Vitamin D Status and Prevalent Early Age-Related Macular Degeneration in African Americans and Caucasians: The Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVES: Vitamin D status has been hypothesized to protect against development of early age-related macular degeneration (AMD) via its anti-inflammatory properties and its possible beneficial influence on blood pressure control. We investigated the association between vitamin D status and prevalent early AMD in a community-based cohort. DESIGN: This was a cross-sectional study. SETTING: This was a secondary data analysis of already existing data from the Atherosclerosis Risk in Communities Study (ARIC) cohort collected from 1990 to 1995. PARTICIPANTS: There were 9,734 (7,779 Caucasians, 1,955 African American) ARIC participants (aged 46 to 70 at visit 2 [1990-1992]) with 25(OH)D data available at visit 2, AMD assessment at visit 3 (1993-1995), and complete covariate data. MEASUREMENTS: Vitamin D status was assessed with serum 25-hydroxyvitamin D (25(OH)D) concentrations from bloods drawn at visit 2. Prevalent, early AMD (n=511) was assessed at visit 3 (1993-95) with nonmydriatic retinal photographs of one randomly chosen eye. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for early AMD by categories of 25(OH)D in nmol/L (deficient <30, inadequate 30-<50, and two categories of adequate status: 50-<75 and ≥75). Linear trend was estimated using continuous 25(OH)D concentrations. ORs were adjusted for age, race, and smoking status. We further adjusted for hypertension status to examine if vitamin D status influenced early AMD via its effects on blood pressure. Exploratory analyses of effect modification by age, sex, race and high risk genotypes [Y402H complement factor H (CFH) rs1061170 and the A69S age-related maculopathy susceptibility 2 (ARMS2) rs10490924 polymorphisms] were conducted. RESULTS: The prevalence of early AMD was 5%, and 5% of participants were vitamin D deficient. The adjusted OR (95% CIs) for early AMD among those with adequate (≥75 nmol/L) compared to deficient (<30 nmol/L) vitamin D status was 0.94 (0.59-1.50), p-trend=0.86. Further adjustment for hypertension status did not influence results (OR [95% CI]=0.95 [0.59-1.52], p-trend=0.84). Results did not vary significantly by age, race, sex, early AMD subtype (soft drusen or retinal pigment epithelium depigmentation), or ARMS2 genotype. Results did not vary significantly by CFH genotype in African Americans. The p for multiplicative interaction between 25(OH)D and CFH genotype was 0.06 in Caucasians, but OR [95% CIs] for AMD by vitamin D status were similar in each CFH genotype and not statistically significant. CONCLUSIONS: Vitamin D status was not associated with early AMD in this cohort sample.

Genome-wide association identifies SKIV2L and MYRIP as protective factors for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. We conducted a genome-wide association study in a series of families enriched for AMD and completed a meta-analysis of this new data with results from reanalysis of an existing study of a late-stage case-control cohort. We tested the top findings for replication in 1896 cases and 1866 controls and identified two novel genetic protective factors for AMD. In addition to the complement factor H (CFH) (P=2.3 × 10⁻64) and age-related maculopathy susceptibility 2 (ARMS2) (P=1.2 × 10⁻6°) loci, we observed a protective effect at rs429608, an intronic SNP in SKIV2L (P=5.3 × 10⁻¹5), a gene near the complement component 2 (C2)/complement factor B (BF) locus, that indicates the protective effect may be mediated by variants other than the C2/BF variants previously studied. Haplotype analysis at this locus identified three protective haplotypes defined by the rs429608 protective allele. We also identified a new potentially protective effect at rs2679798 in MYRIP (P=2.9 × 10⁻4), a gene involved in retinal pigment epithelium melanosome trafficking. Interestingly, MYRIP was initially identified in the family-based scan and was confirmed in the case-control set. From these efforts, we report the identification of two novel protective factors for AMD and confirm the previously known associations at CFH, ARMS2 and C3.

The relationship of retinal vessel diameter to changes in diabetic nephropathy structural variables in patients with type 1 diabetes.

