Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Association of Antihypertensive Medication with Retinal Nerve Fiber Layer and Ganglion Cell-Inner Plexiform Layer Thickness.

PURPOSE: To evaluate the association between different classes of antihypertensive medication with retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness in a nonglaucomatous multiethnic Asian population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 9144 eyes for RNFL analysis (2668 Malays, 3554 Indians, and 2922 Chinese) and 8549 eyes for GC-IPL analysis (2460 Malays, 3230 Indians, and 2859 Chinese) aged 44 to 86 years. METHODS: Participants underwent standardized systemic and ocular examinations and interviewer-administered questionnaires for collection of data on medication and other variables. Intraocular pressure (IOP) readings were obtained by Goldmann applanation tonometry before pupil dilation for fundoscopy and OCT imaging. Blood pressure (BP) was measured with an automatic BP monitor. Mean arterial pressure (MAP) was defined as diastolic BP plus 1/3 (systolic BP - diastolic BP). Regression models were used to investigate the association of antihypertensive medication with OCT measurements of RNFL and GC-IPL. MAIN OUTCOME MEASURES: Average and sectoral RNFL and GC-IPL thickness. RESULTS: After adjusting for age, gender, ethnicity, MAP, IOP, body mass index (BMI), and presence of diabetes, we found that participants taking any type of antihypertensive medication (ß = -0.83; 95% confidence interval [CI], -1.46 to -0.02; P = 0.01), specifically angiotensin-converting enzyme inhibitors (ACEIs) (ß = -1.66; 95% CI, -2.57 to -0.75; P < 0.001) or diuretics (ß = -1.38; 95% CI, -2.59 to -0.17; P < 0.05), had thinner average RNFL in comparison with participants who were not receiving antihypertensive treatment. Use of a greater number of antihypertensive medications was significantly associated with thinner average RNFL (P for trend = 0.001). This association was most evident in the inferior RNFL quadrant in participants using ACEIs (ß = -2.44; 95% CI, -3.99 to -0.89; P = 0.002) or diuretics (ß = -2.76; 95% CI, -4.76 to -0.76; P = 0.007). A similar trend was noted in our analysis of macular GC-IPL thickness. CONCLUSIONS: Use of 2 or more antihypertensive medications, ACEI, and diuretics were associated with a loss of structural markers of retinal ganglion cell health in a multiethnic Asian population.

A deep learning system for predicting time to progression of diabetic retinopathy.

Diabetic retinopathy (DR) is the leading cause of preventable blindness worldwide. The risk of DR progression is highly variable among different individuals, making it difficult to predict risk and personalize screening intervals. We developed and validated a deep learning system (DeepDR Plus) to predict time to DR progression within 5 years solely from fundus images. First, we used 717,308 fundus images from 179,327 participants with diabetes to pretrain the system. Subsequently, we trained and validated the system with a multiethnic dataset comprising 118,868 images from 29,868 participants with diabetes. For predicting time to DR progression, the system achieved concordance indexes of 0.754-0.846 and integrated Brier scores of 0.153-0.241 for all times up to 5 years. Furthermore, we validated the system in real-world cohorts of participants with diabetes. The integration with clinical workflow could potentially extend the mean screening interval from 12 months to 31.97 months, and the percentage of participants recommended to be screened at 1-5 years was 30.62%, 20.00%, 19.63%, 11.85% and 17.89%, respectively, while delayed detection of progression to vision-threatening DR was 0.18%. Altogether, the DeepDR Plus system could predict individualized risk and time to DR progression over 5 years, potentially allowing personalized screening intervals.

Six-Year Incidence of Visual Impairment in a Multiethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study.

