Mary Frances Cotch

Prevalence of Diabetic Retinopathy in the United States, 2005-2008

CONTEXT The prevalence of diabetes in the United States has increased. People with diabetes are at risk for diabetic retinopathy. No recent national population-based estimate of the prevalence and severity of diabetic retinopathy exists. OBJECTIVES To describe the prevalence and risk factors of diabetic retinopathy among US adults with diabetes aged 40 years and older. DESIGN, SETTING, AND PARTICIPANTS Analysis of a cross-sectional, nationally representative sample of the National Health and Nutrition Examination Survey 2005-2008 (N = 1006). Diabetes was defined as a self-report of a previous diagnosis of the disease (excluding gestational diabetes mellitus) or glycated hemoglobin A(1c) of 6.5% or greater. Two fundus photographs were taken of each eye with a digital nonmydriatic camera and were graded using the Airlie House classification scheme and the Early Treatment Diabetic Retinopathy Study severity scale. Prevalence estimates were weighted to represent the civilian, noninstitutionalized US population aged 40 years and older. MAIN OUTCOME MEASUREMENTS Diabetic retinopathy and vision-threatening diabetic retinopathy. RESULTS The estimated prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was 28.5% (95% confidence interval [CI], 24.9%-32.5%) and 4.4% (95% CI, 3.5%-5.7%) among US adults with diabetes, respectively. Diabetic retinopathy was slightly more prevalent among men than women with diabetes (31.6%; 95% CI, 26.8%-36.8%; vs 25.7%; 95% CI, 21.7%-30.1%; P = .04). Non-Hispanic black individuals had a higher crude prevalence than non-Hispanic white individuals of diabetic retinopathy (38.8%; 95% CI, 31.9%-46.1%; vs 26.4%; 95% CI, 21.4%-32.2%; P = .01) and vision-threatening diabetic retinopathy (9.3%; 95% CI, 5.9%-14.4%; vs 3.2%; 95% CI, 2.0%-5.1%; P = .01). Male sex was independently associated with the presence of diabetic retinopathy (odds ratio [OR], 2.07; 95% CI, 1.39-3.10), as well as higher hemoglobin A(1c) level (OR, 1.45; 95% CI, 1.20-1.75), longer duration of diabetes (OR, 1.06 per year duration; 95% CI, 1.03-1.10), insulin use (OR, 3.23; 95% CI, 1.99-5.26), and higher systolic blood pressure (OR, 1.03 per mm Hg; 95% CI, 1.02-1.03). CONCLUSION In a nationally representative sample of US adults with diabetes aged 40 years and older, the prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was high, especially among Non-Hispanic black individuals.

Genetic loci for retinal arteriolar microcirculation

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

Prevalence of refractive error in the United States, 1999-2004

OBJECTIVE To describe the prevalence of refractive error in the United States. METHODS The 1999-2004 National Health and Nutrition Examination Survey (NHANES) used an autorefractor to obtain refractive error data on a nationally representative sample of the US noninstitutionalized, civilian population 12 years and older. Using data from the eye with a greater absolute spherical equivalent (SphEq) value, we defined clinically important refractive error as follows: hyperopia, SphEq value of 3.0 diopters (D) or greater; myopia, SphEq value of -1.0 D or less; and astigmatism, cylinder of 1.0 D or greater in either eye. RESULTS Of 14,213 participants 20 years or older who completed the NHANES, refractive error data were obtained for 12,010 (84.5%). The age-standardized prevalences of hyperopia, myopia, and astigmatism were 3.6% (95% confidence interval [CI], 3.2%-4.0%), 33.1% (95% CI, 31.5%-34.7%), and 36.2% (95% CI, 34.9%-37.5%), respectively. Myopia was more prevalent in women (39.9%) than in men (32.6%) (P < .001) among 20- to 39-year-old participants. Persons 60 years or older were less likely to have myopia and more likely to have hyperopia and/or astigmatism than younger persons. Myopia was more common in non-Hispanic whites (35.2%) than in non-Hispanic blacks (28.6%) or Mexican Americans (25.1%) (P < .001 for both). CONCLUSION Estimates based on the 1999-2004 NHANES vision examination data indicate that clinically important refractive error affects half of the US population 20 years or older.

Vitamin D deficiency in Europe: pandemic?

