Age-Related Macular Degeneration and the Incidence of Cardiovascular Disease: A Systematic Review and Meta-Analysis

Importance Research has indicated some shared pathogenic mechanisms between age-related macular degeneration (AMD) and cardiovascular disease (CVD). However, results from prior epidemiologic studies have been inconsistent as to whether AMD is predictive of future CVD risk. Objective: To systematically review population-based cohort studies of the association between AMD and risk of total CVD and CVD subtypes, coronary heart disease (CHD) and stroke. Data Sources A systematic search of the PubMed and EMBASE databases and reference lists of key retrieved articles up to December 20, 2012 without language restriction. Data Extraction Two reviewers independently extracted data on baseline AMD status, risk estimates of CVD and methods used to assess AMD and CVD. We pooled relative risks using random or fixed effects models as appropriate. Results: Thirteen cohort studies (8 prospective and 5 retrospective studies) with a total of 1,593,390 participants with 155,500 CVD events (92,039 stroke and 62,737 CHD) were included in this meta-analysis. Among all studies, early AMD was associated with a 15% (95% CI, 1.08–1.22) increased risk of total CVD. The relative risk was similar but not significant for late AMD (RR, 1.17; 95% CI, 0.98–1.40). In analyses restricted to the subset of prospective studies, the risk associated with early AMD did not appreciably change; however, there was a marked 66% (95% CI, 1.31–2.10) increased risk of CVD among those with late AMD. Conclusion: Whereas the results from all cohort studies suggest that both early and late AMD are predictive of a small increase in risk of future CVD, subgroup analyses limited to prospective studies demonstrate a markedly increased risk of CVD among people with late AMD. Retrospective studies using healthcare databases may have inherent methodological limitations that obscure such association. Additional prospective studies are needed to further elucidate the associations between AMD and specific CVD outcomes

Impact of Dry Eye Syndrome on Vision-Related Quality of Life

Purpose To evaluate the impact of dry eye syndrome (DES) on vision-associated quality of life. Design Cross-sectional study. Methods We identified 450 participants in the Women’s Health Study (WHS) and 240 participants in the Physicians’ Health Study (PHS) and sent a supplementary questionnaire asking how much their everyday activities were limited by symptoms of dry eye and to what degree problems with their eyes limited them in reading, driving, working at the computer, their professional activity, and watching TV. By design, one-third of study subjects had clinically diagnosed DES or severe symptoms and two-thirds did not. We used logistic regression to examine relationships of DES with reported problems with everyday activities in each cohort and pooled estimates using meta-analysis methods. Results Of the participants invited, 85% completed the supplementary questionnaire, including 135 WHS and 55 PHS participants with DES, and 250 WHS and 149 PHS participants without DES. Controlling for age, diabetes, hypertension and other factors, those with DES were more likely to report problems with reading (OR=3.64, 95% CI 2.45–5.40, P< 0.0001); carrying out professional work (OR=3.49, 95% CI 1.72–7.09, P= 0.001); using a computer (OR=3.37, 95% CI 2.11–5.38, P< 0.0001); TV watching (OR=2.84, 95% CI 1.05–7.74, P=0.04); driving during the day (OR=2.80, 95% CI 1.58–4.96, P< 0.0001); and driving at night (OR=2.20, 95% CI 1.48–3.28, P<0.0001). Conclusions DES is associated with a measurable adverse impact on several common and important tasks of daily living, further implicating this condition as an important public health problem deserving increased attention and resources

Patient Reported Differences in Dry Eye Disease between Men and Women: Impact, Management, and Patient Satisfaction

Purpose Dry eye disease affects women twice as often as men, but there is little information on whether dry eye treatments, treatment satisfaction, or the impact of dry eye disease on patients’ lives and vision might differ by sex. Design: Questionnaire survey of 4000 participants in the Women’s Health Study and the Physicians’ Health Studies I and II with a prior report of a diagnosis of DED. Methods: Among participants who re-confirmed a diagnosis of dry eye disease, we assessed symptoms, treatments, patient satisfaction and impact of dry eye disease, and analyzed differences between men and women using regression models. Results: The final study population consisted of 1,518 women (mean age 70.7 years) and 581 men (mean age 76.7 years), with a mean reported duration of dry eye disease of 10.5 years and 10.1 years, respectively. The frequency and severity of dry eye disease symptoms were higher among women (each P<0.0001), and women reported a greater impact on everyday activities (P<0.0001). Women were more likely to use artificial tears (P<0.0001) use them more often (P<0.0001), and to use Restasis® (P<0.0001), omega-3 fatty acids (P=0.0006), and have punctal occlusion (P=0.005). Women spent more money per month on dry eye treatments (P<0.0001), but reported greater dissatisfaction with treatment side effects (P=0.001), and the amount of time before treatments started working (P=0.03). Conclusions: These data show that dry eye disease is generally experienced as being more severe among women, having a greater impact on their self-assessed well-being

Is Household Air Pollution a Risk Factor for Eye Disease?

In developing countries, household air pollution (HAP) resulting from the inefficient burning of coal and biomass (wood, charcoal, animal dung and crop residues) for cooking and heating has been linked to a number of negative health outcomes, mostly notably respiratory diseases and cancers. While ocular irritation has been associated with HAP, there are sparse data on adverse ocular outcomes that may result from acute and chronic exposures. We consider that there is suggestive evidence, and biological plausibility, to hypothesize that HAP is associated with some of the major blinding, and painful, eye conditions seen worldwide. Further research on this environmental risk factor for eye diseases is warranted

Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies

Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1×10−9). The improvement varied across diseases with a 16% median increase in χ2 test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci

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

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced 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.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H