Purpose: To examine the 6-year incidence of visual impairment (VI) and identify risk factors associated with VI in a multiethnic Asian population. Design: Prospective, population-based, cohort study. Participants: Adults aged ≥ 40 years were recruited from the Singapore Epidemiology of Eye Diseases cohort study at baseline. Eligible subjects were re-examined after 6 years. Subjects included in the final analysis had a mean age of 56.1 ± 8.9 years, and 2801 (50.5%) were female. Methods: All participants underwent standardized examination and interviewer-administered questionnaire at baseline. Incidences were standardized to the Singapore Population Census 2010. A Poisson binomial regression model was used to evaluate the associations between baseline factors and incident presenting VI. Main Outcome Measures: Incident presenting VI was assessed at the 6-year follow-up visit. Visual impairment (presenting visual acuity < 20/40), low vision (presenting visual acuity < 20/40 but ≥ 20/200), and blindness (presenting visual acuity < 20/200) were defined based on United States definition. Results: A total of 5551 subjects (2188 Chinese, 1837 Indians, and 1526 Malays) were evaluated, of whom 514 developed incident presenting VI over 6 years. Malays had a higher incidence of low vision and blindness (13.0%; 0.6%) than Indians (7.0%; 0.1%) and Chinese (7.7%; 0.2%). Among Malay individuals with VI at baseline, 52.8% remained visually impaired after 6 years, which was considerably higher than Chinese (32.4%) and Indians (37.2%). Older age (per decade; relative risk [RR] = 1.59), a history of cardiovascular disease (RR = 1.38), current smoking (RR = 1.31), smaller housing type (1- to 2-room public flat; RR = 2.01), and no formal education (RR = 1.63) at baseline were associated with a higher risk of incident VI (all P ≤ 0.027). Older age (> 60 years) contributed the highest population attributable risk to incident VI (27.1%), followed by lower monthly income (Singapore dollar < $2000; 26.4%) and smaller housing type (24.7%). Overall, undercorrected refractive error (49.1%) and cataract (82.6%) were leading causes for low vision and blindness, respectively. This was consistently observed across the 3 ethnicities. Conclusions: In this multiethnic Asian population, Malays had a higher VI incidence compared to Indians and Chinese. Leading causes of VI are mostly treatable, suggesting that more efforts are needed to further mitigate preventable visual loss. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.

Normative profiles of neuroretinal rim area in a multiethnic Asian population: the Singapore Epidemiology of Eye Diseases study.

AIMS: To evaluate the normative profiles for neuroretinal rim area (RA) in a multiethnic Asian population. METHODS: Subjects were recruited from the Singapore Epidemiology of Eye Diseases (2009-2015) study and underwent standardised examinations. RA measurements were performed using Cirrus high-definition optical coherence tomography (Carl Zeiss Meditec). Multivariable linear regression with generalised estimating equation model was used to evaluate the associations between demographic, systemic and ocular factors with RA. RESULTS: A total of 9394 eyes from 5116 subjects (1724 Chinese, 1463 Malay, 1929 Indian) were included in the final analysis. The mean (±SD) of RA was 1.28 (±0.23) mm2 for Chinese, 1.33 (±0.26) mm2 for Malays, and 1.23 (±0.23) mm2 for Indians. The 5th percentile value for RA was 0.94 mm2 for Chinese, 0.96 mm2 for Malay, and 0.89 mm2 for Indian. In multivariable analysis, following adjustment for age, gender, body mass index, diabetes mellitus, hyperlipidaemia, history of cataract surgery, axial length, intraocular pressure (IOP) and disc area, Indian eyes have smaller RA when compared with Malays (ß=-0.074; 95% CI -0.090 to -0.058; p<0.001) and Chinese (ß=-0.035; 95% CI -0.051 to -0.019; p<0.001), respectively. Additionally, older age (per decade, ß=-0.022), male gender (ß=-0.031), longer axial length (per mm, ß=-0.025), spherical equivalent (per negative dioptre, ß=-0.005), higher IOP (per mm Hg, ß=-0.009) were associated with smaller RA (all p≤0.004). CONCLUSION: In this multiethnic population-based study, we observed significantly smaller RA in Indian eyes, compared with Chinese and Malays. This indicates the need of a more refined ethnic-specific RA normative databases among Asians.