AIMS/HYPOTHESIS: We examined whether retinal vessel diameter in persons with type 1 diabetes mellitus is associated with changes in subclinical anatomical and functional indicators of diabetic nephropathy. METHODS: Persons with type 1 diabetes mellitus had gradable fundus photographs and renal biopsy data at baseline and 5-year follow-up (n = 234). Retinal arteriolar and venular diameters were measured at baseline and follow-up. Central retinal arteriole equivalent (CRAE) and central retinal venule equivalent (CRVE) were computed. Baseline and 5-year follow-up renal structural variables were assessed by masked electron microscopic morphometric analyses from percutaneous renal biopsy specimens. Variables assessed included: mesangial fractional volume, glomerular basement membrane width, mesangial matrix fractional volume and glomerular basement membrane width composite glomerulopathy index. RESULTS: While controlling for other covariates, baseline CRAE was positively associated with change in the glomerulopathy index over the 5-year period. Change in CRAE was inversely related to a change in mesangial matrix fractional volume and abnormal mesangial matrix fractional volume, while change in CRVE was directly related to change in the volume fraction of cortex that was interstitium [Vv((Int/cortex))] over the 5-year period. Baseline CRAE or CRVE or changes in these diameters were not related to changes in other anatomical or functional renal endpoints. CONCLUSIONS/INTERPRETATION: Independently of other factors, baseline CRAE correlated with changes in glomerulopathy index, a composite measure of extracellular matrix accumulation in the mesangium and glomerular basement membrane. A narrowing of the CRAE was related to mesangial matrix accumulation. Changes in CRVE were related to changes in Vv((Int/cortex),) a measure of interstitial expansion in persons with type 1 diabetes mellitus.

Measuring taste impairment in epidemiologic studies: the Beaver Dam Offspring Study.

Taste or gustatory function may play an important role in determining diet and nutritional status and therefore indirectly impact health. Yet there have been few attempts to study the spectrum of taste function and dysfunction in human populations. Epidemiologic studies are needed to understand the impact of taste function and dysfunction on public health, to identify modifiable risk factors, and to develop and test strategies to prevent clinically significant dysfunction. However, measuring taste function in epidemiologic studies is challenging and requires repeatable, efficient methods that can measure change over time. Insights gained from translating laboratory-based methods to a population-based study, the Beaver Dam Offspring Study (BOSS) will be shared. In this study, a generalized labeled magnitude scale (gLMS) method was used to measure taste intensity of filter paper disks saturated with salt, sucrose, citric acid, quinine, or 6-n-propylthiouracil, and a gLMS measure of taste preferences was administered. In addition, a portable, inexpensive camera system to capture digital images of fungiform papillae and a masked grading system to measure the density of fungiform papillae were developed. Adult children of participants in the population-based Epidemiology of Hearing Loss Study in Beaver Dam, Wisconsin, are eligible for this ongoing study. The parents were residents of Beaver Dam and 43-84 years of age in 1987-1988; offspring ranged in age from 21-84 years in 2005-2008. Methods will be described in detail and preliminary results about the distributions of taste function in the BOSS cohort will be presented.

Test-retest reliability of the San Diego Odor Identification Test and comparison with the brief smell identification test.

This study described the San Diego Odor Identification Test (SDOIT) reliability and compared the SDOIT and the Brief Smell Identification Test (B-SIT). Ninety participants aged 50-70 years completed this 2-visit olfaction study. During visit 1, the SDOIT and B-SIT were administered according to standard protocols. Three weeks later, participants returned to retake the SDOIT. The SDOIT score was the total number of odorants correctly identified out of 8 odorants presented, and olfactory impairment was defined as correctly identifying less than 6 odorants. The B-SIT score was the total number of odorants correctly identified out of 12 odorants presented, and participants correctly identifying less than 9 odorants were categorized as abnormal. The SDOIT reliability was high (concordance correlation coefficient = 0.85, 95% confidence interval [CI] = 0.79-0.91). The same score was obtained on retest for 73% of participants, whereas 18% improved, and 9% declined. Test-retest agreement was 96% for the SDOIT; 4% improved from impaired at visit 1 to unimpaired at visit 2. Overall, SDOIT impairment classification and B-SIT abnormal classification agreed in 96% of participants (kappa = 0.81, 95% CI = 0.63-0.99). In conclusion, the SDOIT showed good test-retest reliability. Agreement for impaired/abnormal olfaction was demonstrated for the SDOIT and the B-SIT.

Hypertension genes and retinal vascular calibre: the Cardiovascular Health Study.

