Angiopoietin receptor TEK interacts with CYP1B1 in primary congenital glaucoma.

Primary congenital glaucoma (PCG) is a severe autosomal recessive ocular disorder associated with considerable clinical and genetic heterogeneity. Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene TEK were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of TEK to respond to ligand stimulation, indicating perturbed TEK signaling. Overall, our data suggest that interaction of TEK and CYP1B1 contributes to PCG pathogenesis and argue that TEK-CYP1B1 may perform overlapping as well as distinct functions in manifesting the disease etiology.

Longitudinal Andhra Pradesh Eye Disease Study: rationale, study design and research methodology.

BACKGROUND: The rationale, objectives, study design and procedures for the longitudinal Andhra Pradesh Eye Disease Study are described. DESIGN: A longitudinal cohort study was carried out. PARTICIPANTS: Participants include surviving cohort from the rural component of Andhra Pradesh Eye Disease Study. METHODS: During 1996-2000, Andhra Pradesh Eye Disease Survey was conducted in three rural (n = 7771) and one urban (n = 2522) areas (now called Andhra Pradesh Eye Disease Study 1). In 2009-2010, a feasibility exercise (Andhra Pradesh Eye Disease Study 2) for a longitudinal study (Andhra Pradesh Eye Disease Study 3) was undertaken in the rural clusters only, as urban clusters no longer existed. In Andhra Pradesh Eye Disease Study 3, a detailed interview will be carried out to collect data on sociodemographic factors, ocular and systemic history, risk factors, visual function, knowledge of eye diseases and barriers to accessing services. All participants will also undergo a comprehensive eye examination including photography of lens, optic disc and retina, Optic Coherence Tomography of the posterior segment, anthropometry, blood pressure and frailty measures. MAIN OUTCOME MEASURES: Measures include estimates of the incidence of visual impairment and age-related eye disease (lens opacities, glaucoma and age-related macular degeneration) and the progression of eye disease (lens opacities and myopia) and associated risk factors. RESULTS: Of the 7771 respondents examined in rural areas in Andhra Pradesh Eye Disease Study 1, 5447 (70.1%) participants were traced in Andhra Pradesh Eye Disease Study 2. These participants will be re-examined. CONCLUSIONS: Andhra Pradesh Eye Disease Study 3 will provide data on the incidence and progression of visual impairment and major eye diseases and their associated risk factors in India. The study will provide further evidence to aid planning eye care services.

Prevalence of spectacles use in Andhra Pradesh, India: rapid assessment of visual impairment project.

BACKGROUND: To assess the prevalence and patterns of spectacles use in South India state of Andhra Pradesh. DESIGN: A population-based cross sectional study. PARTICIPANTS: Seven thousand eight hundred subjects aged ≥40 years, sampled from one urban and two locations. METHODS: Two-stage cluster random sampling method was used to enumerate 7800 subjects. Distance visual acuity and near vision were assessed. A questionnaire was used to collect information on current and previous use of spectacles, spectacles providers and type of spectacles. Among those who discontinued use of spectacles, the reasons were elicited. MAIN OUTCOME MEASURES: The prevalence of spectacles use and spectacle coverage. RESULTS: In total, 7378/7800 subjects (95.0%) were examined. Among those examined, 53.6% were female, 49.5% of them aged between 40 and 49 years, and 62% of them had no education. The overall prevalence of spectacles use was 29.5% (95% confidence interval 28.5-30.4), 30.3% (95% confidence interval 29.0-31.6) in rural area compared with 27.9% (95% confidence interval 26.1-29.7) (P < 0.05) in urban location. Bifocals (72.8%) were the most common type of spectacles. Private eye clinics were the leading spectacles provider in all three regions. On applying multiple logistic regression, the odds of spectacles use increased with increasing age and were significantly higher for rural residents and those with higher levels of education. The spectacle coverage was 38.0% and 27% for refractive errors and presbyopia, respectively. CONCLUSIONS: Although prevalence of spectacles use is moderate, the spectacle coverage for both refractive errors and presbyopia is low. The strategies are required to improve the spectacle coverage in the region.