Detecting visually significant cataract using retinal photograph-based deep learning.

Age-related cataracts are the leading cause of visual impairment among older adults. Many significant cases remain undiagnosed or neglected in communities, due to limited availability or accessibility to cataract screening. In the present study, we report the development and validation of a retinal photograph-based, deep-learning algorithm for automated detection of visually significant cataracts, using more than 25,000 images from population-based studies. In the internal test set, the area under the receiver operating characteristic curve (AUROC) was 96.6%. External testing performed across three studies showed AUROCs of 91.6-96.5%. In a separate test set of 186 eyes, we further compared the algorithm's performance with 4 ophthalmologists' evaluations. The algorithm performed comparably, if not being slightly more superior (sensitivity of 93.3% versus 51.7-96.6% by ophthalmologists and specificity of 99.0% versus 90.7-97.9% by ophthalmologists). Our findings show the potential of a retinal photograph-based screening tool for visually significant cataracts among older adults, providing more appropriate referrals to tertiary eye centers.

Albuminuria and Primary Open-Angle Glaucoma: the Singapore Chinese Eye Study (SCES).

AIMS: To determine the association between albuminuria and primary open-angle glaucoma (POAG). METHODS: Participants of the Singapore Chinese Eye study were recruited and underwent standardised ocular and systemic examinations. Albuminuria was determined using urinary albumin-to-creatinine ratio (UACR, mg/g) based on random spot urinary albumin and creatinine measurements. POAG was defined using the International Society of Geographic and Epidemiological Ophthalmology classification. Multivariable logistic regression with generalised estimating equation model was used to evaluate the association between albuminuria and POAG, while accounting for correlation between eyes. RESULTS: A total of 3009 Chinese adults (5963 eyes), aged 40-80 years, were included in this study, of which, 52 subjects (75 eyes) had POAG. Higher UACR (per 50 mg/g increase) was independently associated with POAG (OR=1.04, 95% CI 1.01 to 1.07, p=0.003) following adjustment for age, gender, intraocular pressure, diabetes mellitus, hyperlipidaemia, hypertension, anti-hypertensive medication, history of cardiovascular disease, current smoking status, alcohol intake, body mass index and estimated glomerular filtration rate. Further stratification revealed that individuals with macroalbuminuria were 8.00 times likely to have POAG (95% CI 2.97 to 21.54, p<0.001), compared with those with normoalbuminuria. Microalbuminuria was not significantly associated with POAG (OR=0.49, 95% CI 0.19 to 1.29, p=0.150). The association between macroalbuminuria and POAG remained significant among individuals who were diabetic (OR=9.89, 95% CI 2.49 to 39.30, p=0.001) and hypertensive (OR=8.39, 95% CI 3.07 to 22.94, p<0.001). CONCLUSION: In this population-based study of Chinese adults, albuminuria was independently associated with POAG. Our findings provide further understanding on the pathogenesis of POAG and may potentially help to better identify individuals at risk of POAG.

Referral for disease-related visual impairment using retinal photograph-based deep learning: a proof-of-concept, model development study.

