Adherence to Healthy Lifestyle Prior to Infection and Risk of Post-COVID-19 Condition.

Importance: Few modifiable risk factors for post-COVID-19 condition (PCC) have been identified. Objective: To investigate the association between healthy lifestyle factors prior to SARS-CoV-2 infection and risk of PCC. Design, Setting, and Participants: In this prospective cohort study, 32 249 women in the Nurses' Health Study II cohort reported preinfection lifestyle habits in 2015 and 2017. Healthy lifestyle factors included healthy body mass index (BMI, 18.5-24.9; calculated as weight in kilograms divided by height in meters squared), never smoking, at least 150 minutes per week of moderate to vigorous physical activity, moderate alcohol intake (5 to 15 g/d), high diet quality (upper 40% of Alternate Healthy Eating Index-2010 score), and adequate sleep (7 to 9 h/d). Main Outcomes and Measures: SARS-CoV-2 infection (confirmed by test) and PCC (at least 4 weeks of symptoms) were self-reported on 7 periodic surveys administered from April 2020 to November 2021. Among participants with SARS-CoV-2 infection, the relative risk (RR) of PCC in association with the number of healthy lifestyle factors (0 to 6) was estimated using Poisson regression and adjusting for demographic factors and comorbidities. Results: A total of 1981 women with a positive SARS-CoV-2 test over 19 months of follow-up were documented. Among those participants, mean age was 64.7 years (SD, 4.6; range, 55-75); 97.4% (n = 1929) were White; and 42.8% (n = 848) were active health care workers. Among these, 871 (44.0%) developed PCC. Healthy lifestyle was associated with lower risk of PCC in a dose-dependent manner. Compared with women without any healthy lifestyle factors, those with 5 to 6 had 49% lower risk (RR, 0.51; 95% CI, 0.33-0.78) of PCC. In a model mutually adjusted for all lifestyle factors, BMI and sleep were independently associated with risk of PCC (BMI, 18.5-24.9 vs others, RR, 0.85; 95% CI, 0.73-1.00, P = .046; sleep, 7-9 h/d vs others, RR, 0.83; 95% CI, 0.72-0.95, P = .008). If these associations were causal, 36.0% of PCC cases would have been prevented if all participants had 5 to 6 healthy lifestyle factors (population attributable risk percentage, 36.0%; 95% CI, 14.1%-52.7%). Results were comparable when PCC was defined as symptoms of at least 2-month duration or having ongoing symptoms at the time of PCC assessment. Conclusions and Relevance: In this prospective cohort study, pre-infection healthy lifestyle was associated with a substantially lower risk of PCC. Future research should investigate whether lifestyle interventions may reduce risk of developing PCC or mitigate symptoms among individuals with PCC or possibly other postinfection syndromes.

Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post-COVID-19 Conditions.

