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1.  Is early age‐related macular degeneration related to carotid artery stiffness? The Atherosclerosis Risk in Communities Study 
Background/Purpose
Atherosclerosis and vascular stiffness have been implicated in the pathogenesis of age‐related macular degeneration (AMD). The association of carotid artery stiffness, a measure of arterial elasticity reflecting early atherosclerosis, with early AMD, was examined in this study.
Methods
A population‐based, cross‐sectional study of 9954 middle‐aged people (age range 51–72 years). The presence of AMD signs was determined from fundus photographs according to the Wisconsin grading protocol. Carotid arterial stiffness was measured from high‐resolution ultrasonic echo tracking of the left common carotid artery, and was defined as an adjusted arterial diameter change (AADCμ). A smaller AADC reflects greater carotid artery stiffness. The associations of pulse pressure and carotid artery intima–media thickness (IMT) with early AMD signs were also analysed.
Results
In the study population, 454 (4.6%) had early AMD. The mean (SD) AADC was 403 (127) μ. After adjusting for age, sex, race/centre, education, cigarette smoking, fasting glucose, lipid profile and inflammatory markers, a smaller AADC was found to be not associated with early AMD (odds ratio 0.94; 95% confidence interval, 0.71 to 1.25) or its component lesions. Other measures of arterial stiffness (pulse pressure) and atherosclerosis (carotid IMT) were also not associated with early AMD.
Conclusions
Carotid artery stiffness was not associated with signs of early AMD in this middle‐aged population. These data provide no evidence of a link between age‐related elastoid changes and early atherosclerotic processes in the carotid arteries and early AMD.
doi:10.1136/bjo.2006.106054
PMCID: PMC1994729  PMID: 17035267
2.  Combined Effects of Complement Factor H Genotypes, Fish Consumption, and Inflammatory Markers on Long-Term Risk for Age-related Macular Degeneration in a Cohort 
American Journal of Epidemiology  2008;169(5):633-641.
At baseline in 1992–1994, the authors assessed the combined effects of complement factor H (CFH) genotypes with smoking, fish consumption, and inflammatory markers on the risk of age-related macular degeneration (AMD) in 3,654 persons aged ≥49 years. They reexamined 75% of the survivors after 5 and 10 years, confirming incident AMD by side-by-side photographic grading. Of the 2,452 persons followed in the Blue Mountains Eye Study, 1,881 were genotyped (rs1061170), with CC, CT, and TT identified in 13.6%, 46.7%, and 39.7%, respectively. AMD risk increased with each additional C allele (early AMD: age- and sex-adjusted relative risk (RR) = 1.6, 95% confidence interval (CI): 1.2, 1.9; late AMD: RR = 2.3, 95% CI: 1.5, 3.6). Late AMD risk among current smokers with the CC/CT genotypes (RR = 10.7, 95% CI: 3.4, 33.9) was 5-fold that for genotypically similar nonsmokers (RR = 2.2, 95% CI: 0.9, 5.5) versus current nonsmokers with TT genotypes. Weekly compared with less than weekly consumption of fish was associated with reduced late AMD risk in participants with the CC genotype (RR = 0.15, 95% CI: 0.03, 0.8) but not the CT (RR = 0.7, 95% CI: 0.3, 2.0) or TT (RR = 1.3, 95% CI: 0.2, 7.2) genotypes. This study documents joint contributions from genetic and systemic factors in determining the progression of AMD.
doi:10.1093/aje/kwn358
PMCID: PMC2732972  PMID: 19074778
cohort studies; complement factor H; environmental exposure; genetics; macular degeneration; seafood; smoking
3.  Replication and Meta-Analysis of Candidate Loci Identified Variation at RAB3GAP1 Associated With Keratoconus 
Purpose.
Keratoconus is a common complex corneal ectasia that can lead to severe visual impairment. Although a genetic component is well recognized, the genetic risk factors for keratoconus are yet to be fully elucidated. A recent genome-wide association study (GWAS) by Li et al. identified 15 potentially associated single nucleotide polymorphisms (SNPs). Here, we aimed to replicate these associations, and conduct a meta-analysis of the current and previous studies.
Methods.
We genotyped the 15 reported associated SNPs in 524 Australian Caucasian cases with keratoconus and 2761 controls. Association analysis was conducted in PLINK. A meta-analysis of this study with the adjusted P values of the previously published GWAS was conducted using the method of Fisher to combine P values.
Results.
Our Australian cohort showed association (P < 0.003) at SNPs near RAB3GAP1, KCND3, IMMPL2, and in a gene desert on chromosome 13q33.3, providing evidence of replication of the published results. The meta-analysis showed SNP rs4954218 near RAB3GAP1 gene was associated significantly with keratoconus, with P = 9.26 × 10−9 passing the genome-wide significance level.
Conclusions.
Although the mechanism of disease association is yet to be determined, SNP rs4954218 is associated consistently with keratoconus and likely tags a functional variant that contributes to disease susceptibility.