We examined the associations of single nucleotide polymorphisms (SNPs) in three candidate hypertension genes, alpha-adducin (ADD1/G460W), beta2-adrenergic receptor (ADRB2/Arg16Gly and Gln27Glu) and G-protein beta3 subunit (GNB3/C825T), with retinal arteriolar calibre (an intermediate marker of chronic hypertension) and venular calibre. Data in 1842 participants (1554 whites and 288 African Americans) aged 69-96 years from the Cardiovascular Health Study with genotype and retinal vascular calibre data were included. A computer-assisted method was used to measure retinal vascular calibre. We analysed four SNPs and multilocus interaction for three genes. All SNPs were in Hardy-Weinberg equilibrium in whites and African Americans. The study had sufficient power to detect 0.5% of the total variance of retinal vascular calibre contributed by each SNP in the total population, except for the GNB3 gene variant. No significant associations between these SNPs in the genes studied and mean retinal arteriolar and venular calibre were found in single-gene or multilocus analysis (for example, age-, gender-, race-adjusted mean retinal arteriolar calibre was similar between participants who were ADD1/460W homozygotes and ADD1/G allele carriers, 166.2 vs 167.7 microm). In conclusion, this study found no evidence of an association of SNPs in candidate hypertension genes studied here with retinal vascular calibre.

Association between glycosylated hemoglobin level and 16-year incidence of chronic kidney disease in type 1 diabetes.

CONTEXT: The incidence of recently defined outcome of chronic kidney disease (CKD) has not been widely reported in type 1 diabetes. OBJECTIVE: To examine the prospective association between baseline glycosylated hemoglobin levels and the 16-year incidence of CKD and end-stage renal disease (ESRD) in type 1 diabetes. DESIGN: Prospective cohort study of type 1 diabetes individuals. SETTING: Community based in southwestern Wisconsin. PARTICIPANTS: 547 younger-onset type 1 diabetes individuals who were free of CKD at baseline (1984-86). MAIN OUTCOME MEASURES: Development of CKD (defined as estimated glomerular filtration rate<60 ml/min/1.73 m(2) or ESRD [history of dialysis or renal transplantation]) over 16-year follow-up period, among individuals free of CKD at baseline. Alternate outcome was 16-year incident ESRD. RESULTS: After 16 years of follow-up, there were 158 cases of CKD and 37 cases of ESRD in our cohort. The 16-year cumulative incidence of CKD was 31.7 percent. Elevated glycosylated hemoglobin levels were associated with incident CKD and ESRD in separate models. Multivariable odds ratio (OR) [95% confidence intervals (CI)] comparing the highest quartile of glycosylated hemoglobin (11-15.3%) to the lowest quartile (6-8.6%) was 6.44 (3.61-11.51), p-trend<0.0001 for incident CKD and 21.87 (2.84-168.39), p-trend<0.0001 for ESRD. CONCLUSIONS: Higher baseline glycosylated hemoglobin levels are independently associated with incident CKD and ESRD, among individuals with type 1 diabetes.

Physical activity and the 15-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study.

BACKGROUND: Cardiovascular disease and age-related macular degeneration (AMD) may share common risk factors. Physical activity improves the cardiovascular risk profile; however, there have been few studies investigating a relationship between physical activity and the long-term incidence of AMD. METHODS: The 15-year cumulative incidence of AMD was determined through four examination phases at 5-year intervals of a population-based study conducted in Beaver Dam, Wisconsin, USA, initiated in 1988-90 (n = 3874 men and women between ages 43 and 86 years). Early AMD (pigment abnormalities or soft indistinct drusen), exudative AMD and geographic atrophy were determined by grading stereoscopic colour fundus photographs. Measures of physical activity were obtained through a questionnaire administered at the baseline examination. RESULTS: After controlling for age, sex, history of arthritis, systolic blood pressure, body mass index, smoking and education, people with an active lifestyle (defined as regular activity > or =3 times/week) at baseline were less likely to develop exudative AMD (odds ratio (OR) 0.3, 95% confidence interval (CI) 0.1 to 0.7) compared with people without an active lifestyle. After multivariate adjustment, increased categories of number of blocks walked per day decreased the risk of exudative AMD (OR 0.7, 95% CI 0.6 to 0.97). Physical activity was not related to the incidence of early AMD or pure geographic atrophy. CONCLUSIONS: These data show a protective effect of physical activity for incident exudative AMD, independent of body mass index and other confounders. They also suggest a possible modifiable behaviour that might be protective against developing AMD.

The association between serum uric acid level and long-term incidence of hypertension: Population-based cohort study.