Importance: Few risk factors for long-lasting (≥4 weeks) COVID-19 symptoms have been identified. Objective: To determine whether high levels of psychological distress before SARS-CoV-2 infection, characterized by depression, anxiety, worry, perceived stress, and loneliness, are prospectively associated with increased risk of developing post-COVID-19 conditions (sometimes called long COVID). Design, Setting, and Participants: This prospective cohort study used data from 3 large ongoing, predominantly female cohorts: Nurses' Health Study II, Nurses' Health Study 3, and the Growing Up Today Study. Between April 2020 and November 2021, participants were followed up with periodic surveys. Participants were included if they reported no current or prior SARS-CoV-2 infection at the April 2020 baseline survey when distress was assessed and returned 1 or more follow-up questionnaires. Exposures: Depression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at study baseline early in the pandemic, before SARS-CoV-2 infection, using validated questionnaires. Main Outcomes and Measures: SARS-CoV-2 infection was self-reported during each of 6 monthly and then quarterly follow-up questionnaires. COVID-19-related symptoms lasting 4 weeks or longer and daily life impairment due to these symptoms were self-reported on the final questionnaire, 1 year after baseline. Results: Of 54 960 participants, 38.0% (n = 20 902) were active health care workers, and 96.6% (n = 53 107) were female; the mean (SD) age was 57.5 (13.8) years. Six percent (3193 participants) reported a positive SARS-CoV-2 test result during follow-up (1-47 weeks after baseline). Among these, probable depression (risk ratio [RR], 1.32; 95% CI = 1.12-1.55), probable anxiety (RR = 1.42; 95% CI, 1.23-1.65), worry about COVID-19 (RR, 1.37; 95% CI, 1.17-1.61), perceived stress (highest vs lowest quartile: RR, 1.46; 95% CI, 1.18-1.81), and loneliness (RR, 1.32; 95% CI, 1.08-1.61) were each associated with post-COVID-19 conditions (1403 cases) in generalized estimating equation models adjusted for sociodemographic factors, health behaviors, and comorbidities. Participants with 2 or more types of distress prior to infection were at nearly 50% increased risk for post-COVID-19 conditions (RR, 1.49; 95% CI, 1.23-1.80). All types of distress were associated with increased risk of daily life impairment (783 cases) among individuals with post-COVID-19 conditions (RR range, 1.15-1.51). Conclusions and Relevance: The findings of this study suggest that preinfection psychological distress may be a risk factor for post-COVID-19 conditions in individuals with SARS-CoV-2 infection. Future work should examine the biobehavioral mechanism linking psychological distress with persistent postinfection symptoms.

Vigorous Physical Activity and Cognitive Trajectory Later in Life: Prospective Association and Interaction by Apolipoprotein E e4 in the Nurses' Health Study.

BACKGROUND: The apolipoprotein E (APOE) e4 allele is a well-established genetic risk factor of brain aging. Vigorous physical activity may be particularly important in APOE-e4 carriers, but data have been inconsistent, likely due to differences in the timing of the physical activity assessment, definition of cognitive decline, and/or sample size. METHODS: We prospectively evaluated the association between vigorous physical activity and cognition assessed at least 9 years later, according to APOE-e4 carrier status. Biennially from 1986, Nurses' Health Study participants reported their leisure-time physical activities. Starting in 1995-2001 and through 2008, participants (aged 70+ years) underwent up to 4 repeated cognitive telephone assessments (6 tasks averaged together using z-scores). RESULTS: Among 7252 women, latent process mixed models identified 3 major patterns of cognitive change over 6 years: high-stable, medium-stable, and decline. Taking the high-stable cognitive trajectory as the outcome reference in multinomial logistic regressions, highest tertile of vigorous physical activity (≥5.9 metabolic-equivalent [MET]-hours/wk) compared to lowest tertile (≤0.9 MET-hours/wk) was significantly associated with subsequent lower likelihood of the medium-stable trajectory in the global score (odds ratio [OR] [95% CI] = 0.72 [0.63, 0.82]), verbal memory (OR [95% CI] = 0.78 [0.68-0.89]), and telephone interview of cognitive status score (OR [95% CI] = 0.81 [0.70-0.94]). Vigorous physical activity was also associated with lower likelihood of decline in category fluency (OR [95% CI] = 0.72 [0.56, 0.92]). We observed some evidence (p-interaction = .07 for the global score) that the association was stronger among APOE-e4 carriers than noncarriers (OR [95% CI] = 0.60 [0.39, 0.92] vs 0.82 [0.59, 1.16]). CONCLUSION: Midlife vigorous physical activity was associated with better cognitive trajectories in women in their seventies, with suggestions of stronger associations among APOE-e4 carriers.

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

The COronavirus Pandemic Epidemiology (COPE) Consortium: A Call to Action.