We describe the replication of published findings from a genome-wide association study of keratoconus. We show for the first time, to our knowledge, that SNPs near RAB3GAP1 are associated with keratoconus at genome-wide significance, and also provide further supportive evidence for association at other reported loci.
doi:10.1167/iovs.13-12377
PMCID: PMC3729241  PMID: 23833071
keratoconus; cornea; genetics; genome-wide association study; meta-analysis
4.  Serum Apolipoproteins Are Associated With Systemic and Retinal Microvascular Function in People With Diabetes 
Diabetes  2012;61(7):1785-1792.
Serum apolipoprotein (apo)AI and -B have been shown to be associated with diabetic retinopathy, but the underlying mechanisms are unclear. We investigated whether apoAI and apoB levels are associated with measures of systemic and retinal microvascular function in patients with diabetes. We recruited 224 diabetic patients (85 type 1 and 139 type 2) and assessed serum lipids and lipoproteins from fasting blood, skin responses to sodium nitroprusside (endothelium independent) and acetylcholine (ACh) (endothelium dependent) iontophoresis, flicker-light–induced retinal vasodilatation, and retinal vascular tortuosity. After adjustment for age and sex, every SD increase in apoAI level was associated with ACh-induced skin perfusion (mean change 1.27%; P < 0.001 for apoAI) and flicker-light retinal arteriolar vasodilatation (0.33%; P = 0.003) and was associated inversely with arteriolar tortuosity (−2.83 × 10−5; P = 0.044). Each SD increase in apoB was associated with arteriolar tortuosity only (1.75 × 10−5; P = 0.050). These associations, except for apoB, remained in multivariate models. Serum apoAI was associated with increased vasomotor responsiveness to ACh and flickering light and inversely related to retinal vessel tortuosity—a characteristic that has both structural and functional dimensions. These findings provide additional insights into the potential mechanisms of apos in the pathogenesis of diabetic retinopathy and other diabetic microvascular complications.
doi:10.2337/db11-1272
PMCID: PMC3379684  PMID: 22511207
5.  Retinal Vascular Geometry in Asian Persons with Diabetes and Retinopathy 
Purpose
Our purpose was to examine the relationship of retinal vascular parameters with diabetes and retinopathy in an older Asian population.
Methods
Retinal photographs from participants of a population-based survey of Asian Malay persons aged 40–80 years were analyzed. Specific retinal vascular parameters (tortuosity, branching angle, fractal dimension, and caliber) were measured using a semiautomated computer-based program. Diabetes was defined as random plasma glucose ≥ 11.1 mmol/liter, the use of diabetes medication, or physician-diagnosed diabetes. Retinopathy signs were graded from photographs using the modified Airlie House classification system.
Results
A total of 2735 persons were included in the study. Persons with diabetes (n = 594) were more likely to have straighter (less tortuous) arterioles and wider arteriolar and venular caliber than those without diabetes (n = 2141). Among subjects with diabetes, those with retinopathy had wider venular caliber than those without retinopathy (211.3 versus 204.9 mm, p = .001). Among nondiabetic subjects, however, those with retinopathy had more tortuous venules than those without retinopathy [5.19(×104) versus 4.27(×104), p < .001].
Conclusions
Retinal vascular parameters varied by diabetes and retinopathy status in this older Asian cohort. Our findings suggest that subtle alterations in retinal vascular architecture are influenced by diabetes.
PMCID: PMC3440033  PMID: 22768891
diabetes; epidemiology; imaging; retinopathy
6.  Obesity and the Microvasculature: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(2):e52708.
Background
Overweight and obesity are thought to significantly influence a person's risk of cardiovascular disease, possibly via its effect on the microvasculature. Retinal vascular caliber is a surrogate marker of microvascular disease and a predictor of cardiovascular events. The aim of this systematic review and meta-analysis was to determine the association between body mass index (BMI) and retinal vascular caliber.
Methods and Findings
Relevant studies were identified by searches of the MEDLINE and EMBASE databases from 1966 to August 2011. Standardized forms were used for data extraction. Among over 44,000 individuals, obese subjects had narrower arteriolar and wider venular calibers when compared with normal weight subjects, independent of conventional cardiovascular risk factors. In adults, a 1 kg/m2 increase in BMI was associated with a difference of 0.07 μm [95% CI: −0.08; −0.06] in arteriolar caliber and 0.22 μm [95% CI: 0.21; 0.23] in venular caliber. Similar results were found for children.
Conclusions
Higher BMI is associated with narrower retinal arteriolar and wider venular calibers. Further prospective studies are needed to examine whether a causative relationship between BMI and retinal microcirculation exists.
doi:10.1371/journal.pone.0052708
PMCID: PMC3566162  PMID: 23405065
7.  Language barrier and its relationship to diabetes and diabetic retinopathy 
BMC Public Health  2012;12:781.