Presbyopia, spectacles use and spectacle correction coverage for near vision among cloth weaving communities in Prakasam district in South India.

PURPOSE: To assess the prevalence of presbyopia, spectacles use and spectacle correction coverage for near vision among weaving communities in Prakasam district in the South Indian state of Andhra Pradesh. METHODS: A population based cross sectional study was conducted among a population aged ≥40 years. Distance visual acuity was assessed at 6 m. Near vision was assessed using N notation charts at a fixed distance of 40 cm. Presbyopia was defined as binocular unaided near vision

Visual impairment and blindness due to retinitis pigmentosa in India: 15-year follow-up of the Andhra Pradesh Eye Disease Study cohort.

Purpose: To assess the incidence, visual impairment, and blindness due to retinitis pigmentosa (RP) in a rural southern Indian cohort. Methods: This is a population-based longitudinal cohort study of participants with RP from the Andhra Pradesh Eye Disease Study (APEDS) cohorts I and III, respectively. The study included participants with RP of APEDS I who were followed until APEDS III. Their demographic data along with ocular features, fundus photographs, and visual fields (Humphrey) were collected. Descriptive statistics using mean ± standard deviation with interquartile range (IQR) were calculated. The main outcome measures were RP incidence, visual impairment, and blindness as per the World Health Organization (WHO) definitions. Results: At baseline (APEDS I), 7771 participants residing in three rural areas were examined. There were nine participants with RP with a mean age at baseline of 47.33 ± 10.89 years (IQR: 39-55). There was a male preponderance (6:3), and the mean best-corrected visual acuity (BCVA) of 18 eyes from nine participants with RP was 1.2 ± 0.72 logarithm of minimum angle of resolution (logMAR; IQR: 0.7-1.6). Over a mean follow-up duration of 15 years, 5395/7771 (69.4%) were re-examined, which included seven RP participants from APEDS 1. Additionally, two new participants with RP were identified; so, the overall incidence was 370/ million in 15 years (24.7/million per year). The mean BCVA of 14 eyes of seven participants with RP who were re-examined in APEDS III was 2.17 ± 0.56 logMAR (IQR: 1.8-2.6), and five of these seven participants with RP developed incident blindness during the follow-up period. Conclusion: RP is a prevalent disease in southern India that warrants appropriate strategies to prevent this condition.

Regional variation in the incidence of pseudo-exfoliation in the Andhra Pradesh Eye Disease Study (APEDS).

BACKGROUND: To report the 15-year incidence rate of pseudo-exfoliation (PXF),  PXF glaucoma and regional variation among rural participants in the Andhra Pradesh Eye Disease Study (APEDS) III. METHODS: This population-based longitudinal study was carried out at three rural study sites. Individuals of all ages who participated at baseline with a mean 15-year follow-up visit were included. Detailed Comprehensive ophthalmic examination was performed on all participants. The main outcome measure was development of PXF during the follow-up period in participants who were phakic in one or both eyes without PXF at baseline. RESULTS: Among 5395 participants, 5108 (94.6%) met the inclusion criteria. There were 93 (1.82%; 95% confidence interval (CI), 1.47-2.22) cases of incident PXF. Their median baseline age (1st, 3rd quartiles) was 51 (44, 59) years and the male: female ratio was 1.3:1. There was no case of incident PXF in participants aged <30 years at baseline. The incidence rate per 100 person years (95% CI) among all ages and those aged ≥30 years at baseline was 1.73 (1.64-1.82) and 3.73 (3.53-3.93), respectively. PXF material was located on iris as well as anterior surface of lens and it was often bilateral. Participants living in two study sites and increasing age were associated with the incidence of PXF. The 15-year incidence of PXF glaucoma (95% CI) in participants ≥30 years of age at baseline was 0.33% (0.14-0.66). CONCLUSION: There is significant regional variation in incidence of PXF in south India which warrants further investigation.