Increasing experimental evidence, including recently developed animal models support a causal role for uric acid in the development of hypertension. However, it is not clear whether serum uric acid levels are independently associated with the long-term incidence of hypertension. We examined the association between serum uric acid levels and 10-year incidence of hypertension in a population-based cohort study based in Beaver Dam city and township, Wisconsin, US. We studied 2520 hypertension-free individuals (56.3% women, age: 43-84 years, 98% Caucasian) at the baseline examination (1988-1990). The main outcome of interest was hypertension (systolic blood pressure (BP) of 140 mm Hg or higher, diastolic BP 90 mm Hg or higher, or combination of self-reported high BP diagnosis and use of antihypertensive medications) incidence over 10 years among baseline normotensive individuals. Nine hundred and fifty-six individuals developed hypertension over a 10-year follow-up period. The relative risk (RR) (95% confidence intervals (CI)) of incident hypertension increased in a dose-dependent manner (P-trend < 0.05 in all models) with increasing uric acid quartiles. Multivariable RR (95% CI) comparing the highest quartile of serum uric acid (> or =390 micromol/l) to the lowest quartile (< or =260 micromol/l) was 1.65 (1.41-1.93). This association persisted in subgroup analyses by categories of smoking, alcohol intake, body mass index, baseline blood pressure and estimated glomerular filtration rate (GFR). In conclusion, increasing quartiles of serum uric acid was associated with 10-year incidence of hypertension independent of smoking, alcohol intake and baseline kidney function suggesting an independent positive association between serum uric acid levels and hypertension development among community-dwelling older adults.

The use of hearing protection devices by older adults during recreational noise exposure.

A population-based study to assess the use of hearing protection devices by older adults during noisy recreational activities was performed. The population-based Epidemiology of Hearing Loss Study was designed to measure the prevalence of hearing loss in adults residing in Beaver Dam, Wisconsin. The use of hearing protection devices during noisy recreational activities was assessed by performing three examinations over a period of 10 years (1993-1995, no. of participants (n)=3753, aged 48-92 years; 1998-2000, n=2800, aged 53-97 years; 2003-2005, n=2395, aged 58-100 years). The recreational activities included hunting, target shooting, woodworking/carpentry, metalworking, driving loud recreational vehicles, and performing yard work using either power tools or a chain saw. The prevalence of using hearing protection devices during any of these activities increased with time (9.5%, 15.0%, and 19.9% at baseline, 5 years, and 10 years, respectively). However, the use of hearing protection devices remained low for most activities. Those under the age of 65 were twice as likely to use hearing protection devices during noisy activities than were older adults. Men, those with a hearing handicap, and those with significant tinnitus were more likely to use hearing protection devices. Smokers and the less educated were less likely to use hearing protection devices. The results demonstrated that many adults expose themselves to potentially damaging recreational noise, leaving them at risk for hearing loss.

Intraocular pressure and systemic blood pressure: longitudinal perspective: the Beaver Dam Eye Study.

AIM: To investigate the relation between change in systemic blood pressures and change in intraocular pressure. METHODS: This was a population based study of people 43-86 years old living in Beaver Dam, Wisconsin. Measurements at baseline (1988-90) and 5 year follow up of systemic blood pressures, intraocular pressures, and history of use of blood pressure medications. RESULTS: Intraocular pressures were significantly correlated with systolic and diastolic blood pressures at both baseline and follow up. There were significant direct correlations between changes in systemic blood pressures and changes in intraocular pressure. There was a 0.21 (95% CI: 0.16 to 0.27) mm Hg increase in IOP for a 10 mm Hg increase in systolic and 0.43 (0.35 to 0.52) mm Hg increase in IOP for a 10 mm Hg increase in diastolic blood pressure. Further adjustment for diabetes and medication use did not alter these associations. Decreased systolic or diastolic blood pressures of more than 10 mm Hg over 5 years were significantly associated with decreased IOP. CONCLUSIONS: Reduced systemic blood pressure is associated with reduced intraocular pressure. This finding should be evaluated in other studies, especially with respect to the possibility of resultant decreased risk of open angle glaucoma.

Variation associated with measurement of retinal vessel diameters at different points in the pulse cycle.

BACKGROUND/AIMS: To assess the variability in retinal vessel measurements at different points in the pulse cycle. METHODS: A healthy white male aged 19 years had 30 digitised images taken at three distinct points in the pulse cycle over a one hour period. A pulse synchronised ear clip trigger device was used to capture images at the desired point in the pulse cycle. Two trained graders measured the retinal vessel diameter of one large arteriole, one large venule, one small arteriole, and one small venule 10 times in each of these 30 images. RESULTS: Within an image, variability was similar between graders, pulse point, and vessel type. Across images taken at the same point in the pulse period, the change from the minimum to maximum measurement was between 6% and 17% for arterioles and between 2% and 11% for venules. In addition, measurements of small vessels had greater changes than large vessels and no point in the pulse period was more variable than another. Ignoring pulse cycle increased variability across images in the large venule, but not in the other vessel types. Mixed effect models were fit for each of the vessel types to determine the greatest source of variability. Controlling for pulse point and grader, the largest source of variability for all four vessels measured was across images, accounting for more than 50% of the total variability. CONCLUSION: Measurements of large retinal venules is generally less variable than measurements of other retinal vessels. After controlling for pulse point and grader, the largest source of variation is across images. Understanding the components of variability in measuring retinal vessels is important as these techniques are applied in epidemiological studies.

Retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middle-aged people.

OBJECTIVE: To examine the relation of retinal microvascular abnormalities and MRI signs of cerebral atrophy in healthy middle-aged people. METHODS: A population-based, cross-sectional study involved 1,684 persons aged 51 to 72 years who had cerebral MRI and retinal photography in 1993 to 1995. Sulcal and ventricular size were quantified from the MRI scans and coded as grades 0 to 9, with sulcal widening (SW) and ventricular enlargement (VE) defined as grades 3 or higher. The presence or absence of retinopathy, microaneurysms, hemorrhages, and other characteristics were defined from retinal photographs using a standardized protocol. Generalized arteriolar narrowing was defined from a computer-assisted measurement of arteriolar diameters from digitized photographs. RESULTS: Persons with retinopathy had higher sulcal (p = 0.001) and ventricular (p = 0.03) grades than persons without retinopathy. After adjusting for age, gender, race, mean arterial blood pressure, diabetes, cigarette smoking, common carotid artery intima-media thickness, and other vascular risk factors, retinopathy was significantly associated with SW (odds ratio [OR], 1.9; 95% CI, 1.2, 3.0) and VE (OR, 1.5; 95% CI, 1.0, 2.3). These associations persisted even in people without diabetes or hypertension (OR 1.9, 95% CI, 0.8, 4.4 for SW; OR 2.7, 95% CI, 1.2, 6.5 for VE). Other retinal arteriolar characteristics (arteriovenous nicking, focal and generalized arteriolar narrowing) were not related to sulcal or ventricular grade. CONCLUSIONS: In healthy, middle-aged people, retinopathy is independently associated with sulcal and ventricular enlargement on MRI. This finding is compatible with the hypothesis that microvascular characteristics may influence the development of cerebral atrophic changes.

Associations of selected medications and visual function: the Beaver Dam Eye Study.

AIM: To investigate association of drug use and visual function. METHODS: A cross sectional population based study was carried out on participants in the 1993-5 examination phase of the Beaver Dam Eye Study. All drugs in current use by study participants were recorded. Performance based and self assessed visual functions were obtained at the time of the study evaluation. The main outcome measure was the relation of levels of visual functions by use of specific drugs. RESULTS: Many classes of drugs were associated with decreases in at least two performance based visual functions. For example, high blood pressure drugs were significantly associated with poorer best corrected visual acuity, poorer near vision, and poorer contrast sensitivity (p<0.001 for all). Patterns of association for self assessed visual functions were not as strong. However, use of glaucoma drops and benzodiazepines were associated with poorer self assessed visual functions in most circumstances cited. CONCLUSIONS: Many commonly used medications are inversely associated with visual functions in a middle and older aged population. This may influence the ability to perform complex tasks and quality of life.

Relation of ocular trauma to cortical, nuclear, and posterior subcapsular cataracts: the Beaver Dam Eye Study.

BACKGROUND: The consequences of minor ocular trauma in the general population are unclear. The relation of self reported ocular trauma to cortical, nuclear, and posterior subcapsular cataracts is described in a defined population. METHODS: Population based, cross sectional study involving all people aged 43 to 86 years, living in Beaver Dam, Wisconsin (n=4926). Ocular trauma was ascertained by interview and cataract was graded from lens photographs. The relation of ocular trauma to cortical, nuclear, and posterior subcapsular cataracts was examined. RESULTS: People with a history of ocular trauma were more likely to have cortical (odds ratio (OR): 1.5; 95% confidence interval (CI): 1.0 to 2.2) and posterior subcapsular (OR: 1.7; 95% CI: 1.0 to 3.1) cataracts, compared to people without a history of trauma. These associations were stronger for people with previous trauma caused by a blunt object (OR: 3.3; 95% CI: 1.6 to 6.9 for cortical cataract, and OR: 4.1; 95% CI: 1.5 to 10.8 for posterior subcapsular cataracts). However, in analyses comparing the frequencies of cataract between traumatised and non-traumatised eyes among people with unilateral ocular trauma, the ocular trauma association for cortical cataract was no longer present, although the association for posterior subcapsular cataract persisted (OR: 2.4; 95% CI: 0.8 to 7.8). CONCLUSION: The data provide evidence of a possible association between self reported ocular trauma and posterior subcapsular cataract.