Showing papers by "Ronald Klein published in 2016"

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Abstract: Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

The 15-Year Cumulative Incidence of Retinal Vein Occlusion

Abstract: Results: The 15-year cumulative incidences of branch retinal vein occlusion and central retinal vein occlusion were 1.8% and 0.5%, respectively. Using a generalized estimating equation model, incident retinal vein occlusion was related to baseline age (odds ratio [OR] per 10 years,1.70;95%confidenceinterval[CI],1.36-2.12),history of barbiturate use (OR, 5.30; 95% CI, 2.28-12.31), focalretinalarteriolarnarrowing(OR,2.45;95%CI,1.294.66), glaucoma (OR, 3.17; 95% CI, 1.50-6.69), serum ionized calcium level (OR per 0.4 mg/dL, 0.43; 95% CI, 0.23-0.79), serum phosphorus level (OR per 0.3 mg/dL, 1.15;95%CI,1.01-1.30),andserumcreatininelevel(OR for 1.4 vs1.4 mg/dL, 1.61; 95% CI, 1.00-2.59). Migraine headache history was associated with branch retinal vein occlusion (OR, 1.99; 95% CI, 1.08-3.67). Diabetes history was associated with central retinal vein occlusion (OR, 6.35; 95% CI, 1.90-21.27). Conclusions: Incident retinal vein occlusion is not infrequent in the population, especially after age 65 years. Therelationshipsofbarbiturateuse,serumcreatininelevel, serumionizedcalciumlevel,andserumphosphoruslevel with incident retinal vein occlusion require further assessment in other large population-based studies.

Retinal Vessel Calibers in Predicting Long-Term Cardiovascular Outcomes: The Atherosclerosis Risk in Communities Study.

Abstract: Background —Narrower retinal arterioles and wider retinal venules have been associated with negative cardiovascular outcomes. We investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up and provide incremental value over the 2013 American College of Cardiology/American Heart Association pooled cohort equations (PCE) in predicting Atherosclerotic Cardiovascular Disease Events (ASCVE). Methods —10,470 men and women without prior ASCVE or heart failure (HF) in the Atherosclerosis Risk in Communities (ARIC) study underwent retinal photography at visit 3 (1993-1995). Results —During a mean follow up of 16 years, there were 1779 incident CHD events, 548 ischemic strokes, 1395 HF events and 2793 deaths. Rates of all outcomes were higher in those with wider retinal venules and narrower retinal arterioles. Subjects with wider retinal venules [hazard ratio (HR) 1.13 (95% CI: 1.08-1.18), HR 1.18 (1.07-1.31) and HR 1.10 (1.00-1.20) per standard deviation (SD) increase] and narrower retinal arterioles [HR 1.06 (1.01-1.11), HR 1.14 (1.03-1.26) and HR 1.13 (1.03-1.24) per SD decrease] had a higher risk of death and stroke in both sexes as well as incident CHD in women but not men (interaction p=0.02) after adjustment for the PCE risk-score variables. The association between retinal vessel caliber and HF was non-significant after adjustment for systolic blood pressure. Among women with PCE-predicted 10-year ASCVE risk 5%). Conclusions —Narrower retinal arterioles and wider retinal venules conferred long-term risk of mortality and ischemic stroke in both genders and CHD in women. These measures serve as an inexpensive, reproducible biomarker that added incremental value to current practice guidelines in ASCVE risk prediction in low-risk women.

Age-Related Sensory Impairments and Risk of Cognitive Impairment.

Abstract: Objectives To evaluate the associations between sensory impairments and 10-year risk of cognitive impairment. Design The Epidemiology of Hearing Loss Study (EHLS), a longitudinal, population-based study of aging in the Beaver Dam, Wisconsin community. Baseline examinations were conducted in 1993 and follow-up examinations have been conducted every 5 years. Setting General community. Participants EHLS members without cognitive impairment at EHLS-2 (1998–2000). There were 1,884 participants (mean age 66.7) with complete EHLS-2 sensory data and follow-up information. Measurements Cognitive impairment was defined as a Mini-Mental State Examination score of 25 dB hearing level in either ear, visual impairment was a Pelli-Robson contrast sensitivity of <1.55 log units in the better eye, and olfactory impairment was a San Diego Odor Identification Test score of <6. Results Hearing, visual, and olfactory impairment were independently associated with cognitive impairment risk (hearing: hazard ratio (HR) = 1.90, 95% confidence interval (CI) = 1.11–3.26; vision: HR = 2.05, 95% CI = 1.24–3.38; olfaction: HR = 3.92, 95% CI = 2.45–6.26)). Nevertheless, 85% of participants with hearing impairment, 81% with visual impairment, and 76% with olfactory impairment did not develop cognitive impairment during follow-up. Conclusion The relationship between sensory impairment and cognitive impairment was not unique to one sensory system, suggesting that sensorineural health may be a marker of brain aging. The development of a combined sensorineurocognitive measure may be useful in uncovering mechanisms of healthy brain aging.

Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

The Relation of Markers of Inflammation and Endothelial Dysfunction to the Prevalence and Progression of Diabetic Retinopathy

Abstract: OBJECTIVE To determine the relation of glycemia, blood pressure, and serum total cholesterol level as systemic markers of inflammation and endothelial dysfunction to the prevalence and incidence of diabetic retinal outcomes in persons with long-duration type 1 diabetes mellitus. METHODS Longitudinal population-based study of persons with type 1 diabetes mellitus who received care for their diabetes in south central Wisconsin from July 1, 1979, to June 30, 1980. Data for this investigation were obtained from the 1990-1992 through the 2005-2007 follow-up examinations. Main outcome measures included the severity of diabetic retinopathy (DR) and macular edema (ME). RESULTS In the 1990-1992 prevalence data, soluble vascular cell adhesion molecule, tumor necrosis factor, and homocysteine levels were associated with increased odds of more severe DR (odds ratios [highest vs lowest quartile], 3.95 [95% confidence interval, 1.66-9.39], 5.46 [2.38-12.52], and 7.46 [2.91-19.16], respectively) in those with kidney disease while controlling for relevant confounders. Similar odds were found for proliferative DR. Only total homocysteine level was associated with increased odds of ME (3.80 [95% confidence interval, 1.91-7.54]), irrespective of kidney disease. None of the markers were associated with incidence of proliferative DR, ME, or progression of DR 15 years later. CONCLUSIONS A limited number of markers are associated with increased odds of prevalent retinal outcomes in persons with type 1 diabetes mellitus and kidney disease. Only homocysteine level is associated with ME in those with and without kidney disease. In the absence of kidney disease, the markers do not add to the more conventional descriptors and predictors of DR in persons with type 1 diabetes mellitus. This may reflect the close association of DR and kidney disease in diabetic persons.

Sensory Impairments and Risk of Mortality in Older Adults

Abstract: Background Sensory impairments increase with age and the majority of older people will experience a sensory impairment if they live long enough. However, the relationships of hearing, visual, and olfactory impairments with mortality are not well understood. Methods Epidemiology of Hearing Loss Study participants (n = 2,418) aged 53-97 years (mean = 69 years) were examined in 1998-2000 and hearing, visual acuity, and olfaction were measured. Participants were followed for mortality for up to 17 years (mean = 12.8 years). Cox proportional hazards models were used to assess the association between prevalent sensory impairments and the 15-year cumulative incidence of death. Results A total of 1,099 (45.4%) of participants died during the follow-up period. In age- and sex-adjusted Cox models, the risk of mortality was higher among participants with one (hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.19, 1.64) or two or more (HR = 2.12, 95% CI = 1.74, 2.58) sensory impairments than among participants with no sensory impairments. Olfactory impairment at baseline was significantly associated with mortality (HR = 1.28, 95% CI = 1.07, 1.52) after adjusting for age, sex, sensory comorbidities, cardiovascular risk factors and disease, cognitive impairment, frailty, subclinical atherosclerosis, and inflammatory marker levels (n = 1,745). Hearing and visual impairment were not associated with mortality after adjusting for subclinical atherosclerosis and inflammation. Conclusion Olfactory impairment, but not hearing or visual impairment, was associated with an increased risk of mortality. These results suggest that olfactory impairment may be a marker of underlying physiologic processes or pathology that is associated with aging and reduced survival in older adults.

Urinary proteomics predict onset of microalbuminuria in normoalbuminuric type 2 diabetic patients, a sub-study of the DIRECT-Protect 2 study

Abstract: Background: Early prevention of diabetic nephropathy is not successful as early interventions have shown conflicting results, partly because of a lack of early and precise indicators of disease development. Urinary proteomics has shown promise in this regard and could identify those at high risk who might benefit from treatment. In this study we investigate its utility in a large type 2 diabetic cohort with normoalbuminuria. Methods: We performed a post hoc analysis in the Diabetic Retinopathy Candesartan Trials (DIRECT-Protect 2 study), a multi centric randomized clinical controlled trial. Patients were allocated to candesartan or placebo, with the aim of slowing the progression of retinopathy. The secondary endpoint was development of persistent microalbuminuria (three of four samples). We used a previously defined chronic kidney disease risk score based on proteomic measurement of 273 urinary peptides (CKD273-classifier). A Cox regression model for the progression of albuminuria was developed and evaluated with integrated discrimination improvement (IDI), continuous net reclassification index (cNRI) and receiver operating characteristic curve statistics. Results: Seven hundred and thirty-seven patients were analysed and 89 developed persistent microalbuminuria (12%) with a mean follow-up of 4.1 years. At baseline the CKD273-classifier predicted development of microalbuminuria during follow-up, independent of treatment (candesartan/placebo), age, gender, systolic blood pressure, urine albumin excretion rate, estimated glomerular filtration rate, HbA1c and diabetes duration, with hazard ratio 2.5 [95% confidence interval (CI) 1.4–4.3; P = 0.002] and area under the curve 0.79 (95% CI 0.75–0.84; P < 0.0001). The CKD273-classifier improved the risk prediction (relative IDI 14%, P = 0.002; cNRI 0.10, P = 0.043). Conclusions: In this cohort of patients with type 2 diabetes and normoalbuminuria from a large intervention study, the CKD273-classifier was an independent predictor of microalbuminuria. This may help identify high-risk normoalbuminuric patients for preventive strategies for diabetic nephropathy.

Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B.

Abstract: Widespread genetic modification of cells in the central nervous system (CNS) with a viral vector has become possible and increasingly more efficient. We previously applied an AAV9 vector with the cytomegalovirus/chicken beta-actin (CBA) hybrid promoter and achieved wide-scale CNS transduction in neonatal and adult rats. However, this method transduces a variety of tissues in addition to the CNS. Thus we studied intravenous AAV9 gene transfer with a synapsin promoter to better target the neurons. We noted in systematic comparisons that the synapsin promoter drives lower level expression than does the CBA promoter. The engineered adeno-associated virus (AAV)-PHP.B serotype was compared with AAV9, and AAV-PHP.B did enhance the efficiency of expression. Combining the synapsin promoter with AAV-PHP.B could therefore be advantageous in terms of combining two refinements of targeting and efficiency. Wide-scale expression was used to model a disease with widespread pathology. Vectors encoding the amyotrophic lateral sclerosis (ALS)-related protein transactive response DNA-binding protein, 43 kDa (TDP-43) with the synapsin promoter and AAV-PHP.B were used for efficient CNS-targeted TDP-43 expression. Intracerebroventricular injections were also explored to limit TDP-43 expression to the CNS. The neuron-selective promoter and the AAV-PHP.B enhanced gene transfer and ALS disease modeling in adult rats.

Adequate vitamin D status is associated with the reduced odds of prevalent diabetic retinopathy in African Americans and Caucasians

Abstract: Vitamin D status has been hypothesized to protect against development of diabetic retinopathy via its anti-inflammatory and anti-angiogenic properties. Additionally, in vitro and in vivo studies suggest vitamin D favorably influences blood pressure and blood glucose control, strong risk factors for diabetic retinopathy. We examined the association between vitamin D status and prevalent diabetic retinopathy in participants with diabetes from a population-based cohort. Among participants in the Atherosclerosis Risk in Communities (ARIC) study with diabetes at visit 3 (1993–1995), 1339 (906 Caucasians, 433 African Americans) had serum 25-hydroxyvitamin (25[OH]D) concentrations assessed at visit 2 (1989–1992) and nonmydriatic retinal photographs taken at visit 3. Dietary intake of vitamin D was assessed at visit 1 (1987–1989). Logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for diabetic retinopathy by categories of season-adjusted 25(OH)D (<30 [referent], 30–<50, 50–<75 and ≥75 nmol/L), by quartile of vitamin D intake (IU/day), and use of vitamin D or fish oil supplements (yes/no). P for trend was estimated using continuous 25(OH)D or vitamin D intake. ORs were adjusted for race, and duration of diabetes. We further adjusted for HBA1c and hypertension to examine if 25(OH)D influenced diabetic retinopathy via its effects on either glycemic control or blood pressure. ORs (95 % CIs) for retinopathy, adjusted for race and duration, were 0.77 (0.45–1.32), 0.64 (0.37–1.10), and 0.39 (0.20–0.75), p for trend = 0.001, for participants with 25(OH)D of 30–<50, 50–<75, and ≥75 nmol/L, respectively. Further adjustment for hypertension minimally influenced results (data not show), but adjustment for HBA1c attenuated the OR among those with 25(OH)D ≥75 (0.47 [0.23–0.96], p for trend = 0.030). No statistically significant association was observed between vitamin D intake from foods or supplements and retinopathy. 25(OH)D concentrations ≥75 nmol/L were associated with lower odds of any retinopathy assessed 3 years later. We speculate this may be due in part to vitamin D’s influence on blood glucose control.

Comparison of Common Retinal Vessel Caliber Measurement Software and a Conversion Algorithm

Abstract: Purpose To compare three commonly used retinal vessel caliber measurement software systems, and propose an algorithm for conversion between measurement systems. Methods We used 120 retinal photographs to evaluate the agreement between three commonly used software (Retinal Analysis [RA], Integrative Vessel Analysis [IVAN], and Singapore I Vessel Assessment [SIVA]). Bland-Altman plots were used to evaluate agreement of retinal arteriolar (central retinal artery equivalent, CRAE) and venular (central retinal vein equivalent, CRVE) calibers. Pearson's correlation was used to assess the associations between systemic factors and retinal vessel calibers, and Z-test was used to compare the strength of the correlation coefficients across the three software systems. An algorithm was created to convert measurements, with paired t-test performed to evaluate the differences between SIVA-measured retinal calibers and SIVA-approximates converted from RA- and IVAN-measurements using the algorithm. Results Differences between SIVA- and RA-measured calibers (CRAE: mean difference [MD] = -21.8 μm, 95% limits of agreement [LOA], -47.3 to 3.7 μm; CRVE: MD = -7.7 μm, 95% LOA, -28.0 to 12.6 μm), SIVA- and IVAN-measured calibers (CRAE: MD = -6.7 μm, 95% LOA, -23.8 to 10.4 μm; CRVE: MD = -18.2 μm 95% LOA, -36.7 to 0.4 μm) were large. However, the strength of correlations between systemic factors with SIVA-measured retinal calibers was not significantly different to that measured using RA and IVAN (P ≥ 0.332). SIVA-approximates converted from RA and IVAN measurements using the proposed algorithm was not significantly different from SIVA-measured calibers (P ≥ 0.20). Conclusion Absolute measurements of retinal vessel calibers vary between three common software systems but associations with systemic factors were similar. Translational relevance The proposed algorithm allowed conversions of RA and IVAN measurements to SIVA-approximates. This conversion is important for future data pooling and establishment of normative values for retinal vascular caliber measurements.

