unknown whether diet quality is associated with microvascular structure. The present study aimed to investigate the relationship between diet quality, reflecting adherence to dietary guidelines, with retinal microvascular calibre in older adults. The dietary data of 2720 Blue Mountains Eye Study participants, aged 50+ years, were collected using a semi-quantitative FFQ. A modified version of the Healthy Eating Index for Australians was developed to determine total diet scores (TDS). Fundus photographs were taken and retinal vascular calibre measured using computer-assisted techniques and summarised. After adjusting for age, sex, BMI, mean arterial blood pressure, smoking, serum glucose, leucocyte count and history of diagnosed stroke or CHD, persons with higher TDS had healthier retinal vessels cross-sectionally, with wider retinal arteriolar calibre (by approximately 3 µm, comparing the highest with the lowest quartile of TDS, Ptrend = 0·0001) and narrower retinal venular calibre (by approximately 2·5 µm; Ptrend = 0·02). In younger subjects aged ≤65 years, increasing TDS (lowest to the highest quartile) was associated with healthier retinal vessels: approximately 4·4 µm wider retinal arteriolar (Ptrend < 0·0001) and approximately 2·3 µm narrower venular calibre (Ptrend = 0·03). After multivariable adjustment, however, baseline TDS were not associated with retinal arteriolar (Ptrend = 0·89) or venular calibre (Ptrend = 0·25), 5 years later. Also, baseline TDS were not associated with the 5-year change in retinal arteriolar (ß = 0·14; P=0·29) or venular calibre (ß = - 0·26; P=0·07). Greater compliance with published dietary guidelines (higher diet quality) was cross-sectionally associated with wider retinal arterioles and narrower venules, indicating better retinal microvascular health.

Carbohydrate quality is not associated with liver enzyme activity and plasma TAG and HDL concentrations over 5 years in an older population.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with insulin resistance and obesity. Hence, carbohydrate quality could be of relevance to the risk of NAFLD, but prospective data are lacking. The aim of the present study was to investigate longitudinal associations between carbohydrate quality (including dietary glycaemic index (GI) and intakes of sugar, starch and fibre) and markers of liver function in an older Australian population. The analysis was based on 866 participants ( ≥ 49 years) of the Blue Mountains Eye Study with fasting blood specimens and dietary intake data at baseline and 5-year follow-up. Multi-level mixed regression analysis was used to relate dietary GI and sugar, starch and fibre intake to the liver enzymes alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT), as well as fasting TAG and HDL-cholesterol (HDL-C). After adjustment for potential confounding factors, a lower fibre intake was cross-sectionally related to higher GGT (P= 0.02) and fasting TAG (P= 0.002) levels, with fruit fibre being the most relevant fibre source (P= 0.095 for GGT; P= 0.003 for TAG). A higher dietary GI was associated with lower HDL-C (P= 0.046). Changes in carbohydrate quality during 5 years were not related to changes in ALT, GGT, TAG or HDL-C (P≥ 0.08). In conclusion, the absence of longitudinal associations between carbohydrate quality and liver enzymes and serum lipids in this older population does not support a major role of carbohydrate nutrition in liver function among the elderly.

Factors promoting success and influencing complications in laser-induced central vein bypass.

PURPOSE: To evaluate the factors influencing the successful creation of a laser-induced chorioretinal venous anastomosis (L-CRA) and those involved in the development of complications. DESIGN: Interventional cohort study. PARTICIPANTS: Fifty-five patients with a nonischemic central retinal vein occlusion (CRVO) who were randomized to receive an L-CRA from the total of 108 who completed the follow-up period of the Central Vein Bypass Study. METHODS: Patients who were randomized to L-CRA were followed up for an 18-month period. They were stratified in 2 sets of 2 cohorts: those who did or did not demonstrate an L-CRA and those who did or did not demonstrate neovascular complications at the site of the L-CRA. Subgroup analysis was performed to determine what factors influenced the creation of an L-CRA and the development of complications at each individual laser site. MAIN OUTCOME MEASURES: Identification of systemic and local ocular factors associated with increased success rates of L-CRA creation and those involved with an increased risk of neovascular complications. RESULTS: Younger age (P = 0.03), better baseline visual acuity (P = 0.04), and the absence of hypertension (P = 0.001) were systemic features associated with an increased chance of demonstrating a successful L-CRA at each site, whereas sex and duration of the CRVO were not. The position of the L-CRA site did not influence the outcome; however, evidence of rupture of the vein wall at the time of the attempt was associated with a higher chance of success (P = 0.008). Increased risk of neovascularization, which occurred at 12 sites in 10 eyes, was associated with higher central venous pressure before treatment (P = 0.03), prolonged fluorescein transit time (P = 0.0001), and the presence of some capillary nonperfusion (P = 0.01). CONCLUSIONS: Younger age, better baseline visual acuity, and the absence of hypertension were associated with an improved success rate, as was evidence of rupture of the vein wall. High baseline central venous pressure, prolonged fluorescein transit time, and the presence of any retinal ischemia were associated with a higher incidence of neovascular complications. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Risk of age-related macular degeneration 3 years after cataract surgery: paired eye comparisons.