The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic presents challenges to the real-time collection of population-scale data to inform near-term public health needs as well as future investigations. We established the COronavirus Pandemic Epidemiology (COPE) consortium to address this unprecedented crisis on behalf of the epidemiology research community. As a central component of this initiative, we have developed a COVID Symptom Study (previously known as the COVID Symptom Tracker) mobile application as a common data collection tool for epidemiologic cohort studies with active study participants. This mobile application collects information on risk factors, daily symptoms, and outcomes through a user-friendly interface that minimizes participant burden. Combined with our efforts within the general population, data collected from nearly 3 million participants in the United States and United Kingdom are being used to address critical needs in the emergency response, including identifying potential hot spots of disease and clinically actionable risk factors. The linkage of symptom data collected in the app with information and biospecimens already collected in epidemiology cohorts will position us to address key questions related to diet, lifestyle, environmental, and socioeconomic factors on susceptibility to COVID-19, clinical outcomes related to infection, and long-term physical, mental health, and financial sequalae. We call upon additional epidemiology cohorts to join this collective effort to strengthen our impact on the current health crisis and generate a new model for a collaborative and nimble research infrastructure that will lead to more rapid translation of our work for the betterment of public health.

LOXL1 Polymorphisms: Genetic Biomarkers that Presage Environmental Determinants of Exfoliation Syndrome.

An agnostic high throughput search of the genome revealed a robust association between LOXL1 genetic polymorphisms and exfoliation syndrome (XFS), a discovery that likely would not have been possible with candidate or family-based gene search strategies. While questions remain regarding how LOXL1 gene variants contribute to XFS pathogenesis, it is clear that the frequencies of disease-related alleles do not track with the varying disease burden throughout the world, prompting a search for environmental risk factors. A geo-medicine approach revealed that disease load seemed to increase as a function of the distance from the equator. The exact reason for this extraequatorial disease distribution pattern remains unclear, but a greater amount of time spent outdoors is a robust risk factor for XFS, suggesting climatic factors such as ocular solar exposure and colder ambient temperature may be involved in disease pathogenesis. Prospective studies have also implicated higher coffee consumption and lower dietary folate intake in association with incident XFS. The discovery of environmental risk factors for XFS suggests that preventive measures may help to reduce ocular morbidity from XFS.

A Role for Clusterin in Exfoliation Syndrome and Exfoliation Glaucoma?

The multifunctional protein clusterin (CLU) is a secreted glycoprotein ubiquitously expressed throughout the body, including in the eye. Its primary function is to act as an extracellular molecular chaperone, preventing the precipitation and aggregation of misfolded extracellular proteins. Clusterin is commonly identified at fluid-tissue interfaces, and has been identified in most body fluids. It is a component of exfoliation material, and CLU mRNA is reduced in eyes with exfoliation syndrome compared with controls. SNPs located in the CLU genomic region have been associated with Alzheimer disease (AD) at the genome-wide level and several CLU SNPs located in an apparent regulatory region have been nominally associated with XFS/XFG in Caucasians with European ancestry and in south Indians. Interestingly, clusterin associates with altered elastic fibers in human photoaged skin and prevents UV-induced elastin aggregation in vitro. In light of the known geographic risk factors for XFS/XFG, which could include UV light, investigations of CLU-geographic interactions could be of interest. Future studies investigating rare CLU variation and other complex interactions including gene-gene interactions in XFS/XFG cases and controls may also be fruitful. Although CLU has been considered as a therapeutic target in AD, cancer and dry eye, a role for clusterin in XFS/XFG needs to be better defined before therapeutic approaches involving CLU can be entertained.

Sex hormone levels and risk of primary open-angle glaucoma in postmenopausal women.

