Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma

Abstract Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normalpressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the .06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGFbeta signaling could be effective for multiple forms of glaucoma

Return of Genomic Results to Research Participants: The Floor, the Ceiling, and the Choices In Between

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants’ health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles

Epidemiology of ocular trauma in Australia

Publisher's version is restricted access in accordance with the publisher's policy.Purpose: To describe the prevalence and risk factors of ocular trauma in a representative sample of Australians aged 40 and over who reside in the state of Victoria.Design: Population-based cross-sectional study.Participants: Australians aged 40 years and older living in Victoria.Methods: Cluster, stratified sampling was used to identify permanent residents for a population-based study of eye disease. A standardized examination that included visual acuity and information about ocular trauma was conducted.Main Outcome Measures: Self-reported history of ocular trauma and circumstances surrounding the events.Results: A total of 3271 (83% of eligible) Melbourne residents and 1473 (92% of eligible) rural residents were examined. The overall rate of eye injury history in Victoria was 21.1% (95% confidence limits [CL] 19.6%, 22.5%). Men were far more likely than women to have ever experienced an eye injury (34.2% versus 9.9%), and rural men were more likely than Melbourne men to have ever had an eye injury (42.1% versus 30.5%). The workplace accounted for the majority of eye injuries (60%), followed by the home (24%). The location with the highest percent of people reporting the use of eye protection at the time of the injury was the workplace (18.5%); the workplace accounted for the lowest rate of hospitalization (4.9%). The industry with highest cumulative rate of eye injuries was communication (14 per 1000), whereas the highest occupation-specific cumulative rates of eye injury were recorded for tradespersons (18 per 1000).Conclusions: Although ocular trauma is usually not associated with bilateral vision impairment, it is a major public health problem in Australia. Rural men, people engaged in hammering or sport, and those in the trades are at highest risk and require specific, targeted, prevention messages

The epidemiology of cataract in Australia

Publisher's version is restricted access in accordance with the publisher's policy.Purpose: To describe the prevalence and risk factors for cataract in an Australian population aged 40 years and older. Methods: Participants were recruited by a household census and stratified, random cluster sampling to represent residents of Victoria, Australia, aged 40 years and older. The following information was collected: initial visual acuity and best-corrected visual acuity, demographic details, health history, dietary intake of antioxidants, lifetime ocular ultraviolet B exposure, and clinical eye examination, including lens photography. Cortical opacities were measured in sixteenths. Cortical cataract was defined as opacity greater than or equal to 4/16 of pupil circumference. Nuclear opacities were graded according to the Wilmer cataract grading scheme, and cataract was defined as greater than or equal to nuclear standard 2.0 of four standards. The height and width of any posterior subcapsular opacity was measured and recorded. Posterior subcapsular cataract was defined as posterior subcapsular opacity greater than or equal to 1 mm. The worse eye was selected for analysis. Backward stepwise logistic regression was used to quantify independent risk factors for cataract. RESULTS: A total of 3,271 (83% of eligible) of the urban residents, 403 (90% of eligible) nursing home residents, and 1,473 (92% of eligible) rural residents participated. The urban residents ranged in age from 40 to 98 years (mean, 59 years), and 1,511 (46%) were men. The nursing home residents ranged in age from 46 to 101 years (mean, 82 years), and 85 (21%) were men. The rural residents ranged in age from 40 to 103 years (mean, 60 years), and 701 (47.5%) were men. The overall weighted rate of cortical cataract was 11.3% (95% confidence limits, 9.68%, 13.0%) excluding cata. ract surgery and 12.1% (95% confidence limits, 10.5%, 13.8%) including cataract surgery. The risk factors for cortical cataract that remained in the multivariate logistic regression model were age, female gender, diabetes duration greater than 5 years, gout duration greater than 10 years, arthritis diagnosis, myopia, use of oral beta...blockers, and increased average annual ocular ultraviolet B exposure. Overall, 12.6% (95% confidence limits, 9.61%, 15.7%) of Victorians -aged 40 years and older had nuclear cataract including previous cataract surgery, and 11.60/0 (95% confidence limits, 8.61%, 14.70/0) had nuclear cataract excluding previous cataract surgery. In the urban and rural cohorts, age, female gender, rural residence, brown irides, diabetes diagnosed 5 or more years earlier, myopia, age...related maculopathy, having smoked for greater than 30 years, and an interaction between ocular ultraviolet B exposure and vitamin E were all risk factors for nuclear cataract. The rate of posterior subcapsular cataract excluding previous cataract surgery was 4.08% (95% confidence limits, 3.01%, 5.14%), whereas the overall rate•of posterior subcapsular cataract including previous cataract surgery was 4.93% (95% confidence limits, 3.68%,,6.17%). The independent risk factors for posterior subcapsular cataract in the urban and rural cohorts that remained were age in years, rural location, use of thiazide diuretics, vitamin E intake, and myopia. CONCLUSIONS: The expected increase in the prevalence of cataract with the aging of the population highlights the need to plan appropriate medical services and public health interventions for primary and secondary prevention. Many of the identified risk factors for cataract in the population have the potential for being modified through public health interventions