OBJECTIVE: To clarify possible associations between cataract surgery and progression of age-related macular degeneration (AMD). DESIGN: Clinic-based cohort. PARTICIPANTS: We followed cataract surgical patients aged 65+ years in the Australian Cataract Surgery and Age-related Macular Degeneration (CSAMD) study. Patients who remained unilaterally phakic for at least 24 months after recruitment were included. METHODS: We performed annual examinations with retinal photography. We assessed AMD using side-by-side grading of images from all visits. Paired comparisons between operated and nonoperated fellow eyes (defined as nonoperated or operated <12 months previously) were made using generalized estimating equation models. MAIN OUTCOME MEASURES: Incident early AMD was defined as the new appearance of soft indistinct/reticular drusen or coexisting retinal pigmentary abnormality and soft distinct drusen in eyes at risk of early AMD. Incident late AMD was defined as the new appearance of neovascular AMD or geographic atrophy (GA) in eyes at risk of late AMD. RESULTS: Among 2029 recruited, eligible participants, 1851 had cataract surgery performed at Westmead Hospital, Sydney, and 1244 (70.7%) had 36-month postoperative visits. Of these participants, 1178 had gradable photographs at baseline and at least 1 follow-up visit. Of 308 unilaterally operated participants at risk of late AMD, this developed in 4 (1.3%) operated and 7 (2.3%) nonoperated fellow eyes (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.23-2.36) after adjusting for the presence of early AMD at baseline. Of 217 unilaterally operated participants at risk of early AMD, this developed in 23 (10.6%) operated and 21 (9.7%) nonoperated fellow eyes (OR, 1.07; 95% CI, 0.74-1.65). Incident retinal pigment abnormalities were more frequent in operated than nonoperated fellow eyes (15.3% vs. 9.9%; OR, 1.64; 95% CI, 1.07-2.52). There was no difference in the 3-year incidence of large soft indistinct or reticular drusen between the 2 eyes (8.8% vs. 7.9%; OR, 1.12; 95% CI, 0.79-1.60). CONCLUSIONS: Prospective follow-up data and paired eye comparisons of this older surgical cohort showed no increased risk of developing late AMD, early AMD, or soft/reticular drusen over 3 years. There was a 60% increased detection of retinal pigmentary changes in surgical eyes.

Long-term outcomes of phacoemulsification cataract surgery performed by trainees and consultants in an Australian cohort.

BACKGROUND: It is unclear whether differences exist in surgical complication rates and long-term visual acuity outcomes between patients whose phacoemulsification cataract surgery was performed by ophthalmological trainees and those performed by consultants. DESIGN: Prospective clinical cohort study. PARTICIPANTS: 1851 participants of the Cataract Surgery and Age-related Macular Degeneration study, aged ≥64 years, had cataract surgery performed at Westmead Hospital, Sydney. METHODS: Surgical complication rates and visual acuity at 24-month postoperative visits were compared between patients who were operated on by trainees and those operated on by consultants. MAIN OUTCOME MEASURES: Surgical outcomes included operative complications recorded in surgical audit forms and 24-month postoperative visual acuity. RESULTS: Of 1851 patients, 1274 (68.8%) were reviewed 24 months after surgery. Of these, 976 had data on the type of surgeon who performed the operation. After excluding 152 challenging cases and three cases operated on by first-year trainees at the beginning of their training, 821 patients were included in this study, of those, 498 were operated on by trainees and 323 by consultants. Habitual visual acuity ≥6/12 was achieved in 77.3% (n = 385/498) and 74.3% (n = 240/323), respectively, of the two groups of patients 24 months postoperatively. Of 514 patients who had surgical audit data, the major complication rate was numerically greater, but not significantly different for the 330 trainee-operated (6.1%) patients, compared with the 184 consultant-operated patients (2.7%, P = 0.091). CONCLUSIONS: We found relatively comparable complication rates and visual outcomes after 2 years between patients operated on by ophthalmological trainees and those by consultants, in a cataract surgical cohort at Westmead Hospital.

Fractal analysis of retinal microvasculature and coronary heart disease mortality.

AIM: Fractal analysis provides a global assessment of vascular network architecture. We examined the relationship of retinal vascular fractal dimension (D(f)) with coronary heart disease (CHD) mortality. METHODS AND RESULTS: We examined the relationship of D(f) with 14-year CHD mortality in a prospective, population-based cohort of 3303 participants aged 49 years or older. D(f) was measured from digitized fundus photographs using computer-automated methods; CHD mortality was documented from Australian National Death Index records. Mean D(f) in this population was 1.441 (standard deviation, 0.024). Over 14 years, there were 468 (14.2%) CHD deaths. Participants with suboptimal D(f) (lowest and highest quartiles) had 50% higher 14-year CHD mortality than those with optimal D(f) (middle quartiles), after adjusting for age, blood pressure, and other risk factors. Among participants aged ≤ 70 years, suboptimal D(f) was associated with a nearly two-fold higher risk of CHD mortality [adjusted hazard ratio (HR) 1.89, 95% confidence interval (CI), 1.25, 2.84 for the lowest quartile and HR 1.87, CI 1.30, 2.69 for the highest quartile, compared with middle quartiles]. CONCLUSIONS: D(f) is a novel means of quantifying microvascular branching that independently predicted 14-year CHD mortality. These findings suggest that suboptimal microvascular branching may play a role in development of clinical cardiovascular disease.