Variation in SLC19A3 and Protection From Microvascular Damage in Type 1 Diabetes.

Abstract: The risk of long-term diabetes complications is not fully explained by diabetes duration or long-term glycemic exposure, suggesting the involvement of genetic factors. Because thiamine regulates intracellular glucose metabolism and corrects for multiple damaging effects of high glucose, we hypothesized that variants in specific thiamine transporters are associated with risk of severe retinopathy and/or severe nephropathy because they modify an individual's ability to achieve sufficiently high intracellular thiamine levels. We tested 134 single nucleotide polymorphisms (SNPs) in two thiamine transporters (SLC19A2/3) and their transcription factors (SP1/2) for an association with severe retinopathy or nephropathy or their combination in the FinnDiane cohort. Subsequently, the results were examined for replication in the DCCT/EDIC and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) cohorts. We found two SNPs in strong linkage disequilibrium in the SLC19A3 locus associated with a reduced rate of severe retinopathy and the combined phenotype of severe retinopathy and end-stage renal disease. The association for the combined phenotype reached genome-wide significance in a meta-analysis that included the WESDR cohort. These findings suggest that genetic variations in SLC19A3 play an important role in the pathogenesis of severe diabetic retinopathy and nephropathy and may explain why some individuals with type 1 diabetes are less prone than others to develop microvascular complications.

Associations between recent severe hypoglycemia, retinal vessel diameters, and cognition in adults with type 1 diabetes

Abstract: Aims Mild cognitive dysfunction has been identified in children and adults with type 1 diabetes, but most studies have failed to find a relationship between severe hypoglycemia and cognition, despite reports of such associations in older adults with type 2 diabetes. Focusing on older adults with type 1 diabetes, we examined the associations between cognitive performance and recent episodes of severe hypoglycemia, retinal vessel diameters and the presence of micro- and macrovascular complications. Methods Cognitive functioning was assessed in 244 participants enrolled in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. The mean (SD; range) age at assessment in 2012–14 was 55.2 (8.3; 37–82) years and the mean (SD) duration of diabetes was 41.1 (5.6) years. Three cognitive domains were assessed in this cross-sectional study: mental efficiency and executive function, nonverbal memory, and verbal memory. Results Multivariate modeling demonstrated that although age and/or education are most strongly associated with performance on measures of mental efficiency, three diabetes-related variables were also associated with poorer test scores: an episode of severe hypoglycemia in the past year ( β =−0.360 [95% CI, −0.672, −0.047]), retinal arteriolar and venular diameters ( β =0.140 [95% CI, 0.062, 0.219]; β =−0.127 [95% CI −0.207, −0.047]), and carotid artery plaque ( β =−0.372 [95% CI −0.741, −0.003]). In addition, recent severe hypoglycemia was associated with poorer nonverbal memory ( β =−0.522 [95% CI, −0.849, −0.194]). Conclusions For middle-aged and older adults with long-duration type 1 diabetes, poorer cognition was associated with a recent episode of severe hypoglycemia as well as with the presence of micro- and/or macrovascular conditions. Given the increasing numbers of aging adults with type 1 diabetes, future longitudinal studies are needed to identify causality and to determine whether diabetes management techniques that reduce the onset or severity of vascular complications and hypoglycemia can also reduce the risk of cognitive dysfunction in this population.

Novel Genetic Loci Associated With Retinal Microvascular Diameter.

Abstract: Background-There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size. Methods and Results-This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10- 11; minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10-9; minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10-10; minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10-8; minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10-12). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10-04). Conclusions-Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.

Effects of Prior Intensive Insulin Therapy and Risk Factors on Patient-Reported Visual Function Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort

Abstract: Importance Preservation of vision in patients with diabetes mellitus is critical. Interventions to improve glycemic control through early intensive treatment of diabetes reduce rates of severe retinopathy and preserve visual acuity. Objective To assess the effects of prior intensive insulin treatment and risk factors on patient-reported visual function in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Design, Setting, and Participants Cohort study of 1184 participants with type 1 diabetes from the DCCT/EDIC study (randomized clinical trial followed by an observational follow-up study) who completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) during EDIC years 17 through 20 (September 1, 2009, through April 30, 2014) in 28 institutions across the United States and Canada. Main Outcomes and Measures The primary outcome was the composite NEI-VFQ-25 score. Secondary outcomes were visual acuity (measured by the Early Treatment Diabetic Retinopathy Study protocol), retinopathy level (determined by masked grading of stereoscopic color fundus photographs), and NEI-VFQ-25 subscale scores. The composite NEI-VFQ-25 scale and its subscales were scored 0 to 100, corresponding to poor to excellent function, respectively. Results The overall average NEI-VFQ-25 score for 1184 DCCT/EDIC participants (mean [SD] age, 52.3 [6.9] years; 48% female) with a 30-year duration of diabetes was high (all participants: median, 91.7; interquartile range [IQR], 89.7-96.9; intensive treatment [n = 605]: median, 94.7; IQR, 91.0-97.2; conventional treatment [n = 579]: median, 94.0; IQR, 88.4-96.1; P = .006 for intensive vs conventional). After adjustment for sex, age, hemoglobin A 1c level, and retinopathy level at DCCT baseline, the former intensive treatment group had a significant, albeit modest, improvement in overall NEI-VFQ-25 score compared with the former conventional diabetes treatment group (median difference, −1.0; 95% CI, −1.7 to −0.3; P = .006). This beneficial treatment effect was fully attributed to the prior glycemic control in DCCT (explained treatment effect: 100%). Those with visual acuity worse than 20/100 reported the largest decline in visual function (median difference, −21.0; 95% CI, −40.5 to −1.6; P = .03). Conclusions and Relevance In the DCCT/EDIC cohort, patient-reported visual function remains high in both treatment groups, comparable to previous reports of overall health-related quality of life. Intensive diabetes therapy modestly improved NEI-VFQ-25 score 30 years after the start of the DCCT, the benefit underestimated owing to more nonparticipants from the conventional treatment group. Visual acuity had the greatest effect on patient-reported visual function from among all risk factors. Trial Registration clinicaltrials.gov Identifiers:NCT00360815andNCT00360893

Dietary Intake of Lutein and Diabetic Retinopathy in the Atherosclerosis Risk in Communities Study (ARIC).

Abstract: Purpose: We tested the hypothesis that dietary intake of lutein is inversely associated with prevalence of diabetic retinopathy (DR) due to its antioxidant and anti-inflammatory properties and location within the retina.Methods: We used logistic regression to examine the association between prevalent DR and energy-adjusted lutein intake by quartile (Q) using data collected from 1430 Atherosclerosis Risk in Communities Study (ARIC) participants with diabetes (n = 994 white, n = 508 black). DR was assessed from 45° non-mydriatic retinal photographs of one randomly chosen eye taken at visit 3 (1993–1995). Dietary lutein intake was estimated using a 66-item food frequency questionnaire at visit 1 (1987–1989).Results: Median estimated daily lutein intake was 1370 µg/1000 kcals and prevalence of DR was ~21%. We found a crude association between lutein and DR (odds ratio, OR, 2.11, 95% confidence interval, CI, 1.45–3.09 for Q4, high intake, vs. Q1, low intake; p for trend <0.0001), which was attenuated a...

NSAID Use and Incident Cognitive Impairment in a Population-based Cohort.

Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent dementia, but previous studies have yielded conflicting results. This study estimated the association of prior NSAID use with incident cognitive impairment in the population-based Epidemiology of Hearing Loss Study (EHLS, n=2422 without cognitive impairment in 1998-2000). Prospectively collected medication data from 1988-1990, 1993-1995, and 1998-2000 were used to categorize NSAID use history at the cognitive baseline (1998-2000). Aspirin use and nonaspirin NSAID use were separately examined. Cox regression models were used to estimate the associations between NSAID use history at baseline and incident cognitive impairment in 2003-2005 or 2009-2010. Logistic regression analyses were used to estimate associations with a second outcome, mild cognitive impairment/dementia, available in 2009-2010. Participants using aspirin at baseline but not 5 years prior were more likely to develop cognitive impairment (adjusted hazard ratio=1.77; 95% confidence interval=1.11, 2.82; model 2), with nonsignificant associations for longer term use. Nonaspirin NSAID use was not associated with incident cognitive impairment or mild cognitive impairment/dementia odds. These results provided no evidence to support a potential protective effect of NSAIDs against dementia.

Prevalence of Diabetic Retinopathy in Adult Chinese American Individuals: The Chinese American Eye Study.

Abstract: Importance Chinese American individuals are a fast-growing segment of people in the United States, but the burden and effect of diabetic complications on this group of people is not fully understood. Objective To determine the age- and sex-specific prevalence of diabetic retinopathy (DR) overall and by severity, duration of diabetes, and treatment history in adult Chinese American individuals. Design, Setting, and Participants The Chinese American Eye Study (CHES), a population-based, cross-sectional study, was conducted from February 2010 to October 2013 for 10 census tracts in Monterey Park, California. This analysis, conducted between February 16, 2010, and October 9, 2013, included 4582 Chinese residents 50 years and older. Main Outcomes and Measures Prevalence of nonproliferative DR, proliferative DR, and macular edema, as well as stereoscopic fundus photography of 7 standard Early Treatment Diabetic Retinopathy Study fields. Results Of the 4582 survey participants, most were first-generation immigrants from China (68.7%) and female (63%). In total, 736 participants (16.1%) were identified as having type 2 diabetes. Fundus photographs were gradable for 665 (90.4%) of these participants. The reproducibility of DR grading was evaluated throughout study and showed moderate to excellent agreement (weighted κ = 0.78-0.97). Diabetic retinopathy was present in 35.8% of people with diabetes (95% CI, 32.1%-39.6%). The estimated prevalence of severe nonproliferative DR and proliferative DR was 1.7% (95% CI, 0.8%-2.9%) and 2.4% (95% CI, 1.4%-3.9%), respectively. Macular edema was observed among 4.5% of people with diabetes (95% CI, 3.0%-6.4%), and clinically significant macular edema was observed among 2.0% (95% CI, 1.1%-3.3%). The prevalence of DR was higher (56%) among participants with a longer duration of diabetes (≥15 years; P Conclusions and Relevance Data from CHES and this study indicate that the prevalence of DR in the Chinese American Eye Study Group is relatively lower than studies of Chinese individuals residing in rural northern China or Latino individuals from Los Angeles County, California.