OBJECTIVE: We evaluated the relation of prediagnostic sex hormone levels in postmenopausal women with primary open-angle glaucoma (POAG) and intraocular pressure (IOP). METHODS: Among postmenopausal participants of the Nurses' Health Study, POAG cases (n = 189; diagnosed 1990-2008) and controls (n = 189) were matched on age, fasting status, and postmenopausal hormone use at blood draw (1989-1990). Plasma concentrations of estrone sulfate, estradiol, testosterone, sex hormone binding globulin, and dehydroepiandrosterone sulfate were assessed. The primary outcome was POAG; in secondary analyses, among cases only, we evaluated maximum untreated IOP at diagnosis. Multivariable-adjusted logistic/multiple linear regression models were used to evaluate tertiles (Ts) of biomarker levels and the two outcomes, adjusting for various potential confounders. RESULTS: We observed no significant associations of estrone, estradiol, sex hormone binding globulin, or dehydroepiandrosterone sulfate with POAG risk or with maximum IOP at glaucoma diagnosis among cases. Suggestive significant associations were observed with highest testosterone and POAG risk (T3 vs T1 multivariable-adjusted odds ratio 1.84; 95% confidence interval 1.02, 3.33; P trend 0.10). Similarly, for maximum IOP at diagnosis among cases only (mean 8 years after blood draw), higher testosterone was significantly associated with higher IOP (multivariable-adjusted difference in IOP T3 vs T1 2.17 mm Hg; 95% confidence interval 0.34, 3.99; P trend 0.02). CONCLUSIONS: Overall, plasma sex hormone levels in postmenopausal women were not associated with POAG risk; however, a trend of higher testosterone levels being associated with higher POAG risk and higher IOP at diagnosis was observed and needs confirmation.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses.

PURPOSE: Recent studies indicate that mitochondrial proteins may contribute to the pathogenesis of primary open-angle glaucoma (POAG). In this study, we examined the association between POAG and common variations in gene-encoding mitochondrial proteins. METHODS: We examined genetic data from 3430 POAG cases and 3108 controls derived from the combination of the GLAUGEN and NEIGHBOR studies. We constructed biological-system coherent mitochondrial nuclear-encoded protein gene-sets by intersecting the MitoCarta database with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We examined the mitochondrial gene-sets for association with POAG and with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) subsets using Pathway Analysis by Randomization Incorporating Structure. RESULTS: We identified 22 KEGG pathways with significant mitochondrial protein-encoding gene enrichment, belonging to six general biological classes. Among the pathway classes, mitochondrial lipid metabolism was associated with POAG overall (P = 0.013) and with NTG (P = 0.0006), and mitochondrial carbohydrate metabolism was associated with NTG (P = 0.030). Examining the individual KEGG pathway mitochondrial gene-sets, fatty acid elongation and synthesis and degradation of ketone bodies, both lipid metabolism pathways, were significantly associated with POAG (P = 0.005 and P = 0.002, respectively) and NTG (P = 0.0004 and P < 0.0001, respectively). Butanoate metabolism, a carbohydrate metabolism pathway, was significantly associated with POAG (P = 0.004), NTG (P = 0.001), and HTG (P = 0.010). CONCLUSIONS: We present an effective approach for assessing the contributions of mitochondrial genetic variation to open-angle glaucoma. Our findings support a role for mitochondria in POAG pathogenesis and specifically point to lipid and carbohydrate metabolism pathways as being important.

A survey of preoperative blood tests in primary open-angle glaucoma patients versus cataract surgery patients.

PURPOSE: To investigate biomarker differences in routine preoperative blood tests performed on primary open-angle glaucoma (POAG) case and control patients presenting for anterior segment eye surgery. METHODS: POAG cases and age-related cataract surgery patients (controls) who underwent anterior segment surgery at Massachusetts Eye and Ear from January 2009 through March 2012 were identified by retrospective record review. Patients with diabetes mellitus, secondary glaucoma, and cataract due to trauma or steroid exposure were excluded. Data on demographic features, preoperative ophthalmological and medical diagnosis, blood pressure, anthropometric measures, basic metabolic panel, and complete blood count were extracted from the medical records. Univariate differences in lab values between POAG cases and controls were assessed using unpaired t tests. Multivariate logistic regression analysis was completed to determine the independent associations of biomarkers with POAG. RESULTS: A total of 150 cases and 150 age-related controls were included. In multivariate analysis, higher AG was inversely associated with POAG (odds ratio [OR] = 0.90; 95% confidence interval [CI], 0.80-1.00), and higher Cl- level was positively associated with POAG (OR = 1.15; 95% CI, 1.02-1.29). The lower AG in POAG patients could be explained by higher IgG levels as the available data in post hoc analysis showed a nonsignificant trend toward higher IgG in cases compared to controls (17 vs 23; 1142 ± 284 mg/dl vs 1028 ± 291 mg/dl; P = 0.22). Furthermore, in multivariable analysis, a higher red blood cell count was also associated with POAG (OR = 1.91; 95% CI, 1.11-3.28). CONCLUSIONS: Patients with POAG presenting for anterior segment surgery had a lower AG compared to age-related cataract surgery patients. The etiology of this reduced gap is unclear but the possible contribution of IgG warrants further exploration. The etiology of higher red blood cell counts in POAG cases is unknown and deserves further exploration.