Background
Language barrier is an important determinant of health care access and health. We examined the associations of English proficiency with type-2 diabetes (T2DM) and diabetic retinopathy (DR) in Asian Indians living in Singapore, an urban city where English is the predominant language of communication.
Methods
This was a population-based, cross-sectional study. T2DM was defined as HbA1c ≥6.5%, use of diabetic medication or a physician diagnosis of diabetes. Retinal photographs were graded for the severity of DR including vision-threatening DR (VTDR). Presenting visual impairment (VI) was defined as LogMAR visual acuity > 0.30 in the better-seeing eye. English proficiency at the time of interview was assessed.
Results
The analyses included 2,289 (72.1%) English-speaking and 885 (27.9%) Tamil- speaking Indians. Tamil-speaking Indians had significantly higher prevalence of T2DM (46.2 vs. 34.7%, p < 0.001) and, among those with diabetes, higher prevalence of DR (36.0 vs. 30.6%, p < 0.001), VTDR (11.0 vs. 6.5%, p < 0.001), and VI (32.4 vs. 14.6%) than English speaking Indians. Oaxaca decomposition analyses showed that the language-related discrepancies (defined as the difference in prevalence between persons speaking different languages) in T2DM, DR, and VTDR could not be fully explained by socioeconomic measures.
Conclusions
In an English dominant society, Tamil-speaking Indians are more likely to have T2DM and diabetic retinopathy. Social policies and health interventions that address language-related health disparities may help reduce the public health impact of T2DM in societies with heterogeneous populations.
doi:10.1186/1471-2458-12-781
PMCID: PMC3462107  PMID: 22974298
English proficiency; Asian indians; Diabetes; Diabetic retinopathy; Visual impairment
8.  10-Year Longitudinal Changes in Retinal Microvascular Lesions: The Atherosclerosis Risk in Communities Study 
Ophthalmology  2011;118(8):1612-1618.
Objective
There are limited data on the natural history and longitudinal changes of retinal microvascular lesions. We examined 10-year changes in retinal microvascular lesions, focusing on those related to hypertension and shown to predict development of cardiovascular disease.
Design
Prospective cohort
Participants
1,120 middle-aged participants without diabetes of the Atherosclerosis Risk in Communities (ARIC) Study in 1993–5 and again 10 years later in 2003–5.
Methods
. Retinal microvascular lesions were graded from retinal photographs using the same protocol at both examinations, with changes (incidence or disappearance) adjudicated by a side-by-side comparison of photographs. The study sample was stratified by carotid intima-media thickness (IMT) and ARIC field center; thus all analyses were weighted by these factors. Persons with diabetes were excluded because the frequency and pathophysiology of diabetic retinal lesions is different.
Main Outcome Measures
Incidence and disappearance rates of lesions.
Results
. The 10 year incidence of focal arteriolar narrowing, arteriovenous (AV) nicking, and retinopathy in persons without diabetes was 3.4% (95% confidence intervals 2.3–4.9), 2.5% (1.6–3.9), and 2.2% (1.3–3.5) respectively. Over the 10 year period, of 32, 219, and 24 eyes with focal arteriolar narrowing, AV nicking and retinopathy at baseline, 50.3% (28.6–71.9), 40.7% (32.7–49.4) and 65.9% (42.4–83.5), respectively, disappeared. Higher baseline plasma fibrinogen and white cell count were associated with incident focal arteriolar narrowing; antihypertensive medication use associated with incident AV nicking; and higher diastolic blood pressure, carotid IMT and white cell count associated with incident retinopathy. Higher fasting serum glucose was not significantly associated with incident retinopathy, though this may be related to the small number of lesions.(Odds ratio 5.88, 95% confidence interval 0.74–46.64 per standard deviation difference)
Conclusions
In this sample of middle-aged adults, new retinal microvascular lesions appeared at a rate between 2–4% over 10 years. A high percentage of lesions (40% or more) disappeared over the same period, suggesting considerable remodeling in the retinal microvasculature.
doi:10.1016/j.ophtha.2011.01.003
PMCID: PMC3150229  PMID: 21529953
microvascular signs; hypertension; microcirculation; retina; ARIC
9.  Retinal Vascular Geometry Predicts Incident Retinopathy in Young People With Type 1 Diabetes 
Diabetes Care  2011;34(7):1622-1627.
OBJECTIVE
To examine the association between retinal vascular geometry and subsequent development of incident retinopathy in young patients with type 1 diabetes.
RESEARCH DESIGN AND METHODS
A prospective cohort study of 736 people with type 1 diabetes aged 12 to 20 years, retinopathy-free at baseline, attending an Australian tertiary care hospital. Retinopathy was determined from seven-field retinal photographs according to the modified Airlie House Classification. Retinal vascular geometry, including length/diameter ratio (LDR) and simple tortuosity (ST), was quantified in baseline retinal photographs. Generalized estimating equations were used to determine risk of retinopathy associated with baseline LDR and ST, adjusting for other factors.