Incidence of primary open angle glaucoma in the Andhra Pradesh Eye Disease Study (APEDS).

BACKGROUND: To report 15-year incidence rate of primary open angle glaucoma (POAG) in the Andhra Pradesh Eye Disease Study (APEDS). METHODS: A population-based longitudinal study was carried out at three rural study sites. Phakic participants aged ≥40 years who participated at baseline (APEDS I) and the mean 15-year follow-up visit (APEDS III) were included. A comprehensive ophthalmic examination was performed on all participants. Mean intraocular pressure (IOP) was average of IOPs of right and left eyes. The definition of glaucoma was based on the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) classification. The main outcome measure was incidence of POAG during the follow-up period in participants without glaucoma or suspicion of glaucoma at baseline. RESULTS: Data from the available and eligible participants from the original cohort (1241/2790; 44.4%) were analysed. The mean age (standard deviation) of participants at baseline was 50.2 (8.1) years; 580 (46.7%) were men. Thirty-six participants developed POAG [bilateral in 17 (47.2%)] over 15 years. The incidence rate of POAG per 100-person years (95% confidence interval) was 2.83 (2.6, 3.08). Compared to baseline, the reduction in mean IOP [median (range) mm Hg] was -0.75 (-7.5, 9) in participants with incident POAG and -2.5 (-14.5, 14.5) in those without. The inter-visit difference in mean IOP was a significant risk factor on logistic regression analysis. CONCLUSION: We report the long-term incidence of POAG in rural India. A longitudinal change in IOP, specifically a less pronounced reduction in IOP with increasing age, was a novel risk factor.

Fifteen-Year Incidence Rate of Primary Angle Closure Disease in the Andhra Pradesh Eye Disease Study.

PURPOSE: To report on the 15-year incidence of primary angle closure disease (PACD) among participants aged ≥40 years in rural southern India DESIGN: Population-based longitudinal incidence rate study METHODS: Setting: 3 rural study centres. STUDY POPULATION: Phakic participants aged ≥40 years who participated in both examination time points. OBSERVATION PROCEDURES: All participants at the baseline and at the mean 15-year follow-up visit underwent a detailed interview, anthropometry, blood pressure measurement, and comprehensive eye examination. Automated perimetry was attempted based on predefined criteria. Main outcome measures included development of any form of PACD, as defined by the International Society for Geographical and Epidemiological Ophthalmology (ISGEO), during the follow-up period in phakic participants, who did not have the disease at baseline. RESULTS: We analyzed data obtained from 1,197 (81.4% out of available 1,470) participants to calculate the incidence of the disease. The mean age (standard deviation) of the study participants at the baseline was 50.2 (8.1) years, with 670 male (45.5%) and 800 female (54.4%) participants. The incidence rate per 100 person-years (95% confidence interval) for primary angle closure suspect, primary angle closure, and primary angle closure glaucoma was 8.8 (8.4, 9.2), 6.2 (5.9, 6.6), and 1.6 (1.4, 1.8), respectively. Thus, the incidence of all forms of PACD was 16.4 (15.9, 17) per 100 person-years. On logistic regression analysis, female gender was a significant risk factor whereas presence of myopia was protective. CONCLUSIONS: This study reports long-term incidence of PACD from rural India. It has implications for eye health care policies, strategies, and planning.

Fifteen-year incidence rate and risk factors of pterygium in the Southern Indian state of Andhra Pradesh.