Clinical characteristics of acute appendiceal diverticulitis.

PURPOSE: Diverticulitis of vermiform appendix is known as a rare cause of acute appendicitis, most of which are diagnosed after surgery. We compared appendiceal diverticulitis with acute appendicitis to study the clinical characteristics of appendiceal diverticulitis. METHODS: Among 1,029 patients who received appendectomy from January 2009 to May 2011, 38 patients with appendiceal diverticulitis (diverticulitis group) were compared with 98 randomly collected patients with acute appendicitis (appendicitis group) during the same period. Patients' characteristics, clinical features, laboratory findings, operative findings, and postoperative course were compared between the two groups. RESULTS: Thirty-eight patients (3.7%) were pathologically diagnosed with acute appendiceal diverticulitis among 1,029 cases of appendectomy. The mean age of patients in the diverticulitis group was significantly older than that of the appendicitis group (49.0 ± 15.2 years vs. 25.4 ± 14.2 years, P < 0.05). Mean duration of preoperative symptoms was longer in the diverticulitis group (3.6 ± 3.8 days vs. 1.8 ± 3.2 days, P < 0.05). The site of abdominal pain, fever, signs of localized peritonitis, accompanying gastrointestinal symptoms, and white blood cell count showed no differences between the two groups. Twenty-five patients (65.8%) of the diverticulitis group and 10 patients (10.2%) of the appendicitis group showed perforation of appendix (P < 0.05). Mean operating time and postoperative hospital stay were longer in the diverticulitis group (55.3 ± 28.8 minutes vs. 41.4 ± 17.8 minutes, 6.8 ± 3.4 days vs. 4.9 ± 1.5 days, P < 0.05). CONCLUSION: Acute diverticulitis of the appendix can be classified into quite different disease entities compared with acute appendicitis. Regarding high rates of perforation, immediate surgical treatment is needed for patients with a high index of suspicion of acute diverticulitis of the appendix.

Long-term multivitamin supplementation and cognitive function in men: a randomized trial.

BACKGROUND: Despite widespread use of multivitamin supplements, their effect on cognitive health-a critical issue with aging-remains inconclusive. To date, no long-term clinical trials have studied multivitamin use and cognitive decline in older persons. OBJECTIVE: To evaluate whether long-term multivitamin supplementation affects cognitive health in later life. DESIGN: Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to 1 June 2011. The cognitive function substudy began in 1998. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years. (ClinicalTrials.gov: NCT00270647) SETTING: The Physicians' Health Study II. PATIENTS: 5947 male physicians aged 65 years or older. INTERVENTION: Daily multivitamin or placebo. MEASUREMENTS: A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary end point was a verbal memory score combining 4 tests of verbal memory, which is a strong predictor of Alzheimer disease. RESULTS: No difference was found in mean cognitive change over time between the multivitamin and placebo groups or in the mean level of cognition at any of the 4 assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was -0.01 SU (95% CI, -0.04 to 0.02 SU) when treatment was compared with placebo. Similarly, cognitive performance did not differ between the multivitamin and placebo groups on the secondary outcome, verbal memory (mean difference in cognitive change over follow-up, -0.005 SU [CI, -0.04 to 0.03 SU]). LIMITATION: Doses of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin. CONCLUSION: In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits. PRIMARY FUNDING SOURCE: National Institutes of Health, BASF, Pfizer, and DSM Nutritional Products.