RESULTS
After a median 3.8 (interquartile range 2.4–6.1) years of follow-up, incident retinopathy developed in 287 of 736 (39%). In multivariate analysis, lower arteriolar LDR (odds ratio 1.8 [95% CI 1.2–2.6]; 1st vs. 4th quartile) and greater arteriolar ST (1.5 [1.0–2.2]; 4th vs. 1st quartile) predicted incident retinopathy after adjusting for diabetes duration, sex, A1C, blood pressure, total cholesterol, and BMI. In subgroup analysis by sex, LDR predicted incident retinopathy in male and female participants (2.1 [1.1–4.0] and 1.7 [1.1–2.7]; 1st vs. 4th quartiles, respectively) and greater arteriolar ST predicted incident retinopathy in male participants (2.4 [1.1–4.4]; 4th vs. 1st quartile) only.
CONCLUSIONS
Lower arteriolar LDR and greater ST were independently associated with incident retinopathy in young people with type 1 diabetes. These vascular geometry measures may serve as risk markers for diabetic retinopathy and provide insights into the early structural changes in diabetic microvascular complications.
doi:10.2337/dc10-2419
PMCID: PMC3120178  PMID: 21593293
10.  Diabetic Retinopathy Is Related to Both Endothelium-Dependent and -Independent Responses of Skin Microvascular Flow 
Diabetes Care  2011;34(6):1389-1393.
OBJECTIVE
Endothelial dysfunction has been hypothesized as a possible pathogenic factor in the development of diabetic retinopathy (DR). We examined the relationship of DR to endothelium-dependent and endothelium-independent responses in skin microvascular flow.
RESEARCH DESIGN AND METHODS
Participants consisted of 224 individuals with diabetes: 85 with type 1 diabetes and 139 with type 2 diabetes. Sodium nitroprusside (SNP) and acetylcholine (ACh) were delivered across the skin by iontophoresis. Laser Doppler flowmetry was used to assess the skin microcirculation response to SNP (endothelium-independent response) and ACh (endothelium-dependent response). The presence and severity of DR were graded from retinal photographs using a standard protocol.
RESULTS
Of 224 participants, 64.3% had DR. After multivariable adjustment, participants with reduced responses to SNP or ACh were more likely to have DR, with an odds ratio (OR) of 2.33 (95% CI 1.09–5.01) for SNP and 2.20 (1.05–4.61) for ACh, comparing participants with responses below and above the median values. Participants with reduced responses (below the median) to both SNP and ACh were nearly four times more likely to have DR (OR 3.86 [1.45–10.3]) than those with SNP and ACh both above the median values.
CONCLUSIONS
The presence of DR was associated with a reduction in skin microcirculation responses to iontophoresis of both SNP and ACh, suggesting that vascular processes associated with both endothelial dysfunction and endothelial function-independent mechanisms may be pathogenically related to DR.
doi:10.2337/dc10-1985
PMCID: PMC3114354  PMID: 21515845
11.  Retinopathy Signs in People without Diabetes: The Multi-Ethnic Study of Atherosclerosis 
Ophthalmology  2010;118(4):656-662.
Objective
To describe the prevalence of retinopathy and associations with cardiovascular risk factors in persons without diabetes in four racial/ethnic groups (white, black, Hispanic and Chinese).
Design
Population-based cross-sectional study.
Participants
6,176 subjects aged 45 to 84 years without diabetes, selected from six United States communities.
Methods
Fundus images were taken using 45° digital camera through dark adapted pupils and were graded for retinopathy as defined by the Early Treatment Diabetic Retinopathy Study severity scale: microaneurysms, hemorrhages, cotton wool spots, intraretinal microvascular abnormalities, hard exudates, venous beading and new vessels.
Main Outcome Measures
Retinopathy and the association with cardiovascular risk factors
Results
Prevalence rates of retinopathy in persons without diabetes were 12.5% overall, varying from 11.9% (white), 13.9% (black), 12.6% (Hispanic) to 17.2% (Chinese). Hypertension was strongly associated with retinopathy (odds ratio [OR] of 1.47, 95% confidence interval [CI] 1.23, 1.75). After adjusting for age, sex, race and other parameters, smoking (OR 1.50, 95% CI 1.09, 2.06) and increased internal carotid intima media thickness (OR 1.22, 95% CI 1.05, 1.41) were associated with retinopathy. A range of serum inflammatory factors were examined but none were found to be statistically significant.
Conclusions
Retinopathy in persons without diabetes is common, varies with race/ethnicity and associated with cardiovascular risk factors, including hypertension, smoking and carotid artery intima media thickness.
doi:10.1016/j.ophtha.2010.08.007
PMCID: PMC3045651  PMID: 21055817
12.  Prevalence and Risk Factors for Epiretinal Membranes in a Multi-Ethnic United States Population 
Ophthalmology  2010;118(4):694-699.