BACKGROUND: In current approaches to vision screening in the community, a simple and efficient process is needed to identify individuals who should be referred to tertiary eye care centres for vision loss related to eye diseases. The emergence of deep learning technology offers new opportunities to revolutionise this clinical referral pathway. We aimed to assess the performance of a newly developed deep learning algorithm for detection of disease-related visual impairment. METHODS: In this proof-of-concept study, using retinal fundus images from 15 175 eyes with complete data related to best-corrected visual acuity or pinhole visual acuity from the Singapore Epidemiology of Eye Diseases Study, we first developed a single-modality deep learning algorithm based on retinal photographs alone for detection of any disease-related visual impairment (defined as eyes from patients with major eye diseases and best-corrected visual acuity of <20/40), and moderate or worse disease-related visual impairment (eyes with disease and best-corrected visual acuity of <20/60). After development of the algorithm, we tested it internally, using a new set of 3803 eyes from the Singapore Epidemiology of Eye Diseases Study. We then tested it externally using three population-based studies (the Beijing Eye study [6239 eyes], Central India Eye and Medical study [6526 eyes], and Blue Mountains Eye Study [2002 eyes]), and two clinical studies (the Chinese University of Hong Kong's Sight Threatening Diabetic Retinopathy study [971 eyes] and the Outram Polyclinic Study [1225 eyes]). The algorithm's performance in each dataset was assessed on the basis of the area under the receiver operating characteristic curve (AUC). FINDINGS: In the internal test dataset, the AUC for detection of any disease-related visual impairment was 94·2% (95% CI 93·0-95·3; sensitivity 90·7% [87·0-93·6]; specificity 86·8% [85·6-87·9]). The AUC for moderate or worse disease-related visual impairment was 93·9% (95% CI 92·2-95·6; sensitivity 94·6% [89·6-97·6]; specificity 81·3% [80·0-82·5]). Across the five external test datasets (16 993 eyes), the algorithm achieved AUCs ranging between 86·6% (83·4-89·7; sensitivity 87·5% [80·7-92·5]; specificity 70·0% [66·7-73·1]) and 93·6% (92·4-94·8; sensitivity 87·8% [84·1-90·9]; specificity 87·1% [86·2-88·0]) for any disease-related visual impairment, and the AUCs for moderate or worse disease-related visual impairment ranged between 85·9% (81·8-90·1; sensitivity 84·7% [73·0-92·8]; specificity 74·4% [71·4-77·2]) and 93·5% (91·7-95·3; sensitivity 90·3% [84·2-94·6]; specificity 84·2% [83·2-85·1]). INTERPRETATION: This proof-of-concept study shows the potential of a single-modality, function-focused tool in identifying visual impairment related to major eye diseases, providing more timely and pinpointed referral of patients with disease-related visual impairment from the community to tertiary eye hospitals. FUNDING: National Medical Research Council, Singapore.

Agreement in Measures of Macular Perfusion between Optical Coherence Tomography Angiography Machines.

We evaluated the agreements in foveal avascular zone (FAZ) area and vessel density (VD) parameters (within the superficial capillary plexus region), between two widely used optical coherence tomography angiography machines. Participants who attended the Singapore Malay Eye Study III between 29th March and 6th August 2018, were enrolled in this study. Participants underwent fovea-centered 6×6-mm macular cube scan, using both AngioVue and Cirrus HDOCT machines. Scans were analyzed automatically using built-in review software of each machine. 177 eyes (95 participants) without retinal diseases were included for final analysis. Mean FAZ area was 0.38 ± 0.11 mm2 and 0.30 ± 0.10 mm2, based on AngioVue and Cirrus HDOCT, respectively. Mean parafoveal VD was 0.50 ± 0.04 in Angiovue, and 0.43 ± 0.04 in Cirrus HDOCT. Cirrus HDOCT measurements were consistently lower than those by AngioVue, with a mean difference of -0.08 (95% limits of agreement [LOA], -0.30-0.13) mm2 for FAZ area, and -0.07 (95% LOA, -0.17-0.03) for parafoveal VD. Intraclass correlation coefficients for FAZ area and parafoveal VD were 0.33 and 0.07, respectively. Our data suggest that agreements between AngioVue and Cirrus HDOCT machines were poor to fair, thus alternating use between these two machines may not be recommended especially for follow up evaluations.

Association Between Visual Impairment and Decline in Cognitive Function in a Multiethnic Asian Population.