Age-Related Macular Degeneration and Quality of Life in Latinos: The Los Angeles Latino Eye Study.

Abstract: Importance This study found evidence of a threshold effect in which the presence of bilateral soft drusen and depigmentation of retinal pigment epithelium was associated with substantially low health-related quality of life (HRQoL) in adult Latinos from the United States. Objective To assess the association of general and vision-specific HRQoL with age-related macular degeneration (AMD), overall and by bilaterality and severity, in adult Latinos. Design, Setting, and Participants This cross-sectional, population-based study included 4876 participants from the general urban community in 6 US Census tracts in La Puente, California. The data for these analyses were collected as part of a population-based study of ocular diseases in adult Latinos in the Los Angeles Latino Eye Study from February 1, 2000, through May 31, 2003. The analysis was performed from November 2010 to February 2011. Additional analyses were performed in June 2014. Main Outcomes and Measures Mean-adjusted HRQoL scores and effect sizes. Results Of the 4876 participants included in the analysis, 4402 (90.3%) had no AMD, and 474 (9.7%) had any AMD, with 453 having early (9.3%) and 21 (0.4%) having late stages of the disease. The mean (SD) age of the cohort was 54.8 (10.7) years. Of the 4876 participants, 2001 (41.0%) were male and 2875 (59.0%) were female. In this cohort of Latinos, participants with AMD had lower vision-specific HRQoL scores. General HRQoL was assessed by the Medical Outcomes Study 12-Item Short-Form Health Survey and self-reported vision-related HRQoL by the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25). Composite NEI-VFQ-25 scores were 59.5 (95% CI, 50.8-68.1) for those with late-stage AMD and 79.4 (95% CI, 72.5-86.1) for those with early-stage AMD, compared with participants without AMD 80.7 (95% CI, 73.9-82.4); P 125 μm in diameter with drusen area ≥196 350 μm 2 ) and depigmentation of retinal pigment epithelium (slope of −19.17 for the NEI-VFQ-25 composite score). Measures of general health, as assessed by the Medical Outcomes Study 12-Item Short-Form Health Survey, were not affected in this cohort. Conclusions and Relevance In this study of adult Latinos, early AMD lesions are associated with lower self-reported, vision-specific HRQoL but not general HRQoL. Severity and bilaterality of AMD are associated with measurably lower HRQoL scores, with the largest difference in scores occurring for individuals with both eyes affected. A concatenated approach to incorporate bilateral severity might be more useful and provide better insight into the association of AMD and HRQoL.

Sex‐Specific Association of Obstructive Sleep Apnea With Retinal Microvascular Signs: The Multi‐Ethnic Study of Atherosclerosis

Abstract: Background Obstructive sleep apnea (OSA) is a common condition affecting more men than women. The relationship of OSA with microvascular disease is unclear, complicated by possible sex difference. Assessment of the relationship of OSA with retinal microvascular signs in men and women may provide insights into such a relationship. Methods and Results We examined the sex‐specific cross‐sectional association of OSA severity with retinal vascular calibers in 1808 participants, and with specific retinopathy signs in 1831 participants from a sample of 2060 participants aged 54 to 93 years who underwent successful polysomnography in the Multi‐Ethnic Study of Atherosclerosis, 2010–2012. OSA severity was defined by the apnea–hypopnea index (events/h) as none (<5), mild (5–14.9), moderate (15–29.9), and severe (≥30). As compared to no OSA, moderate/severe OSA in men was associated with retinal arteriolar narrowing (odds ratio [OR] and 95% CI for the narrowest quartile: 1.65 [1.00–2.71]) and retinal venular widening (1.80 [1.07–3.04] for the widest quartile), but not in women (odds ratio: 1.10 [0.67–1.81] and 0.91 [0.58–1.43], respectively) after adjusting for age, race/ethnicity, body mass index, pack‐years of cigarette smoking, alcohol intake, hypertension duration, diabetes mellitus duration, HbA1c levels, lipid profile, micro‐/macroalbuminuria, estimated glomerular filtration rate, β‐blockers use, antihypertensive therapy, and lipid‐lowering therapy. In contrast, severe OSA was associated with retinal microaneurysms in women, but not in men (odds ratio: 3.22 [1.16–8.97] and 0.59 [0.27–1.30], respectively). Conclusions The associations of OSA severity with retinal microvascular signs may differ by sex. Whether these findings were related to sex differences in OSA exposure needs further investigation.