Purpose
To describe the prevalence of and risk factors for epiretinal membrane (ERM) in a multi-ethnic population and to evaluate possible racial/ethnic differences.
Design
Cross-sectional study.
Participants
Participants of the Multi-Ethnic Study of Atherosclerosis (MESA), examined at the second visit of the MESA when retinal photography was performed.
Methods
Data on 5960 participants aged 45 to 84 years from MESA, including white, blacks, Hispanic and Chinese from six United States communities, were analysed. ERM was assessed from digital non-stereoscopic fundus photographs and defined as cellophane macular reflex (CMR) without retinal folds or pre-retinal macular fibrosis (PMF) with retinal folds. Risk factors were assessed from standardized interviews, clinical examinations, and laboratory investigations.
Main outcome measures
ERM prevalence by ethnic/racial group, and risk factors associated with ERM.
Results
The prevalence of any ERM was 28.9%, of which 25.1% were CMR and 3.8% were PMF. The prevalence of ERM was significantly higher in Chinese (39.0%), compared to Hispanics (29.3%), whites (27.5%), and blacks (26.2%), p<0.001. In multivariable models, increasing age (odds ratio [OR] 1.19, 95% confidence intervals [CI], 1.06, 1.34, per year increase in age), diabetes (OR 1.92, 95% CI, 1.39, 2.65) and hypercholesterolemia (OR 1.33, 95% CI, 1.04, 1.69) were significantly associated with CMR.
Conclusions
This study showed that ERM was significantly more common in Chinese persons compared to whites, blacks and Hispanics. Risk factors for epiretinal membrane were increasing age, presence of diabetes and hypercholesterolemia.
doi:10.1016/j.ophtha.2010.08.009
PMCID: PMC3070851  PMID: 21035863
13.  Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes: The Candidate Gene Association Resource (CARe) 
Cardiovascular disease candidate genes, including genes previously associated with type 2 diabetes and diabetic nephropathy, were not associated with diabetic retinopathy, although a limited number of variants merit further investigation in larger cohorts.
Purpose.
To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).
Methods.
Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥14 and ≥30. The χ2 analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.
Results.
Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10−5, after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.
Conclusions.
Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.
doi:10.1167/iovs.11-7510
PMCID: PMC3183981  PMID: 21873659
14.  Aspirin for the prevention of cognitive decline in the elderly: rationale and design of a neuro-vascular imaging study (ENVIS-ion) 
BMC Neurology  2012;12:3.
Background
This paper describes the rationale and design of the ENVIS-ion Study, which aims to determine whether low-dose aspirin reduces the development of white matter hyper-intense (WMH) lesions and silent brain infarction (SBI). Additional aims include determining whether a) changes in retinal vascular imaging (RVI) parameters parallel changes in brain magnetic resonance imaging (MRI); b) changes in RVI parameters are observed with aspirin therapy; c) baseline cognitive function correlates with MRI and RVI parameters; d) changes in cognitive function correlate with changes in brain MRI and RVI and e) whether factors such as age, gender or blood pressure influence the above associations.
Methods/Design
Double-blind, placebo-controlled trial of three years duration set in two Australian academic medical centre outpatient clinics. This study will enrol 600 adults aged 70 years and over with normal cognitive function and without overt cardiovascular disease. Subjects will undergo cognitive testing, brain MRI and RVI at baseline and after 3 years of study treatment. All subjects will be recruited from a 19,000-patient clinical outcome trial conducted in Australia and the United States that will evaluate the effects of aspirin in maintaining disability-free longevity over 5 years. The intervention will be aspirin 100 mg daily versus matching placebo, randomized on a 1:1 basis.
Discussion
This study will improve understanding of the mechanisms at the level of brain and vascular structure that underlie the effects of aspirin on cognitive function. Given the limited access and high cost of MRI, RVI may prove useful as a tool for the identification of individuals at high risk for the development of cerebrovascular disease and cognitive decline.
Trial Registration
clinicaltrials.gov Identifier: NCT01038583
doi:10.1186/1471-2377-12-3
PMCID: PMC3297524  PMID: 22315948
15.  Serum Apolipoprotein AI and B Are Stronger Biomarkers of Diabetic Retinopathy Than Traditional Lipids 
Diabetes Care  2011;34(2):474-479.
OBJECTIVE
To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy.
RESEARCH DESIGN AND METHODS
This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) from a diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non–HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed.
RESULTS
Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16–0.94], highest versus lowest quartile; Ptrend = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59–0.98]), whereas apoB (per SD increase, 1.31 [1.02–1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13–1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%.
CONCLUSIONS
ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures.
doi:10.2337/dc10-0793
PMCID: PMC3024371  PMID: 21270203
16.  Alterations in Retinal Microvascular Geometry in Young Type 1 Diabetes 
Diabetes Care  2010;33(6):1331-1336.