PURPOSE: To report 15-year incidence rate and associated risk factors of pterygium among people aged 30 years and above at baseline in the rural clusters of longitudinal Andhra Pradesh Eye Disease Study (APEDS III). METHODS: The baseline APEDS I included 7771 participants of which 6447 (83%) were traced and 5395 (83.7%) were re-examined in APEDS III. To estimate the incidence of pterygium, we selected participants who were 30 years and above at baseline (4188), of which 2976 were traced and 2627 (88.3%) were examined, and based on inclusion criteria, 2290 participants were included in the study. The incidence rate of pterygium was defined as the proportion of people free of pterygium at baseline who had developed the condition at 15-year follow-up (range 13-17 years). Univariate and multivariable analyses for risk factors were undertaken. RESULTS: The sex-adjusted incidence rate of pterygium was 25.2 per 100 person-years (95% CI 24.8 to 25.7) which was significantly higher for men than women (26.3 per 100 person-years (95% CI 25.6 to 27.0) and 24.7 (95% CI 24.1 to 25.3) respectively). At the multivariable analysis, male gender (RR: 1.35, 95% CI 1.0 to 1.83), no formal education (RR: 2.46, 95% CI 1.22 to 4.93), outdoor occupation (RR: 1.47, 95% CI 1.14 to 1.9) and lower body mass index (BMI) (<18.5) (RR: 1.25, 95% CI 1.02 to 1.55) were associated with increased risk of pterygium. CONCLUSIONS: The overall incidence rate of pterygium was high in this rural population, especially in men and those engaged in outdoor activities, lack of formal education and with lower BMI. It is likely that greater exposure to ultraviolet light is a major contributing factor, thus warranting preventive strategies.

Incidence, Incident Causes, and Risk Factors of Visual Impairment and Blindness in a Rural Population in India: 15-Year Follow-up of the Andhra Pradesh Eye Disease Study.

PURPOSE: To report 15-year incidence rate of visual loss (blindness and visual impairment [VI]), causes, and risk factors for participants in Andhra Pradesh Eye Disease Study III (APEDS III). DESIGN: Population-based cohort study. METHODS: From 2012 to 2016, all rural participants were interviewed and underwent a comprehensive eye examination, including dilated fundus examination and imaging. Presenting visual acuity (PVA) and best-corrected visual acuity (BCVA) were measured using a standard logarithm of Minimum Angle of Resolution chart at 3 meters. World Health Organization (WHO) and United States of America (USA) categories of VI and blindness were used. Incident visual loss was defined as the development of or worsening of visual loss of one or more categories. RESULTS: In APEDS I, 7,771 rural participants were examined using stratified, random-cluster systematic sampling; in APEDS III, 5,395 participants (69.4% of rural or 52.4% of total participants) were re-examined. Using WHO categories, the crude incidence rate of any visual loss based on PVA and BCVA were 14.6 (95% confidence interval [CI]:13.6-15.7) and 6.3 (95% CI: 6.1-6.4) per 100 person-years, respectively. Using USA criteria, the values were 22.6 (95% CI: 22.3-23.0) and 10.6 (95% CI: 10.3-10.8) per 100 person-years, respectively. More than 90% of visual loss was attributable to cataract and uncorrected refractive error. Using WHO categories, significant independent risk factors for the incident visual loss were increasing age, female gender, illiteracy, past or current smoker, and current use of alcohol. Using the USA definition, an additional risk factor was lower level of education. CONCLUSIONS: The high incidence likely reflects poor access to eye care in this population, which needs to be taken into account when planning eye care programs.

Population-Based Assessment of Unilateral Visual Impairment in the South Indian State of Andhra Pradesh: Rapid Assessment of Visual Impairment (RAVI) Project.

PURPOSE: To assess the prevalence and causes of unilateral visual impairment (VI) in the South Indian state of Andhra Pradesh. METHODS: A population-based cross-sectional study was conducted among individuals aged ≥40 years in one urban and two rural locations, using rapid assessment methodology. A 2-stage cluster random sampling method was used to select 7800 individuals from 156 clusters. Distance visual acuity (VA) was assessed using a standard Snellen chart at a distance of 6 m. Eye examinations were conducted using a torchlight and distance direct ophthalmoscopy. Unilateral VI was defined as presenting VA <6/18 in one eye and presenting VA ≥6/18 in the other, and included moderate unilateral VI (<6/18 to 6/60) and unilateral blindness (<6/60). RESULTS: In total, 7378 individuals (94.6%) were examined. After excluding 918 individuals with VI in the better eye, data were analyzed for the remaining 6460 individuals. Among those included in the analysis, mean age was 50 years (standard deviation 9.6 years), 46.7% were male, 58.9% had no education, and 34.1% were urban residents. The prevalence of unilateral VI was 11.3% (95% confidence interval 10.5-12.1%; n = 730). Uncorrected refractive error was found to be the leading cause (44%; n = 321) of unilateral VI followed by cataract (39.7%; n = 290). CONCLUSIONS: Unilateral VI is common in the South Indian state of Andhra Pradesh. As most of this VI can be addressed with interventions such as cataract surgery and spectacles, service models need to be streamlined to address this need.