Association of the Fractal Dimension of Retinal Arteries and Veins with Quantitative Brain MRI Measures in HIV-Infected and Uninfected Women.

Abstract: Objective The fractal dimension of retinal arteries and veins is a measure of the complexity of the vascular tree. We hypothesized that retinal fractal dimension would be associated with brain volume and white matter integrity in HIV-infected women. Design Nested case-control within longitudinal cohort study. Methods Women were recruited from the Brooklyn site of the Women’s Interagency HIV study (WIHS); 34 HIV-infected and 21 HIV-uninfected women with analyzable MRIs and retinal photographs were included. Fractal dimension was determined using the SIVA software program on skeletonized retinal images. The relationship between predictors (retinal vascular measures) and outcomes (quantitative MRI measures) were analyzed with linear regression models. All models included age, intracranial volume, and both arterial and venous fractal dimension. Some models were adjusted for blood pressure, race/ethnicity, and HIV-infection. Results The women were 45.6 ± 7.3 years of age. Higher arterial dimension was associated with larger cortical volumes, but higher venous dimension was associated with smaller cortical volumes. In fully adjusted models, venous dimension was significantly associated with fractional anisotropy (standardized β = -0.41, p = 0.009) and total gray matter volume (β = -0.24, p = 0.03), and arterial dimension with mean diffusivity (β = -0.33,.p = 0.04) and fractional anisotropy (β = 0.34, p = 0.03). HIV-infection was not associated with any retinal or MRI measure. Conclusions Higher venous fractal dimension was associated with smaller cortical volumes and lower fractional anisotropy, whereas higher arterial fractal dimension was associated with the opposite patterns. Longitudinal studies are needed to validate this finding.

Sleep apnea and retinal signs in cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis.

Abstract: The aim of the study was to examine the relationship between sleep apnea, retinal vascular caliber and retinopathy, and their impact on cardiovascular disease (CVD) risk. A multi-ethnic cohort of 5,803 participants was examined based on standardized grading of retinal vascular caliber and retinopathy from digital fundus photographs, self-reported physician-diagnosed sleep apnea (PDSA), and incident cardiovascular events. In women, PDSA was associated with narrower arterioles (regression coefficient [β] −5.76; 95 % confidence Interval [CI] −8.51, −3.02) after adjusting for cardio-metabolic risk factors. The incident rate ratio (IRR) of CVD was also associated with narrower arterioles (IRR for highest versus lowest tertile 1.91; 95 % CI 1.08, 3.38). In men, PDSA was not associated with arteriolar caliber. However, incident CVD was associated with narrower arterioles (IRR 1.67; 95 % CI 1.10, 2.52), wider venules (IRR 1.71; 95 % CI 1.13, 2.59) and PDSA (IRR 2.03, 95 % CI 1.17, 3.51). The IRR of CVD in men with PDSA increased minimally to 2.06 (95 % CI 1.18, 3.56) after adjustment for retinal arteriolar and venular caliber. Combining women and men, the IRR of CVD was 3.41 (95 % CI 1.79, 6.50) in those with both PDSA and narrower retinal arterioles. Sleep apnea was associated with narrower retinal arterioles in women but not in men. However, sleep apnea was also associated with incident CVD in men. These suggest potential gender differences in susceptibility to microvascular disease in association with sleep apnea.

Association of Blood Glucose Control and Lipids With Diabetic Retinopathy in the Veterans Affairs Diabetes Trial (VADT)

Abstract: OBJECTIVE This study examined whether lipids modify the relationship between intensive glucose control (INT) and diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS The incidence and progression of DR were assessed in 858 of 1,791 participants with 7-field stereoscopic fundus photographs at baseline and 5 years later. RESULTS Odds of DR progression were lower by ∼40% in those with baseline total cholesterol (TC) ≥200 mg/dL ( P = 0.007), LDL-C ≥120 mg/dL ( P < 0.02), or HDL-C ≥40 mg/dL ( P < 0.007) in the INT arm versus standard glycemic treatment. Odds of DR progression were reduced by ∼40% in those who had TC ≤140 mg/dL ( P ≤ 0.024), triglycerides (TG) ≤120 mg/dL ( P = 0.004), or HDL-C ≥45 mg/dL ( P = 0.01) at the fifth year. Odds of DR progression were lower by ∼40–50% with reductions of TC by ≥40 mg/dL ( P < 0.0001), of LDL-C of ≥40 mg/dL ( P < 0.004), and of TG by ≥60 mg/dL ( P = 0.004) at the fifth year. Odds of DR progression increased by 80% with increases in TC of ≥20 mg/dL ( P < 0.0001) and by 180% with increases in LDL-C by ≥60 mg/dL ( P < 0.004). After adjusting for covariants, those with higher TC at baseline and lower TC during and at the fifth year and higher HDL-C throughout study had significantly decreased odds of DR progression in INT. CONCLUSIONS INT was associated with decreased odds of progression but not with onset of retinopathy in those with worse lipid levels at baseline and more improved lipid levels during the study. Higher HDL-C was consistently associated with better response to INT throughout the study.

Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent

Abstract: Purpose Ocular refraction is measured in spherical equivalent as the power of the external lens required to focus images on the retina. Myopia (nearsightedness) and hyperopia (farsightedness) are the most common refractive errors, and the leading causes of visual impairment and blindness in the world. The goal of this study is to identify rare and low-frequency variants that influence spherical equivalent.

Sequential Adeno-Associated Viral Vector Serotype 9–Green Fluorescent Protein Gene Transfer Causes Massive Inflammation and Intense Immune Response in Rat Striatum

Abstract: Green fluorescent protein (GFP) is a broadly used live cell reporter for gene transduction although side effects associated with GFP in gene transfer are reported. The present study was designed to systematically examine host responses, including inflammatory and immune responses, induced by persistent overexpression of the GFP gene mediated by adeno-associated viral vector serotype 9 (AAV9), and their effects on GFP gene transduction in rat striatum. Our results show that host responses against AAV9-GFP transduction, and GFP transgene expression in the striatum exhibited a temporal and dose-dependent pattern. Both muscular and striatal delivery of AAV9-GFP increased levels of inflammation and immune reactions against sequential AAV9-GFP transduction in the striatum, leading to reduced levels of GFP expression. We also observed that rat sera from sequential administrations of AAV9-GFP group had significantly higher levels of neutralizing antibody against AAV9 vectors when compared with the age-matched rat...

Prevalence of Age-Related Macular Degeneration in Chinese American Adults: The Chinese American Eye Study

Abstract: Importance Population-based prevalence estimates of age-related macular degeneration (AMD) need to be determined to assess its burden among Chinese Americans, the fastest growing racial group in the United States. Objective To determine the age- and sex- specific prevalence of AMD among Chinese Americans. Design The Chinese American Eye Study (CHES) was conducted in a general urban community of 10 census tracts in Monterey Park, California. A total of 4582 Chinese American adults aged 50 years or older participated in this population-based, cross-sectional study from February 16, 2010, through October 9, 2013, and underwent an interview as well as comprehensive clinical and eye examinations, including detailed retinal photography of both eyes. Fundus photographs were graded for drusen and retinal pigment epithelium abnormalities and were evaluated for AMD. Main Outcomes and Measures The prevalence of early and advanced AMD, drusen, geographic atrophy, and neovascular AMD were determined by using a modified Wisconsin Age-Related Maculopathy Grading Scale (a 6-level scale: 10, no AMD; 60, advanced AMD). Results Of the 4582 participants completing both the home survey and clinical examination, 4172 individuals (91.1%) had at least 1 gradable photograph. A total of 1526 (36.6%) participants were men, and the mean (SD) age was 61.2 (8.8) years. When examined by 10-year age groups, the prevalence of early AMD ranged from 5.8% (n = 119) in participants aged 50 to 59 years to 17.6% (n = 37) in those 80 years or older, retinal pigment epithelium abnormalities from 4.1% (n = 85) to 7.2% (n = 16), large drusen (≥125 µm) from 9.8% to 32.4%, soft drusen from 27.6% (n = 567) to 58.6% (n = 123), and soft indistinct drusen from 3.7% (n = 76) to 15.2% (n = 32). The prevalence of advanced AMD ranged from 0.2% (n = 3) in participants aged 50 to 59 years to 1.0% (n = 2) in those 80 years or older. Of the 14 cases of advanced AMD, 85.7% (95% CI, 57.2%-98.2%; n = 12) were neovascular AMD and 14.3% (95% CI, 2.0%-42.8%; n = 2) were geographic atrophy. Acute macular degeneration was more common in men (10.9% [9.3%-12.5%]; n = 166) than women (5.8% [4.9%-6.7%]; n = 154) in this cohort. Conclusions and Relevance Data from CHES suggest that Chinese Americans have a lower prevalence of early and advanced AMD compared with non-Hispanic white individuals. The prevalence of early AMD, advanced AMD, and large drusen was higher among Chinese Americans in CHES than among the Chinese population living in urban/rural China but lower than that in urban-dwelling Taiwanese.

Body Fat Distribution and Diabetic Retinopathy in People With Type 2 Diabetes

Abstract: Retinopathy is a major complication of diabetes, and although intensive glucose control can reduce its incidence and progression, the effect is limited. Other factors associated with diabetes, such as obesity, may also be relevant. Obesity results in a variety of metabolic disorders that can influence retinopathy and other microvascular complications of diabetes.1 Although diabetes is associated with retinopathy, a populationbased study in Rochester, Minnesota, of patients with type 2 diabetes found that within this cohort, obesity was an independent and modifiable risk factor for developing retinopathy (hazard ratio, 2.01; 95% CI, 1.35-3.13).2 This study differed from others that did not find obesity related to retinopathy by defining obesity by relative weight instead of body mass index (BMI, calculated as weight in kilograms divided by height in meters squared). For example, in the Wisconsin Epidemiologic Study of Diabetic Retinopathy, obesity when defined by BMI criteria was not independently associated with the incidence or progression of retinopathy in persons with type 2 diabetes over a 10-year period.3 Similarly, in the Hoorn Study, no statistically significant association of BMI with the incidence of retinopathy was found in persons with type 2 diabetes.4 Related article at jamaophthalmology.com JAMA OPHTHALMOLOGY