Dietary intakes of berries and flavonoids in relation to cognitive decline.

OBJECTIVE: Berries are high in flavonoids, especially anthocyanidins, and improve cognition in experimental studies. We prospectively evaluated whether greater long-term intakes of berries and flavonoids are associated with slower rates of cognitive decline in older women. METHODS: Beginning in 1980, a semiquantitative food frequency questionnaire was administered every 4 years to Nurses' Health Study participants. In 1995-2001, we began measuring cognitive function in 16,010 participants, aged ≥70 years; follow-up assessments were conducted twice, at 2-year intervals. To ascertain long-term diet, we averaged dietary variables from 1980 through the initial cognitive interview. Using multivariate-adjusted, mixed linear regression, we estimated mean differences in slopes of cognitive decline by long-term berry and flavonoid intakes. RESULTS: Greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline (eg, for a global score averaging all 6 cognitive tests, for blueberries: p-trend = 0.014 and mean difference = 0.04, 95% confidence interval [CI] = 0.01-0.07, comparing extreme categories of intake; for strawberries: p-trend = 0.022 and mean difference = 0.03, 95% CI = 0.00-0.06, comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect estimates were equivalent to those we found for approximately 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Additionally, in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were associated with slower rates of cognitive decline (p-trends = 0.015 and 0.053, respectively, for the global score). INTERPRETATION: Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults.

Small-cell neuroendocrine carcinoma of the breast.

A small-cell carcinoma is one of the histologic subtypes of primary neuroendocrine carcinomas of the breast. A small-cell carcinoma is a rare entity of the breast and exhibits similar morphologic features as neuroendocrine tumors of the gastrointestinal tract and lung. We present the imaging and pathologic findings of a primary small-cell neuroendocrine carcinoma of the breast. This is the first report of a primary small-cell carcinoma arising from the breast in Korea.

Demographic and geographic features of exfoliation glaucoma in 2 United States-based prospective cohorts.

PURPOSE: To examine prospectively the association between demographic and geographic factors in relation to exfoliation glaucoma (EG) or exfoliation glaucoma suspect (EGS). DESIGN: Prospective cohort study. PARTICIPANTS: Seventy-eight thousand nine hundred fifty-five women in the Nurses' Health Study and 41 191 men in the Health Professionals Follow-up Study. METHODS: Female and male health professionals were followed prospectively from 1980 through 2008 and from 1986 through 2008, respectively. Eligible participants were 40 years of age or older, did not have EG or EGS at baseline, and reported undergoing eye examinations during follow-up. Information regarding demographic features, lifetime geographic residence, and potential confounders was collected. During follow-up, 348 EG or EGS cases were confirmed with medical record review. The relative risk of EG or EGS in each cohort was estimated separately and the results were pooled with meta-analysis. MAIN OUTCOME MEASURES: Multivariate rate ratios (MVRRs) of EG or EGS and their 95% confidence intervals (CIs). RESULTS: Exfoliation glaucoma or EGS was strongly age related with subjects 75 years of age or older at 46.22-fold (95% CI, 22.77-93.80) increased risk compared with those between 40 and 55 years of age. Although men were 68% less likely to develop EG or EGS than women (MVRR, 0.32; 95% CI, 0.23-0.46), no predisposition to EG or EGS by ancestry, particularly Scandinavian ancestry, emerged. Compared with a lifetime of living in the northern tier of the continental United States, lifetime residence in the middle geographic tier (MVRR, 0.53; 95% CI, 0.40-0.71) and in the southern geographic tier (MVRR, 0.25; 95% CI, 0.09-0.71) was associated with markedly reduced risks of EG or EGS. CONCLUSIONS: In this mainly white cohort from the United States, increasing age and female gender were significant risk factors for EG or EGS; however, Scandinavian heritage was not. Living in the middle or southern regions of the United States relative to living in the northern region was associated with a reduced risk of EG or EGS. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Reproductive factors and NOS3 variant interactions in primary open-angle glaucoma.