The epidemiology of dry eye in Melbourne, Australia

OBJECTIVE: To describe the epidemiology of dry eye in the adult population of Melbourne, Australia. DESIGN: A cross-sectional prevalence study. PARTICIPANTS: Participants were recruited by a household census from two of nine clusters of the Melbourne Visual Impairment Project, a population-based study of age-related eye disease in the 40 and older age group of Melbourne, Australia. Nine hundred and twenty-six (82.3% of eligible) people participated; 433 (46.8%) were male. They ranged in age from 40 to 97 years, with a mean of 59.2 years. MAIN OUTCOME MEASURES: Self-reported symptoms of dry eye were elicited by an interviewer-administered questionnaire. Four objective assessments of dry eye were made: Schirmer\u27s test, tear film breakup time, rose bengal staining, and fluorescein corneal staining. A standardized clinical slit-lamp examination was performed on all participants. Dry eye for the individual signs or symptoms was defined as: rose bengal > 3, Schirmers < 8, tear film breakup time < 8, > 1/3 fluorescein staining, and severe symptoms (3 on a scale of 0 to 3). RESULTS: Dry eye was diagnosed as follows: 10.8% by rose bengal, 16.3% by Schirmer\u27s test, 8.6% by tear film breakup time, 1.5% by fluorescein staining, 7.4% with two or more signs, and 5.5% with any severe symptom not attributed to hay fever. Women were more likely to report severe symptoms of dry eye (odds ratio [OR] = 1.85; 95% confidence limits [CL] = 1.01, 3.41). Risk factors for two or more signs of dry eye include age (OR = 1.04; 95% CL = 1.01, 1.06), and self-report of arthritis (OR = 3.27; 95% CL = 1.74, 6.17). These results were not changed after excluding the 21 people (2.27%) who wore contact lenses. CONCLUSIONS: These are the first reported population-based data of dry eye in Australia. The prevalence of dry eye varies by sign and symptom

The prevalence of glaucoma in the Melbourne Visual Impairment Project

PURPOSE: The purpose of the study was to determine the prevalence of glaucoma in Melbourne, Australia. METHODS: All subjects were participants in the Melbourne Visual Impairment Project (Melbourne VIP), a population-based prevalence study of eye disease that included residential and nursing home populations. Each participant underwent a standardized eye examination, which included a Humphrey Visual Field test, applanation tonometry, fundus examination including fundal photographs, and a medical history interview. Glaucoma status was determined by a masked assessment and consensus adjudication of visual fields, optic disc photographs, intraocular pressure, and glaucoma history. RESULTS: A total of 3271 persons (83% response rate) participated in the residential Melbourne VIP. The overall prevalence rate of definite primary open-angle glaucoma in the residential population was 1.7% (95% confidence limits = 1.21, 2.21). Of these, 50% had not been diagnosed previously. Only two persons (0.1%) had primary angle-closure glaucoma and six persons (0.2%) had secondary glaucoma. The prevalence of glaucoma increased steadily with age from 0.1% at ages 40 to 49 years to 9.7% in persons aged 80 to 89 years. There was no relationship with gender. The authors examined 403 (90.2% response rate) nursing home residents. The age standardized rate for this component was 2.36% (95% confidence limits = 0, 4.88). CONCLUSION: The rate of glaucoma in Melbourne rises significantly with age. With only half of patients being diagnosed, glaucoma is a major eye health problem and will become increasingly important as the population ages

The epidemiology of dry eye in Melbourne, Australia

Publisher's version is restricted access in accordance with the publisher's policy.Objective: To describe the epidemiology of dry eye in the adult population of Melbourne, Australia.Design: A cross-sectional prevalence study.Participants: Participants were recruited by a household census from two of nine clusters of the Melbourne Visual Impairment Project, a population-based study of age-related eye disease in the 40 and older age group of Melbourne, Australia. Nine hundred and twenty-six (82.3% of eligible) people participated; 433 (46.8%) were male. They ranged in age from 40 to 97 years, with a mean of 59.2 years.Main Outcome Measures: Self-reported symptoms of dry eye were elicited by an interviewer-administered questionnaire. Four objective assessments of dry eye were made: Schirmer's test, tear film breakup time, rose bengal staining, and fluorescein corneal staining. A standardized clinical slit-Iamp examination was performed on all participants. Dry eye for the individual signs or symptoms was defined as: rose Bengal > 3, Schirmers 1/3 fluorescein staining, and severe symptoms (3 on a scale of 0 to 3).Results: Dry eye was diagnosed as follows: 10.8% by rose Bengal, 16.3% by Schirmer's test, 8.6% by tear film breakup time, 1.5% by fluorescein staining, 7.4% with two or more signs, and 5.5% with any severe symptom not attributed to hay fever. Women were more likely to report severe symptoms of dry eye (odds ratio [OR] = 1.85; 95% confidence limits [CL] = 1.01, 3.41). Risk factors for two or more signs of dry eye include age (OR = 1.04; 95% CL = 1.01, 1.06), and self-report of arthritis (OR = 3.27; 95% CL = 1.74, 6.17). These results were not changed after excluding the 21 people (2.27%) who wore contact lenses.Conclusions: These are the first reported population-based data of dry eye in Australia. The prevalence of dry eye varies by sign and symptom