Background: Vitamin D deficiency has been described as being pandemic, but serum 25-hydroxyvitamin D [25(OH)D] distribution data for the European Union are of very variable quality. The NIH-led international Vitamin D Standardization Program (VDSP) has developed protocols for standardizing existing 25(OH)D values from national health/nutrition surveys. Objective: This study applied VDSP protocols to serum 25(OH)D data from representative childhood/teenage and adult/older adult European populations, representing a sizable geographical footprint, to better quantify the prevalence of vitamin D deficiency in Europe. Design: The VDSP protocols were applied in 14 population studies [reanalysis of subsets of serum 25(OH)D in 11 studies and complete analysis of all samples from 3 studies that had not previously measured it] by using certified liquid chromatography–tandem mass spectrometry on biobanked sera. These data were combined with standardized serum 25(OH)D data from 4 previously standardized studies (for a total n = 55,844). Prevalence estimates of vitamin D deficiency [using various serum 25(OH)D thresholds] were generated on the basis of standardized 25(OH)D data. Results: An overall pooled estimate, irrespective of age group, ethnic mix, and latitude of study populations, showed that 13.0% of the 55,844 European individuals had serum 25(OH)D concentrations <30 nmol/L on average in the year, with 17.7% and 8.3% in those sampled during the extended winter (October–March) and summer (April–November) periods, respectively. According to an alternate suggested definition of vitamin D deficiency (<50 nmol/L), the prevalence was 40.4%. Dark-skinned ethnic subgroups had much higher (3- to 71-fold) prevalence of serum 25(OH)D <30 nmol/L than did white populations. Conclusions: Vitamin D deficiency is evident throughout the European population at prevalence rates that are concerning and that require action from a public health perspective. What direction these strategies take will depend on European policy but should aim to ensure vitamin D intakes that are protective against vitamin D deficiency in the majority of the European population.

Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

Background Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. Methods A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. Results No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, −1.3±0.23 (beta ± standard error), p = 6.6×10−9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r2 ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. Conclusions This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

Relationship of Retinal Vascular Caliber With Diabetes and Retinopathy The Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE—To examine the relationship of retinal vascular caliber with diabetes, glycemia, and diabetic retinopathy. RESEARCH DESIGN AND METHODS—Population-based study using data from the Multi-Ethnic Study of Atherosclerosis (MESA), comprising 5,976 individuals (whites, blacks, Hispanics, and Chinese) residing in six U.S. communities who were free of clinical cardiovascular disease at baseline. Retinal vascular caliber was measured from digital retinal photographs. RESULTS—There were 4,585 individuals with normal fasting glucose (NFG), 499 with impaired fasting glucose (IFG), 165 with diabetes with retinopathy signs, and 727 with diabetes without retinopathy signs. After multivariate analysis, retinal arteriolar caliber increased from 143.8 μm in subjects with NFG to 144.5 μm in IFG and 146.1 μm in diabetes (P < 0.001 for trend). Retinal venular caliber increased from 214.4 μm in NFG to 216.7 μm in IFG and 218.0 μm in diabetes (P < 0.001 for trend). Retinal venular caliber was significantly larger with increasing levels of fasting glucose and A1C. In a subgroup analysis by ethnicity, the association between wider arteriolar caliber and diabetes was evident in whites only, whereas wider venular caliber and diabetes was evident in Hispanics and Chinese only. In people with diabetes, eyes with retinopathy had larger retinal venular but not arteriolar caliber. CONCLUSIONS—Retinal arteriolar and venular calibers are larger in individuals with diabetes, but the pattern of associations appears to vary by ethnicity. Retinal venular caliber is additionally associated with retinopathy signs. These findings add further to the concept that variations in retinal vascular caliber may reflect early diabetic microvascular damage.