PURPOSE: To investigate whether associations with the nitric oxide synthase gene (NOS3) variants and risk of primary open-angle glaucoma (POAG) depend on female reproductive factors. METHODS: Two functional and two tagging single nucleotide polymorphisms (SNPs; T-786C: rs2070744, Glu298Asp: rs1799983, rs7830, and rs3918188) were evaluated in a nested case-control study from the Nurses' Health Study (women followed 1980 - 2002). Participants were aged ≥40 years and Caucasian, who were followed biennially with update information on reproductive factors. We included 374 Nurses' Health Study (NHS) cases and 1,085 controls, matched on age and eye exam at the matched cases' diagnosis dates. Relative risks (RRs) were estimated using multivariable conditional logistic regression. RESULTS: Among women with age at menarche <13 years, compared with the CC homozygotes of the rs3918188 tagging SNP, the wild-type AA homozygotes were at significantly reduced risk of POAG (RR=0.31, 95% CI=0.16, 0.59); however, for women with age at menarche ≥13 years, the SNP was not associated with POAG (p-interaction=0.0007). Among parous women with 3+ children, carriers of the minor variant (T) allele of the functional Glu298Asp SNP were at increased risk, while among parous women with 1-2 children, they were not (p-interaction=0.003). No significant interactions between NOS3 SNPs and oral contraceptive use in POAG were detected. CONCLUSIONS: These data provide further support for the notion that NOS3 genotype - female reproductive health interactions are important in POAG pathogenesis.

Geographic and climatic factors associated with exfoliation syndrome.

OBJECTIVE: To identify geographic and climatic risk factors associated with exfoliation syndrome (ES). METHODS: A retrospective study of 626 901 eye care recipients, dating from 2001 to 2007 from 47 US states in a managed care network. Incident ES cases-patients (N = 3367) were identified by using billing codes. We assessed the risk of ES by geographic latitude tier in the continental United States and assigned state-level climatic data (eg, ambient temperature, elevation, and sun exposure) according to patients' residential location. The hazard of ES was calculated by using multivariable-adjusted Cox proportional hazards regression models. RESULTS: Compared with middle-tier residence, northern-tier residence (above 42°N) was associated with an increased hazard of ES (adjusted hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.94-2.35). Southern-tier (below 37°N) was associated with a reduced hazard of ES (HR, 0.83; 95% CI, 0.75-0.93). Excluding whites did not change these associations. After adjustment for joint environmental effects, for every 1° increase in July high temperature, the hazard of ES decreased by 9% (HR, 0.91; 95% CI, 0.89-0.93); for every 1° increase in January low temperature, the hazard decreased 3% (0.97; 0.96-0.98). For each additional sunny day annually, the hazard increased by 1.5% (HR, 1.02; 95% CI, 1.01-1.02) in locations with average levels of other climatic factors. CONCLUSION: Ambient temperature and sun exposure may be important environmental triggers of ES.

Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma in Caucasians from the USA.

Primary open-angle glaucoma (POAG) is a genetically complex common disease characterized by progressive optic nerve degeneration that results in irreversible blindness. Recently, a genome-wide association study (GWAS) for POAG in an Icelandic population identified significant associations with single nucleotide polymorphisms (SNPs) between the CAV1 and CAV2 genes on chromosome 7q31. In this study, we confirm that the identified SNPs are associated with POAG in our Caucasian US population and that specific haplotypes located in the CAV1/CAV2 intergenic region are associated with the disease. We also present data suggesting that associations with several CAV1/CAV2 SNPs are significant mostly in women.