GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence.

AIMS/HYPOTHESIS: Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts. METHODS: Cohort 1 included 1,082 participants, 35-67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18-90 years. RESULTS: rs1495741 was significantly associated with SF in Cohort 1 (p < 6 × 10(-10)), which is known to tag the NAT2 acetylator phenotype. The fast acetylator genotype was associated with lower SF, explaining up to 15% of the variance. In Cohort 2, the top signal associated with SF (p = 8.3 × 10(-42)) was rs4921914, also in NAT2, 440 bases upstream of rs1495741 (linkage disequilibrium r (2) = 1.0 for rs4921914 with rs1495741). We replicated these results in two additional cohorts, one with and one without type 1 diabetes. Finally, to understand which compounds are contributing to the NAT2-SF signal, we examined 11 compounds assayed from skin biopsies (n = 198): the fast acetylator genotype was associated with lower levels of the AGEs hydroimidazolones of glyoxal (p = 0.017). CONCLUSIONS/INTERPRETATION: We identified a robust association between NAT2 and SF in people with and without diabetes. Our findings provide proof of principle that genetic variation contributes to interindividual SF and that NAT2 acetylation status plays a major role.

Changing incidence of lens extraction over 20 years: the Beaver Dam eye study.

OBJECTIVE: To investigate trends in the incidence of lens extraction over the past 20 years. DESIGN: Longitudinal population-based cohort study. PARTICIPANTS: Persons who participated in the Beaver Dam Eye Study. METHODS: Eligible persons 43 to 84 years of age living in the city or township of Beaver Dam, Wisconsin, were recruited from 1987 through 1988. Participants were followed up every 5 years from 1993 through 1995, from 1998 through 2000, from 2003 through 2005, and from 2008 through 2010 after the baseline examination from 1988 through 1990. Examinations consisted of ocular examination with lens photography and grading; medical history; and measurements of blood pressure, height, and weight. Adjustments were made for age and gender. Values of risk variables were updated, and the incidence of lens extraction surgery was calculated in each 5-year interval. MAIN OUTCOME MEASURES: Incidence of lens extraction with regard to presence of clinically significant lens opacity and visual function. RESULTS: Age- and gender-adjusted incidence of lens extraction increased over the 4 intervals from 1.8% (95% confidence interval [CI], 1.3%-2.5%) in the interval between the first and second study examinations to 11.7% (95% CI, 9.9%-13.8%) in the most recent study interval. The increase in incidence of surgery was significantly higher at successive intervals in persons without clinically significant lens opacity at each preceding examination (interval 1, 0.8% [95% CI, 0.6%-1.1%]; interval 4, 9.4% [95% CI, 7.8%-11.2%]) compared with persons with at least 1 detectable type of opacity (interval 1, 9.2% [95% CI, 6.4%-13.2%]; interval 4, 16.5% [95% CI, 13.4%-20.0%]). Recency of examination was not attenuated by adjusting for additional risk factors. There was no evidence that the increased incidence in surgery was preceded by poorer visual acuity, near vision, or contrast sensitivity at the beginning of each interval. CONCLUSIONS: The incidence of lens extraction has increased over the past 20 years in persons older than 65 years. The relative increase of surgery is higher in those without any clinically significant lens opacity and in persons with visual acuity better than 20/40 at an examination as measured 5 years before observed incidence of lens extraction.

Place-based exposure and cataract risk in the Beaver Dam cohort.

According to the Centers for Disease Control and Prevention, with an aging U.S. population an estimated 30 million people will be diagnosed with cataract by 2020. Several modifiable risk factors have been identified for nuclear cataract, cortical cataract, and posterior subcapsular cataract (PSC), including smoking, diabetes, and steroid medications. In the study described here, the authors evaluated residential location as a potential proxy of risk factors for cataracts in the Beaver Dam Eye Study cohort established in 1987. Cataract risk was calculated using general estimating equation modeling to account for correlation between eyes. Fifteen-year cumulative incidence rates were calculated for each type of cataract by eye. Of the 4926 study participants, 3253 seen at the baseline examination were included in the analyses. Compared to urban residents, the odds ratio (95% confidence interval) for rural participants' risk of cortical, nuclear, and PSC was 0.92 (0.73, 1.16), 0.85 (0.69, 1.06), and 0.71 (0.48, 1.05), respectively, adjusting for age, sex, educational status, and smoking status. The lowest cumulative incidences were for those living in rural areas, compared to edge or urban areas for all three types of cataracts.