Importance: With the rapidly aging population, the burden of visual impairment (VI) and cognitive decline is expected to increase. Previous cross-sectional studies suggest an association between these 2 health outcomes. However, few longitudinal reports have examined this association, and to our knowledge, no studies have been performed in Asian populations. Further investigation on this association may help to better identify individuals at risk of cognitive decline. Objective: To examine the longitudinal association between VI and decline in cognitive function in a multiethnic Asian population. Design, Setting, and Participants: In this longitudinal, population-based, prospective cohort study, Chinese, Indian, and Malay adults 60 years or older at baseline were recruited from the Singapore Epidemiology of Eye Diseases (SEED) study. At baseline, participants from the SEED study were recruited under 3 studies: the Singapore Malay Eye Study (SiMES; 2004-2006), the Singapore Indian Eye Study (SINDI; 2007-2009), and the Singapore Chinese Eye Study (SCES; 2009-2011). Eligible participants were reexamined after 6 years (2011-2013 for SiMES, 2013-2015 for SINDI, and 2015-2017 for SCES). Data analysis was performed from November 1 to 24, 2019. Exposures: Visual impariment was defined as presenting visual acuity worse than 20/40 based on the better-seeing eye. Main Outcomes and Measures: Cognitive function was assessed using a locally validated Abbreviated Mental Test (AMT). The association between baseline VI and change in AMT score was determined using the multivariable linear regression model adjusting for baseline age; sex; race/ethnicity; presence of diabetes, hyperlipidemia, hypertension, and chronic kidney disease; history of cardiovascular disease; smoking status; alcohol intake; body mass index; educational status; and AMT score. Results: A total of 2478 individuals (1256 [50.7%] male; 1073 Chinese, 768 Indian, and 637 Malay adults) with mean (SD) age of 67.6 (5.6) years were evaluated, of whom 489 (19.7%) had reduction in AMT scores over 6 years. Baseline VI was associated with a decrease in AMT score over 6 years (ß = -0.27; 95% CI, -0.37 to -0.17; P < .001). When change in vision over 6 years was evaluated, unchanged or deteriorated VI was associated with a decrease in AMT score over 6 years (ß = -0.29; 95% CI, -0.40 to -0.18; P < .001). Among individuals with baseline VI and a substantial decrease in AMT score of 3 units or more over 6 years, the leading causes of VI were undercorrected refractive error (14 [45.2%]) and cataract (11 [35.5%]). Conclusions and Relevance: In this study, poor vision was independently associated with a decline in cognitive function. Causes of visual loss in these cases were mostly preventable, further suggesting that preserving good vision may be an important interventional strategy for mitigating cognitive decline.

Association of Diabetes With Central Corneal Thickness Among a Multiethnic Asian Population.

Importance: Thicker or thinner central corneas may lead to either overestimation or underestimation of intraocular pressure, which is the most important causal and treatable risk factor for glaucoma. However, the findings on the associations between diabetes, random glucose, and glycated hemoglobin A1c (HbA1c) with central corneal thickness (CCT) are conflicting. Objective: To evaluate the associations between diabetes, random glucose, and HbA1c with CCT in a multiethnic Asian population. Design, Setting, and Participants: Cross-sectional analysis of the Singapore Epidemiology of Eye Diseases (SEED) Study conducted from 2004 to 2011. A total of 10 033 Chinese, Malay, and Indian individuals 40 years or older residing in Singapore were recruited. Participants with incomplete information on diabetes status (448 participants), prior refractive or cataract surgery (1940 eyes), and corneal edema or dystrophy (29 eyes) were excluded. A meta-analysis was conducted to estimate the overall association of diabetes with CCT. Exposures: Standardized clinical examinations and interviewer-administered questionnaire to collect information about demographic, systemic, and ocular factors. Main Outcomes and Measures: Measurement of CCT using ultrasound pachymetry. Results: A total of 8846 adults (mean [SD] age, 57.9 [9.9] years; 4447 women [50.3%]) (17 201 eyes) were included in the final analyses. The CCT profile was similar among participants with and without diabetes (mean [SD] CCT, 545.3 [33.7] µm vs 544.8 [33.9] µm; P = .39). Following adjustments of age, sex, ethnicity, corneal curvature, axial length, and body mass index, CCT was a mean (SD) of 4.9 (0.8) µm (95% CI, 3.3-6.5 µm) thicker in patients with diabetes than those without diabetes. Multivariable analyses also showed that thicker CCT was associated with higher random glucose (per 10 mg/dL [to convert to mmol/L, multiply by 0.0555], ß = 0.3; 95% CI, 0.2-0.4) and higher HbA1c (per percentage, ß = 1.5; 95% CI, 1.0-2.1) (all P < .001). These associations were significant in the subgroup with diabetes but not in the subgroup without diabetes. A meta-analysis including 12 previous population- and clinical-based studies showed that CCT was 12.8 µm (95% CI, 8.2-17.5 µm) thicker in eyes of patients with diabetes. Conclusions and Relevance: These findings suggest that diabetes and hyperglycemia were associated with thicker CCT. This study provides useful information on the interpretation of intraocular pressure in patients with diabetes.