Outcomes of Cataract Surgery in Urban and Rural Population in the South Indian State of Andhra Pradesh: Rapid Assessment of Visual Impairment (RAVI) Project.

OBJECTIVE: To assess the visual outcomes after cataract surgery among urban and rural population aged ≥40 years in the South India state of Andhra Pradesh. METHODS: A population based cross-sectional study was conducted in which 7800 subjects were sampled from two rural and one urban location. Visual Acuity was assessed and eye examination were performed by trained personnel. A questionnaire was used to collect personal and demographic information, and history of cataract surgery. Blindness and moderate Visual Impairment (MVI) was defined as presenting VA <6/60 and <6/18 to 6/60 in the better eye respectively. RESULTS: In total, 7378 (94.6%) were examined. Of these, 1228 eyes of 870 individuals were operated for cataract. The mean age of operated subjects was 63.7 years (SD: 10.7 years). Overall, 56.3% of those operated were women, 76% were illiterate and 42% of them were using spectacles after cataract surgery. Even after surgery, 12.2% of the operated eyes had MVI and blindness was seen in 14.7% of the eyes. A significantly higher proportion of subjects in urban area had good outcome as compared to those in the rural area (p = 0.01). Uncorrected refractive error (58.7%) was the leading cause of MVI, and posterior segment disease (34.3%) was the leading cause of blindness. On applying multiple logistic regression, risk factors for poor outcomes were age ≥ 70 years (OR: 1.9, 95% CI: 1.3-2.8), rural residence (OR: 1.3, 95% CI:1.0-1.8) and presence of aphakia (OR: 8.9, 95% CI: 5.7-13.8). CONCLUSIONS: Post cataract surgery, refractive errors remain an important correctable cause of MVI, in the south Indian state of Andhra Pradesh. The correction of refractive errors is required to provide good visual recovery and achieve the benefit of cataract surgery.

A population-based cross-sectional study of barriers to uptake of eye care services in South India: the Rapid Assessment of Visual Impairment (RAVI) project.

OBJECTIVE: To assess the barriers to uptake of eye care services among those with avoidable impairment in the population aged ≥40 years in the South Indian state of Andhra Pradesh. DESIGN: Cross-sectional study. SETTING: Community setting. PARTICIPANTS: Of 7800 participants recruited from one urban and two rural locations using a two-stage cluster random sampling methodology, 7378 (95%) were examined. Eye examinations were conducted using a rapid assessment protocol. Visual impairment (VI) was defined as presenting visual acuity <6/18 in the better eye. For the purpose of this study, VI caused due to cataract or uncorrected refractive error was considered avoidable VI. A validated questionnaire was used to collect information on barriers for uptake of services among those who had avoidable VI. PRIMARY OUTCOME: Barriers to uptake of services among those with avoidable VI. RESULTS: The prevalence of avoidable VI was 11.8% (95% CI 11.0% to 12.5%; n=868). Among these, 71.1% (n=617) individuals reported 'person-related' barriers whereas 28.9% (n=251) individuals reported 'service-related' barriers to uptake of services. Among the 'person-related' barriers, the leading barrier was 'lack of perceived need' (61.1%; n=377) for reasons such as old age, good vision in the other eye. This was followed by 'no one to accompany' (20.3%; n=125). Of the 251 individuals who had 'service-related' barriers, lack of affordability was the major barrier (76.1%; n=191) followed by lack of accessibility (12.7%; n=32). Over 11% (n=28) of the individuals were advised to wait for cataract surgery. CONCLUSIONS: Person-related barriers are more common than service-related barriers in Andhra Pradesh. As the barriers trend more towards 'person-related' phenomenon such as person's attitude and 'felt need' to improve vision, newer and much intensive awareness campaigns are needed to bring about an attitudinal/behavioural change among individuals to improve the uptake of services.