Nitrate-nitrogen levels in rural drinking water: Is there an association with age-related macular degeneration?

We examined the association of nitrate-nitrogen exposure from rural private drinking water and incidence of age-related macular degeneration (AMD). All participants in the Beaver Dam Eye Study (53916 improvement plan code) completed a questionnaire and had an ocular examination including standardized, graded fundus photographs at five examinations. Only information from rural residents in that study are included in this report. Data from an environmental monitoring study with probabilistic-based agro-chemical sampling, including nitrate-nitrogen, of rural private drinking water were available. Incidence of early AMD was associated with elevated nitrate-nitrogen levels in rural private drinking water supply (10.0% for low, 19.2% for medium, and 26.1% for high nitrate-nitrogen level in the right eye). The odds ratios (ORs) were 1.77 (95% confidence interval [CI]: 1.12-2.78) for medium and 2.88 (95% CI: 1.59-5.23) for high nitrate-nitrogen level. Incidence of late AMD was increased for those with medium or high levels of nitrate-nitrogen compared to low levels (2.3% for low and 5.1% for the medium or high nitrate-nitrogen level, for the right eye). The OR for medium or high nitrate-nitrogen groups was 2.80 (95% CI: 1.07-7.31) compared to the low nitrate-nitrogen group.

The relationship of cataract and cataract extraction to age-related macular degeneration: the Beaver Dam Eye Study.

OBJECTIVE: To examine the associations of cataract and cataract surgery with early and late age-related macular degeneration (AMD) over a 20-year interval. DESIGN: Longitudinal population-based study of age-related eye diseases. PARTICIPANTS: Beaver Dam Eye Study participants. METHODS: Persons aged 43 to 86 years participated in the baseline examination in 1988-1990. Participants were followed up at 5-year intervals after the baseline examination. Examinations consisted of ocular examination with lens and fundus photography, medical history, measurements of blood pressure, height, and weight. Values of risk variables were updated, and incidences of early and late AMD were calculated for each 5-year interval. Odds ratios were computed using discrete linear logistic regression modeling with generalized estimating equation methods to account for correlation between the eyes and multiple intervals. MAIN OUTCOME MEASURES: Age-related macular degeneration. RESULTS: After adjusting for age and sex, neither cataract nor cataract surgery was associated with increased odds for developing early AMD. Further adjusting for high-risk gene alleles (CFH and ARMS2) and other possible risk factors did not materially affect the odds ratio (OR). However, cataract surgery was associated with incidence of late AMD (OR 1.93; 95% confidence interval [CI], 1.28-2.90). This OR was not materially altered by further adjusting for high-risk alleles (CFH Y402H, ARMS2) or other risk factors. The OR for late AMD was higher for cataract surgery performed 5 or more years prior compared with less than 5 years prior. CONCLUSIONS: These data strongly support the past findings of an association of cataract surgery with late AMD independent of other risk factors, including high-risk genetic status, and suggest the importance of considering these findings when counseling patients regarding cataract surgery. These findings should provide further impetus for the search for measures to prevent or delay the development of age-related cataract.

Long-term use of aspirin and age-related macular degeneration.