Normative pattern and determinants of outer retinal thickness in an Asian population: the Singapore Epidemiology of Eye Diseases Study.

BACKGROUND/AIMS: To evaluate the distribution and determinants of outer retinal thickness in eyes without retinal diseases, using spectral-domain optical coherence tomography (SD-OCT). METHODS: Participants were recruited from the Singapore Epidemiology of Eye Diseases Study, a population-based study among Chinese, Malays and Indians in Singapore. A total of 5333 participants underwent SD-OCT imaging in which a 6×6 mm2 measurement area centred at the fovea. Outer retinal thickness was defined as the distance from the outer plexiform layer to the retinal pigment epithelium layer boundary. RESULTS: 7444 eyes from 4454 participants were included in final analysis. Of them, mean age was 58.4 years (SD 8.3), and 2294 (51.5%) were women. Women (121.0±8.1 µm) had thinner average outer retinal thickness than men (125.6±8.2 µm) (p<0.001). Malays (121.4±8.7 µm) had thinner average outer retinal thickness than Indians (124.3±8.6 µm) and Chinese (123.7±7.9 µm) (both p<0.001). In multivariable models, thinner average outer retinal thickness was associated with older age (per decade, ß=-1.02, p<0.001), hypertension (ß=-0.59, p=0.029), diabetes (ß=-0.73, p=0.013), chronic kidney disease (ß=-1.25, p=0.017), longer axial length (per mm, ß=-0.76, p<0.001), flatter corneal curvature (per mm, ß=-2.00, p<0.001) and higher signal strength (ß=-1.46, p<0.001). CONCLUSION: In this large sample of Asian population, we provided normative SD-OCT data on outer retinal thickness in eyes without retinal diseases. Women had thinner outer retina than men. For the first time, these findings provide fundamental knowledge on normative profile of outer retinal thickness in Asians.

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Trends of Visual Impairment and Blindness in the Singapore Chinese Population over a Decade.

We evaluated the prevalence of visual impairment (VI) and blindness among Chinese adults in the Singapore Chinese Eye Study (SCES, 2009-2011), and compared the trends with the Tanjong Pagar Survey, Singapore (TPS), conducted a decade earlier. The SCES comprised of 3,353 Chinese adults aged ≥40 years (response rate, 72.8%). Participants underwent standardized examinations, including measurements of presenting, and best-corrected visual acuity (VA). Bilateral VI (VA < 20/40 to ≥20/200) and blindness (VA < 20/200) were defined based on the United States definition (better-seeing eye). Age-standardized prevalence was calculated using the 2010 Singapore Chinese Population Census. Primary causes and factors associated with VI and blindness were evaluated. In SCES, the age-standardized prevalence of presenting bilateral VI and blindness were 17.7% and 0.6%, respectively; the age-standardised prevalence of best-corrected bilateral VI and blindness were 3.4% and 0.2%, respectively. The previous TPS reported similar rates of best-corrected bilateral VI (3.8%) and blindness (0.3%). In SCES, cataract remains the main cause for both best-corrected bilateral VI (76.0%) and blindness (50.0%). Older age, female, lower income, lower educational level, and smaller housing type were associated with presenting bilateral VI or blindness (all P ≤ 0.025). These findings will be useful for the planning of eye care services and resource allocation.