OBJECTIVE
To describe retinal microvascular geometric parameters in young patients with type 1 diabetes.
RESEARCH DESIGN AND METHODS
Patients with type 1 diabetes (aged 12–20 years) had clinical assessments and retinal photography following standardized protocol at a tertiary-care hospital in Sydney. Retinal microvascular geometry, including arteriolar and venular tortuosity, branching angles, optimality deviation, and length-to-diameter ratio (LDR), were measured from digitized photographs. Associations of these geometric characteristics with diabetes duration, A1C level, systolic blood pressure (SBP), and other risk factors were assessed.
RESULTS
Of 1,159 patients enrolled, 944 (81.4%) had gradable photographs and 170 (14.7%) had retinopathy. Older age was associated with decreased arteriolar (P = 0.024) and venular (P = 0.002) tortuosity, and female subjects had larger arteriolar branching angle than male subjects (P = 0.03). After adjusting for age and sex, longer diabetes duration was associated with larger arteriolar branching angle (P ≤ 0.001) and increased arteriolar optimality deviation (P = 0.018), higher A1C was associated with increased arteriolar tortuosity (>8.5 vs. ≤8.5%, P = 0.008), higher SBP was associated with decreased arteriolar LDR (P = 0.002), and higher total cholesterol levels were associated with increased arteriolar LDR (P = 0.044) and decreased venular optimality deviation (P = 0.044). These associations remained after controlling for A1C, retinal vessel caliber, and retinopathy status and were seen in subjects without retinopathy.
CONCLUSIONS
Key diabetes-related factors affect retinal microvascular geometry in young type 1 diabetes, even in those without evidence of retinopathy. These early retinal alterations may be markers of diabetes microvascular complications.
doi:10.2337/dc10-0055
PMCID: PMC2875449  PMID: 20299479
17.  The Prevalence of Retinal Vein Occlusion: Pooled Data from Population Studies from the United States, Europe, Asia, and Australia 
Ophthalmology  2010;117(2):313-9.e1.
Objective
To summarize the prevalence of retinal vein occlusion (RVO) from studies in the United States, Europe, Asia, and Australia.
Design
Pooled analysis using individual population-based data.
Participants
Individual participant data from population-based studies around the world that had ascertained RVO from fundus photographs.
Methods
Each study provided data on branch RVO and central RVO by age, sex, and ethnicity. Prevalence rates were directly age and sex standardized to the 2008 world population aged 30 years and older. Estimates were calculated by study and, after pooling, by ethnicity. Summary estimates included studies in which RVO was assessed from fundus photographs on ≥2 fields of both eyes.
Main Outcome Measures
Any RVO, CRVO, or BRVO.
Results
The combined pooled data contained 68,751 individuals from 15 studies, with participants’ ages ranging from 30 to 101 years. In analyses of 11 studies that assessed ≥2 fundus fields of both eyes (n=49,869), the age- and sex-standardized prevalence was 5.20 per 1000 (confidence interval [CI], 4.40–5.99) for any RVO, 4.42 per 1000 (CI, 3.65–5.19) for BRVO, and 0.80 per 1000 (CI, 0.61–0.99) for CRVO. Prevalence varied by race/ethnicity and increased with age, but did not differ by gender. The age- and sex-standardized prevalence of any RVO was 3.7 per 1000 (CI, 2.8–4.6) in whites (5 studies), 3.9 per 1000 (CI, 1.8–6.0) in blacks (1 study), 5.7 per 1000 (CI, 4.5–6.8) in Asians (6 studies), and 6.9 per 1000 (CI, 5.7–8.3) in Hispanics (3 studies). Prevalence for CRVO was lower than BRVO in all ethnic populations. On the basis of these data, an estimated 16.4 million (CI, 13.9–18.9) adults are affected by RVO, with 2.5 million (CI, 1.9–3.1) affected by CRVO and 13.9 million (CI, 11.5–16.4) affected by BRVO. Study limitations include non-uniform sampling frames in identifying study participants and in acquisition and grading of RVO data.
Conclusions
Our study provides summary data on the prevalence of RVO and suggests that approximately 16 million people may have this condition. Research on preventive and treatment strategies for this sight-threatening eye disease is needed.
doi:10.1016/j.ophtha.2009.07.017
PMCID: PMC2945292  PMID: 20022117
18.  The role of toll-like receptor variants in acute anterior uveitis 
Molecular Vision  2011;17:2970-2977.
Purpose
Acute anterior uveitis (AAU) is the most common form of uveitis; however, while it is presumed to have an immunological basis, the precise underlying etiology remains elusive. Toll-like receptors (TLRs) have a key role in linking innate and adaptive immunity, thereby forming a molecular bridge between microbial triggers and the development of AAU. The purpose of this study was to investigate the role of TLR2 and TLR4 gene polymorphisms in the pathogenesis of AAU.