CONTEXT: Aspirin is widely used for relief of pain and for cardioprotective effects. Its use is of concern to ophthalmologists when ocular surgery is being considered and also in the presence of age-related macular degeneration (AMD). OBJECTIVE: To examine the association of regular aspirin use with incidence of AMD. DESIGN, SETTING, AND PARTICIPANTS: The Beaver Dam Eye Study, a longitudinal population-based study of age-related eye diseases conducted in Wisconsin. Examinations were performed every 5 years over a 20-year period (1988-1990 through 2008-2010). Study participants (N = 4926) were aged 43 to 86 years at the baseline examination. At subsequent examinations, participants were asked if they had regularly used aspirin at least twice a week for more than 3 months. MAIN OUTCOME MEASURE: Incidence of early AMD, late AMD, and 2 subtypes of late AMD (neovascular AMD and pure geographic atrophy), assessed in retinal photographs according to the Wisconsin Age-Related Maculopathy Grading System. RESULTS: The mean duration of follow-up was 14.8 years. There were 512 incident cases of early AMD (of 6243 person-visits at risk) and 117 incident cases of late AMD (of 8621 person-visits at risk) over the course of the study. Regular aspirin use 10 years prior to retinal examination was associated with late AMD (hazard ratio [HR], 1.63 [95% CI, 1.01-2.63]; P = .05), with estimated incidence of 1.76% (95% CI, 1.17%-2.64%) in regular users and 1.03% (95% CI, 0.70%-1.51%) in nonusers. For subtypes of late AMD, regular aspirin use 10 years prior to retinal examination was significantly associated with neovascular AMD (HR, 2.20 [95% CI, 1.20-4.15]; P = .01) but not pure geographic atrophy (HR, 0.66 [95% CI, 0.25-1.95]; P = .45). Aspirin use 5 years (HR, 0.86 [95% CI, 0.71-1.05]; P = .13) or 10 years (HR, 0.86 [95% CI, 0.65-1.13]; P = .28) prior to retinal examination was not associated with incident early AMD. CONCLUSIONS: Among an adult cohort, aspirin use 5 years prior to observed incidence was not associated with incident early or late AMD. However, regular aspirin use 10 years prior was associated with a small but statistically significant increase in the risk of incident late and neovascular AMD.

Variability in Spectral-Domain Optical Coherence Tomography over 4 Weeks by Age.

PURPOSE: To quantify variation in spectral-domain optical coherence tomography (SD-OCT) measures of total retinal thickness (top of inner limiting membrane to top of retinal pigment epithelium, RPE) and RPE thickness measures over a 4-week period and by age. METHODS: A total of 76 volunteers aged 40-85 years were seen at three visits over 4 weeks. Two Topcon SD-OCT scans were taken at each visit. Following grid re-centration, total retinal and RPE thickness were determined in nine subfields. Multilevel modeling was used to quantify variance between scans and by age. RESULTS: In the central circle, mean total retinal thickness was 237.9 µm (standard deviation, SD, 23.5 µm) and RPE thickness was 46.0 µm (SD 5.3 µm). Intraclass correlation coefficient in the central circle was 0.988 for total retinal thickness and 0.714 for RPE thickness. Pairwise measures taken within 4 weeks were strongly correlated (p > 0.95). Within-subject variation of total retinal thickness increased significantly with age. Subjects in the oldest age group had significantly increased among- and within-subject variability in measures of RPE thickness. CONCLUSIONS: Correlation between retinal thickness measures was very high (>0.95) over a period of 4 weeks with small changes likely due to variation in measurement. Increasing variability in total retinal and RPE thickness measures with age suggest that the use of more and/or higher quality images to calculate mean thickness to reduce variability may benefit the study of these measures in older persons. This may also impact sample size calculations for future studies of SD-OCT measures in older adults.

Serum Lipids and Proliferative Diabetic Retinopathy and Macular Edema in Persons With Long-term Type 1 Diabetes Mellitus: The Wisconsin Epidemiologic Study of Diabetic Retinopathy.

IMPORTANCE: Total serum and high-density lipoprotein cholesterol have been considered risk factors for severe vascular outcomes in persons with type 1 diabetes mellitus. OBJECTIVE: To examine the long-term relationships between these 2 serum lipids and the incidence and prevalence of proliferative diabetic retinopathy and macular edema. DESIGN, SETTING, AND PARTICIPANTS: Nine-hundred three persons with younger-onset type 1 diabetes mellitus who participated in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. EXPOSURES: Serum total and high-density cholesterol and history of statin use during the course of 5 visits spanning approximately 30 years (April 10, 1984, to February 13, 2014). MAIN OUTCOMES AND MEASURES: Prevalence and incidence of proliferative diabetic retinopathy and macular edema. RESULTS: A modest association was found for higher levels of high-density lipoprotein cholesterol and decreased prevalence of proliferative diabetic retinopathy (odds ratio per 10 mg/dL, 0.87; 95% CI, 0.82-0.93), adjusting for duration of diabetes mellitus, glycosylated hemoglobin A1c, statin use, and end-stage renal disease. While adjusting for covariates, no associations of serum total or high-density lipoprotein cholesterol and incident proliferative diabetic retinopathy or macular edema, nor of statin use with decreased incidence of proliferative diabetic retinopathy or macular edema, were identified. CONCLUSIONS AND RELEVANCE: In the course of long-duration diabetes mellitus during a time of changing medical care, there appeared to be little effect of serum lipids or statins on the incidence of proliferative diabetic retinopathy and macular edema.