Cerebral microbleeds, retinopathy, and dementia The AGES-Reykjavik Study

Objective: To determine whether microvascular damage, indicated by cerebral microbleeds (CMBs) and retinal microvascular signs, is associated with cognitive function and dementia in older persons. Methods: This is a cross-sectional study of 3,906 participants (mean age 76 years; 58% women) in the AGES-Reykjavik Study (2002–2006). We assessed CMBs on MRI and retinal microvascular signs on digital retinal images. Composite Z scores of memory, processing speed, and executive function were derived from a battery of neurocognitive tests. Dementia and subtypes were diagnosed following international criteria. Regression models were used to relate cognitive Z scores and dementia to CMBs and retinal microvascular signs, adjusting for demographics, cardiovascular factors, and brain ischemic lesions. Results: People with multiple (≥2) CMBs had lower Z scores on tests of processing speed (β-coefficient −0.16; 95% confidence interval −0.26 to −0.05) and executive function (−0.14; −0.24 to −0.04); results were strongest for having multiple CMBs located in the deep hemispheric or infratentorial areas. The odds ratio of vascular dementia was 2.32 (95% confidence interval 1.02 to 5.25) for multiple CMBs and 1.95 (1.04 to 3.62) for retinopathy. Having both CMBs and retinopathy, compared to having neither, was significantly associated with markedly slower processing speed (−0.25; −0.37 to −0.12), poorer executive function (−0.19; −0.31 to −0.07), and an increased odds ratio of vascular dementia (3.10; 1.11 to 8.62). Conclusion: Having multiple CMBs or concomitant CMBs and retinopathy is associated with a profile of vascular cognitive impairment. These findings suggest that microvascular damage, as indicated by CMBs and retinopathy lesions, has functional consequences in older men and women living in the community.

Aortic Distensibility and Retinal Arteriolar Narrowing. The Multi-Ethnic Study of Atherosclerosis

Increased aortic stiffness and retinal arteriolar narrowing are subclinical vascular effects of chronic hypertension and predict future cardiovascular events. The relationship between these 2 vascular measures is uncertain and is examined in the Multi-Ethnic Study of Atherosclerosis. This cross-sectional analysis involves 3425 participants (aged 45 to 85 years) free of clinical cardiovascular disease. Retinal vascular caliber was quantified from digital retinal photographs using standardized protocols. Aortic distensibility was determined from chest MRI. After controlling for age, squared age, gender, race, study center, height, weight, heart rate, cigarette smoking, past and current systolic blood pressure, use of antihypertensive medications, diabetes, fasting glucose, lipid profile, and C-reactive protein, reduced aortic distensibility (first versus fourth distensibility quartile) was associated with increased odds of retinal arteriolar narrowing (odds ratio: 1.72; 95% CI: 1.15 to 2.58, comparing lowest to highest quartile of arteriolar caliber). Further adjustments for atherosclerotic measures (carotid intima-media thickness, coronary calcium score, and ankle brachial index) had minimal impact on this association (odds ratio: 1.70; 95% CI: 1.13 to 2.55). Reduced aortic distensibility was not associated with retinal venular caliber. We conclude that increased aortic stiffness is associated with retinal arteriolar narrowing, independent of measured blood pressure levels and vascular risk factors. These data suggest that changes in the microvasculature may play a role linking aortic stiffness with clinical cardiovascular events.

Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo

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.

Traditional and novel cardiovascular risk factors for retinal vein occlusion: the multiethnic study of atherosclerosis.

PURPOSE To describe the prevalence of retinal vein occlusion (RVO) and its association with cardiovascular, inflammatory, and hematologic risk factors in a multiethnic cohort. METHODS This was a population-based, cross-sectional study of 6147 participants (whites, blacks, Hispanics, Chinese) from six U.S. communities. RVO was defined from retinal photographs taken from both eyes according to a standardized protocol. Risk factors were assessed from interviews, examinations, and laboratory and radiologic investigations. RESULTS The prevalence of RVO was 1.1% (0.9% for branch RVO and 0.2% for central RVO) and was similar across different ethnic groups: 0.9% in whites, 1.2% in blacks, 1.2% in Hispanics, and 1.1% in Chinese (P = 0.76). Independent risk factors associated with RVO were hypertension (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.18-3.59), older age (OR, 1.34; 95% CI, 1.00-1.81, per decade increase), less education (OR, 4.08; 95% CI, 2.20-7.54), hypertriglyceridemia (OR, 1.98; 95% CI, 1.10-3.56), renal dysfunction (OR, 1.85; 95% CI, 1.01-3.39), and the presence of retinal arteriovenous nicking (OR, 4.01; 95% CI, 2.06-7.81) and focal arteriolar narrowing (OR, 4.38; 95% CI, 1.44-13.34). RVO was not significantly associated with direct measures of subclinical atherosclerosis (e.g., carotid intima media thickness and coronary artery calcium scores) or markers of inflammation (e.g., C reactive protein, interleukin-6) and endothelial dysfunction (e.g., soluble intercellular adhesion molecule-1) or coagulation (e.g., D-dimer). CONCLUSIONS The prevalence of RVO is similar across different racial/ethnic groups. In the general population, RVO is associated with hypertension, dyslipidemia, and renal dysfunction, but not with atherosclerotic disease, systemic inflammation, and hematologic abnormalities.