Methods
The study comprised 225 confirmed cases of idiopathic or human leukocyte antigen (HLA) B27 (subtypes B*2701-2759; HLA-B27)-related AAU and 2,534 population-based controls from the Blue Mountains Eye Study. All participants were of Anglo-Celtic descent. Blood samples were collected for DNA extraction and genotyping. A total of 16 single nucleotide polymorphisms (SNPs) were selected for analysis and either directly genotyped or imputed to cover the common variations within the TLR genes. Data were analyzed at the allelic, genotypic and haplotypic levels.
Results
Control subjects were significantly older than case subjects (p<0.0001). There was no significant difference in the gender composition between the case and control cohorts (p=0.18). One TLR2 SNP (rs11938228) was found to be associated with AAU at the allelic level (OR=1.28; p=0.017); however this association did not remain following adjustment for age and sex (p=0.067). None of the SNPs at the TLR4 locus were found to differ significantly between cases or controls, irrespective of adjustment for age and gender.
Conclusions
This study has confirmed that common TLR variants of moderate effect size do not predispose to AAU, undermining the implication of reported mutations in the selective perturbations of TLR expression and function evident in AAU.
PMCID: PMC3224833  PMID: 22128242
19.  Early Age-Related Macular Degeneration, Cognitive Function and Dementia: The Cardiovascular Health Study 
Archives of ophthalmology  2009;127(5):667-673.
Objective
To describe the association of cognitive function and dementia with early age-related macular degeneration (AMD) in older individuals.
Methods
A population-based study of 2,088 persons (1769 whites and 319 blacks) aged 69 to 97 years participating in the Cardiovascular Health Study. AMD was assessed from retinal photographs based on a modified Wisconsin AMD grading system. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination (3MSE). Participants were also evaluated for dementia with detailed neuropsychological testing.
Results
After controlling for age, gender, race, and center, persons with low DSST scores (lowest quartile of scores, ≤30) were more likely to have early AMD (odds ratio [OR] 1.38; 95% confidence intervals [CI] 1.03, 1.85) than persons with higher DSST scores. In analyses further controlling for education, systolic blood pressure, total cholesterol, diabetes, smoking status and APOE genotype, this association was stronger (OR 2.00; 95% CI, 1.29, 3.10). There was no association with low 3MSE scores, dementia or Alzheimer’s disease with early AMD.
Conclusions
In this older population, cognitive impairment may share common age-related pathophysiology and risk factors with early AMD.
doi:10.1001/archophthalmol.2009.30
PMCID: PMC3001290  PMID: 19433718
20.  Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis 
American Journal of Epidemiology  2009;170(11):1323-1332.
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.
doi:10.1093/aje/kwp306
PMCID: PMC2800263  PMID: 19884126
cohort studies; meta-analysis; retinal vessels; risk; stroke
21.  Retinal vessel diameters and risk of hypertension: the Multiethnic Study of Atherosclerosis 
Journal of hypertension  2009;27(12):2386-2393.
Objective
To describe the prospective relationship of retinal vessel diameters with risk of hypertension in a multiethnic population-based cohort.
Methods
The Multi-Ethnic Study of Atherosclerosis is a population-based study of subclinical cardiovascular disease among white, African–American, Hispanic, and Chinese American adults aged 45–84 years. Retinal vessel diameters were measured using a standardized imaging software at the second examination (considered baseline in this analysis) and summarized as the central retinal artery/vein equivalent. Presence of retinopathy and retinal focal arteriolar narrowing and arteriovenous nicking was assessed by trained graders. Incidence of hypertension was defined among participants at risk as systolic blood pressure at least 140 mmHg, diastolic blood pressure at least 90 mmHg, or use of an antihypertensive medication.
Results
Of the initial 6237 participants at baseline, 2583 were at risk of hypertension. After 3.2±0.5 years of follow-up, 448 (17.3%) participants developed hypertension. After adjusting for age, sex, race/ethnicity, the average of mean arterial blood pressure in the first and second examination, and other vascular risk factors, persons with narrower retinal arteriolar diameter and wider venular diameter at baseline were more likely to develop hypertension [odds ratio per SD decrease in central retinal artery equivalent 1.20, 95% confidence intervals 1.02, 1.42; and odds ratio per SD increase in central retinal vein equivalent 1.18, 95% confidence interval 1.02, 1.37]. Persons with focal arteriolar narrowing were also more likely to develop hypertension (odds ratio 1.80, 95% confidence interval 1.09, 2.97).
Conclusion
Findings from this multiethnic population confirm that narrower retinal arteriolar diameter and wider venular diameter are associated with the development of hypertension independent of traditional risk factors.
doi:10.1097/HJH.0b013e3283310f7e
PMCID: PMC2935621  PMID: 19680136
hypertension; microcirculation; retinal vessel diameter; retinopathy; the Multi-Ethnic Study of Atherosclerosis
22.  Relative Importance of Systemic Determinants of Retinal Arteriolar and Venular Caliber: The ARIC Study 
Archives of ophthalmology  2008;126(10):1404-1410.