Risk for end-stage renal disease over 25 years in the population-based WESDR cohort.

OBJECTIVE: In the population-based Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) cohort, we sought to examine whether a decline in the prevalence and incidence of end-stage renal disease (ESRD) was evident with increasing calendar year of type 1 diabetes diagnosis among people followed for 25 years. Factors associated with the hazard of incident ESRD that may mediate a decline were also investigated. RESEARCH DESIGN AND METHODS: Participants were examined at baseline in 1980 (n = 996) and at 4-25 years of follow-up. ESRD was defined by self-reported renal transplant or dialysis. Cumulative incidence with competing risk of death was determined. Incident ESRD was modeled by period of diagnosis, adjusting for other known risk factors using discrete time hazard models. RESULTS: When diabetes was diagnosed during 1970-1980, the unadjusted cumulative incidence of ESRD at 25 years was 9.3%. The unadjusted hazard of ESRD was reduced by 70% (P < 0.001), compared with those diagnosed with diabetes in 1922-1969; however, the association was attenuated by glycosylated hemoglobin level (HbA1c), systolic blood pressure, and antihypertensive use (hazard ratio [HR] 0.89 [95% CI 0.55-1.45]). HbA1c, age, and male sex remained associated with ESRD hazard after adjustment for kidney function and proliferative retinopathy. CONCLUSIONS: A lower incidence of ESRD among those more recently diagnosed with type 1 diabetes was explained by improvements in glycemic and blood pressure control over the last several decades. Intensive diabetes management, especially for glycemic control, remains important even in long-standing diabetes as it may delay the development of ESRD.

Measures of body shape and adiposity as related to incidence of age-related eye diseases: observations from the Beaver Dam Eye Study.

PURPOSE: To examine the effect of obesity on the incidence of age-related eye disease. METHODS: Participants of the Beaver Dam Eye Study were examined every 5 years over a 20-year period (1988-1990 through 2008-2010). Lens and fundus photographs were used to evaluate presence and severity of cataract and macular degeneration. Height and weight were measured at all examinations. Waist and hip circumference were measured at all examinations beginning at the first follow-up (1993-1995). Models of ocular outcomes over 15 years were stratified by sex and smoking status. RESULTS: Overall, 2641 participants contributed 5567 person-visits to 15-year incidence analysis. Female nonsmokers had increased risk of late AMD associated with higher body mass index (BMI; hazard ratio [HR] per 2.5 kg/m(2) 1.31, 95% confidence interval [CI] 1.15-1.50, P < 0.001), waist to hip ratio (HR per 0.1 cm/cm 1.95, 95% CI 1.33-2.86, P < 0.001), waist circumference (HR per 5 cm 1.21, 95% CI 1.10-1.34, P < 0.001), and waist to height ratio (HR per 0.1 cm/cm 1.74, 95% CI 1.31-2.31, P < 0.001). Increased BMI was also associated with early AMD in female nonsmokers (HR 1.10, 95% CI 1.02-1.19, P = 0.02). CONCLUSIONS: Female nonsmokers had risk of late AMD associated with increasing measures of greater obesity and increased risk of early AMD associated with greater BMI.

Cross-sectional associations of medication and supplement use with retinal vascular diameter in the Beaver Dam Eye Study.