Visual impairment among weaving communities in Prakasam district in South India.

PURPOSE: To assess the prevalence and causes of visual impairment in weaving communities in Prakasam district in South India state of Andhra Pradesh. METHODS: Using Rapid Assessment of Visual Impairment (RAVI) methodology, a population based cross-sectional study was conducted. A two-stage sampling strategy was used to select 3000 participants aged ≥40 years. Visual Acuity (VA) was assessed using a tumbling E chart and ocular examinations were performed by trained Para medical ophthalmic personnel. A questionnaire was used to collect personal and demographic information. Blindness and moderate Visual Impairment (VI) was defined as presenting VA <6/60 and <6/18 to 6/60 respectively. VI included blindness and moderate VI. RESULTS: 2848 of 3000 enumerated subjects (94.0%) participated. 39% were in 40-49 years age group and 11.8% were aged ≥70 years, 55% were women and nearly half of them had no formal education. 400 (14%; 95% CI: 12.8-15.3) subjects had VI, including blindness in 131 (4.6%; 95% CI: 3.8-5.4) and moderate VI in 269 (9.4%; 95% CI: 8.3-10.5) individuals. On applying multiple logistic regression, VI was significantly associated with older age and no formal education. Though the odds of having VI were higher in females, it was of borderline statistical significance (p = 0.06). Refractive error was the leading cause of all VI followed by cataract (56%). However, refractive errors were the leading cause of moderate VI (73.2%) and cataract was the leading cause of blindness (62.6%). 'Cannot afford the cost of services' was the leading barrier for utilization of eye care services (47%). CONCLUSIONS: There is a significant burden of VI in weaving communities in Andhra Pradesh, India most of which is avoidable. With this information as baseline, services need to be streamlined to address this burden.

Visual impairment in the South Indian state of Andhra Pradesh: Andhra Pradesh - rapid assessment of visual impairment (AP-RAVI) project.

PURPOSE: To assess the prevalence and causes of visual impairment in urban and rural population aged ≥ 40 years in the South India state of Andhra Pradesh. METHODS: A population based cross-sectional study was conducted in which 7800 subjects were sampled from two rural and an urban locations. Visual Acuity (VA) was assessed using a tumbling E chart and eye examinations were performed by trained vision technicians. A questionnaire was used to collect personal and demographic information and previous consultation to eye care providers. Blindness and moderate Visual Impairment (VI) was defined as presenting VA <6/60 and <6/18 to 6/60 in the better eye respectively. VI included blindness and moderate VI. RESULTS: Of the 7800 subjects enumerated, 7378 (94.6%) were examined. Among those examined, 46.4% were male and 61.8% of them had no education. The mean age of those examined (51.7 years; standard deviation 10.9 years) was similar to those not examined (52.8 years; standard deviation 9.9 years) (p=0.048). Age and gender adjusted prevalence of VI was 14.3% (95% CI: 13.5-15.0). Refractive errors were the leading cause of VI accounting for 47.6% of all VI followed by cataract (43.7%). Together, they contributed to over 91.3% of the total VI. With multiple logistic regression, the odds of having VI increased significantly with increasing age. Those respondents who had no education were twice (95% CI: 1.7-2.5) more likely to have VI compared to those who were educated. VI was associated with rural residence (OR: 1.3; 95% CI: 1.1-1.6). The association between VI and gender was not statistically significant. CONCLUSIONS: The visual impairment remains a public health challenge in Andhra Pradesh, most of which can be addressed with relatively straight forward interventions like cataract surgery and spectacles. The eye care services need to be streamlined to address this challenge.