Objectives
To examine the relative contributions of systemic cardiovascular factors to retinal arteriolar and venular caliber in men and women and in whites and African-Americans.
Methods
In the Atherosclerosis Risk in Communities (ARIC) study, retinal arteriolar caliber (central retinal arteriolar equivalent, CRAE) and venular caliber (central retinal venular equivalent, CRVE) were measured from digitized retinal photographs for 8,794 participants.
Results
The main systemic determinants of narrower CRAE were, in order of decreasing relative contribution, higher current mean arterial blood pressure (MABP), lower serum albumin, current alcohol consumption and higher body mass index. The main systemic determinants of wider CRVE were current cigarette smoking and higher current MABP, followed by higher white cell count, body mass index and plasma LDL cholesterol levels. These associations were generally similar in whites and African-Americans and in men and women.
Conclusions
The major systemic determinant of narrower retinal arteriolar caliber is higher blood pressure, while those of wider retinal venular caliber are cigarette smoking, higher blood pressure, systemic inflammation and obesity. These data offer further insights into systemic processes influencing arteriolar and venular characteristics, and may help explain the observed associations of retinal vascular caliber and the risk of clinical cardiovascular disease.
doi:10.1001/archopht.126.10.1404
PMCID: PMC2995700  PMID: 18852419
arteriolar caliber; venular caliber; arterioles; venules; retinal vessels
23.  Correction: Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo 
PLoS Genetics  2010;6(11):10.1371/annotation/841bfadf-85d1-4059-894f-2863d73fa963.
doi:10.1371/annotation/841bfadf-85d1-4059-894f-2863d73fa963
PMCID: PMC2988687
24.  Flicker Light–Induced Retinal Vasodilation in Diabetes and Diabetic Retinopathy 
Diabetes Care  2009;32(11):2075-2080.
OBJECTIVE
Flicker light–induced retinal vasodilation may reflect endothelial function in the retinal circulation. We investigated flicker light–induced vasodilation in individuals with diabetes and diabetic retinopathy.
RESEARCH DESIGN AND METHODS
Participants consisted of 224 individuals with diabetes and 103 nondiabetic control subjects. Flicker light–induced retinal vasodilation (percentage increase over baseline diameter) was measured using the Dynamic Vessel Analyzer. Diabetic retinopathy was graded from retinal photographs.
RESULTS
Mean ± SD age was 56.5 ± 11.8 years for those with diabetes and 48.0 ± 16.3 years for control subjects. Mean arteriolar and venular dilation after flicker light stimulation were reduced in participants with diabetes compared with those in control subjects (1.43 ± 2.10 vs. 3.46 ± 2.36%, P < 0.001 for arteriolar and 2.83 ± 2.10 vs. 3.98 ± 1.84%, P < 0.001 for venular dilation). After adjustment for age, sex, diabetes duration, fasting glucose, cholesterol and triglyceride levels, current smoking status, systolic blood pressure, and use of antihypertensive and lipid-lowering medications, participants with reduced flicker light–induced vasodilation were more likely to have diabetes (odds ratio 19.7 [95% CI 6.5–59.1], P < 0.001 and 8.14 [3.1–21.4], P < 0.001, comparing lowest vs. highest tertile of arteriolar and venular dilation, respectively). Diabetic participants with reduced flicker light–induced vasodilation were more likely to have diabetic retinopathy (2.2 [1.2–4.0], P = 0.01 for arteriolar dilation and 2.5 [1.3–4.5], P = 0.004 for venular dilation).
CONCLUSIONS
Reduced retinal vasodilation after flicker light stimulation is independently associated with diabetes status and, in individuals with diabetes, with diabetic retinopathy. Our findings may therefore support endothelial dysfunction as a pathophysiological mechanism underlying diabetes and its microvascular manifestations.
doi:10.2337/dc09-0075
PMCID: PMC2768208  PMID: 19641162
25.  Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo 
PLoS Genetics  2010;6(10):e1001184.
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.
Author Summary
The microcirculation plays an important role in the development of cardiovascular diseases. Retinal vascular caliber changes reflect early microvascular disease and predict incident cardiovascular events. In order to identify genetic variants associated with retinal vascular caliber, we performed a genome-wide association study and 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). We found evidence for association of four loci with retinal venular caliber: on chromosomes 19q13 within the RASIP1 locus, 6q24 adjacent to the VTA1 and NMBR loci, 12q24 in the region of ATXN2,SH2B3 and PTPN11 loci, and 5q14 adjacent to the MEF2C locus. In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. In the present study, we demonstrate that four novel loci were associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. Our findings will help focus research on novel genes and pathways involving the microcirculation and its role in the development of cardiovascular disease.
doi:10.1371/journal.pgen.1001184
PMCID: PMC2965750  PMID: 21060863

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