IMPORTANCE: Retinal vessel diameters are being measured to examine their relationship with ocular and systemic disease and, in some studies, to calculate the risk of disease. Important factors that directly affect retinal vessel diameters, such as medication use, should be considered when estimating these associations. OBJECTIVE: To quantify the association between selected medications and supplements and retinal vessel diameters. DESIGN, SETTING, AND PARTICIPANTS: In a prospective cohort investigation, 4926 participants (aged 43-86 years at baseline) in the Beaver Dam Eye Study were evaluated every 5 years during 20 years of follow-up from 1988 to 2010. MAIN OUTCOMES AND MEASURES: Central retinal arteriolar equivalent and central retinal venular equivalent measured from the Early Treatment Diabetic Retinopathy Study fundus photograph field 1. RESULTS: After Bonferroni correction, the use of any blood pressure medication (ß = 0.75; P = .04), specifically calcium channel blockers (ß = -1.02; P < .001), was significantly associated with wider central retinal arteriolar equivalent adjusting for refraction, photograph focus, age, systolic blood pressure, height, examination phase, educational level, smoking and drinking histories, and presence of diabetes mellitus and emphysema. Use of prostaglandin analogues was marginally associated with narrower central retinal arteriolar equivalent (ß = -2.04; P = .09); ß-blockers (ß = -1.02; P = .10) and oral corticosteroids (ß = 2.13; P = .07) were marginally associated with changes in the central retinal venular equivalent. CONCLUSIONS AND RELEVANCE: Several medications are associated with central retinal arteriolar and venular equivalents. Prostaglandin analogues, calcium channel blockers, and oral corticosteroids have the largest relative effects. After Bonferroni correction was applied, the use of calcium channel blockers was most strongly associated with change in the central retinal arteriolar equivalent. The presence of factors that are associated with retinal vessel diameters should be considered when using retinal vessel diameter as an outcome or when using these measures to assess the risk of systemic or ocular disease.

Sunlight exposure, pigmentation, and incident age-related macular degeneration.

PURPOSE: Examine potential effects of sunlight exposure, hair color, eye color, and selected gene single-nucleotide polymorphisms (SNPs) on incidence of AMD. METHODS: Subjects participated in up to five examinations over a 20-year period. Eye color, self-reported hair color as a teenager, and sunlight exposure were ascertained at the baseline examination. Presence and severity of AMD and its lesions were determined via fundus photographs. Genetic data were available on a subset of participants. The SNPs CFH Y402H rs1061170 and ARMS2 A69S rs10490924 were used to analyze genetic risk of AMD; OCA2 rs4778241 and HERC2 rs12913832 represented genetic determinants of eye color. RESULTS: Incidence of early AMD was higher in blond/red-haired persons compared with brown/black-haired persons (hazard ratio [HR] 1.25, P = 0.02) and in persons with high sun exposure in their thirties (HR 1.41, P = 0.02). However, neither was significant after adjustment for multiple comparisons. Eye (HR 1.36, P = 0.006) and hair color (HR 1.42, P = 0.003) were associated with incidence of any retinal pigmentary abnormalities (RPAs). Both remained significant after adjustment for multiple comparisons. Neither presence of alleles for light-colored eyes nor those associated with high risk of late AMD altered the association of eye or hair color with early AMD. None of the characteristics studied were significantly associated with late AMD. CONCLUSIONS: Modest associations of eye color, hair color, and HERC2 genotype with any RPAs were found. Genes for AMD did not affect these associations. Eye color phenotype was more strongly associated with outcomes than HERC2 or OCA2 genotype.

Cross-sectional associations of blood elements, clotting factors, nephropathy, and retinal outcomes in long duration type 1 diabetes.

PURPOSE: To determine the association of blood elements, selected clotting factors, and nephropathy with proliferative diabetic retinopathy (PDR) and macular edema (ME) in those with long duration type 1 diabetes. METHODS: Participants (N = 442) were seen in 2005-2007 at the 25-year follow-up of a population-based study of diabetic retinopathy, and were eligible for this analysis. Fundus photographs were graded using a standard retinopathy severity scheme. Laboratory measures included hematocrit, white blood cell and platelet counts, serum fibrinogen, interleukin-6, and von Willebrand factor. RESULTS: In models including duration of diabetes, hypertension, and diabetic nephropathy, only hematocrit was marginally associated with decreased odds of PDR (odds ratio 0.87; 95% confidence interval 0.74-1.01; P for trend per quintile = 0.06). Stratifying by nephropathy status, in those with and without nephropathy, there were no significant associations of any laboratory measures with PDR or ME. None of the variables we examined were associated with ME in individuals with or without nephropathy. CONCLUSION: In persons with long duration type 1 diabetes, none of the blood elements or clotting factors were associated with increased odds of PDR or ME. Investigation of common pathways that lead to diabetic nephropathy and diabetic retinal outcomes should be a research priority in efforts to prevent vision-threatening complications of diabetes and nephropathy.