Falls and Recurrent Falls among Adults in A Multi-ethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study.

We evaluated the rate and risk factors associated with falls and recurrent falls in a multi-ethnic Asian population. 10,009 participants aged ≥40 years (mean[SD] age = 58.9[10.4] years) underwent clinical examinations and completed interviewer-administered questionnaires. Participants who self-reported at least one fall or ≥2 falls in past 12 months were defined as fallers and recurrent fallers, respectively. Age-standardized rates for falls and recurrent falls were 13.8% (95%CI, 13.1-14.6%) and 4.6% (95%CI, 4.2-5.1%), respectively. Multivariable analyses showed older age (OR = 1.20; 95%CI, 1.11-1.30), female gender (OR = 1.79; 95%CI, 1.54-2.07), diabetes (OR = 1.22; 95%CI, 1.07-1.40), cardiovascular disease (CVD, OR = 1.37; 95%CI, 1.14-1.65), ≥3 systemic comorbidities (OR = 1.35; 95%CI, 1.09-1.67), lower European Quality of Life-5 Dimensions (EQ-5D) score (OR = 1.36; 95%CI, 1.29-1.44), alcohol consumption (OR = 1.41, 95%CI, 1.11-1.78) and presenting visual impairment (VI, OR = 1.23; 95%CI, 1.02-1.47) were associated with falls. For recurrent falls, female gender (OR = 2.27; 95%CI, 1.75-2.94), diabetes (OR = 1.28; 95%CI, 1.03-1.61), CVD (OR = 2.00; 95%CI, 1.53-2.62), ≥3 systemic comorbidities (OR = 1.69; 95%CI, 1.19-2.39), lower EQ-5D score (OR = 1.47; 95%CI, 1.35-1.59), living in 1-2 room public flat (OR = 1.57; 95%CI, 1.05-2.33), monthly income <2000 Singapore Dollar (OR = 1.62; 95%CI, 1.13-2.31), alcohol consumption (OR = 1.81, 95%CI, 1.23-2.66) and presenting VI (OR = 1.34; 95%CI, 1.01-1.79) were significant risk factors. These findings will be useful for the formulation of fall prevention programs.

Direct and Indirect Associations Between Diabetes and Intraocular Pressure: The Singapore Epidemiology of Eye Diseases Study.

Purpose: The association between diabetes and IOP is controversial; diabetes is associated with thicker central corneal thickness (CCT), and thicker CCT is associated with higher IOP. We therefore aimed to clarify the diabetes-IOP association, considering CCT as a potential mediator. Methods: We included 8636 participants from the Singapore Epidemiology of Eye Diseases (SEED) Study. Associations of diabetes, serum glucose, or HbA1c with IOP were assessed using regressions models, with adjustments for potential confounding factors. Regression-based mediation (path) analyses were further performed to evaluate the indirect effects of diabetes on IOP through the mediator (CCT), in addition to the direct effect of diabetes on IOP. Results: Of the 8636 participants, 2524 (29.23%) had diabetes. Diabetes, higher serum glucose, or HbA1c levels were all associated with higher IOP (all P < 0.01). The effect of diabetes on IOP was partially and minimally mediated through CCT; the proportion of mediating effect of CCT was 11.09% of the total effect of diabetes on IOP. Axial length and spherical equivalent were not mediating variables in the diabetes-IOP association. Findings were consistent across three ethnicity groups. Conclusions: Diabetes or higher long-term hyperglycemia was associated with higher IOP. CCT contributed a small proportion of mediating effect to the total effect of diabetes on IOP. We conclude that high IOP observed in diabetes is mainly due to the direct association of diabetes and IOP, and this finding may have pathophysiologic significance with respect to the risk of glaucoma among persons with diabetes.