Methodology of the Singapore Indian Chinese Cohort (SICC) Eye Study: Quantifying ethnic variations in the epidemiology of eye diseases in Asians
TL;DR: In conjunction with the Singapore Malay Eye Study, the SICC study will permit an in-depth evaluation of the prevalence, risk factors, and impact of major eye diseases in Chinese, Indians and Malays, three distinct Asian ethnic groups, whose combined numbers represent half the world’s population.
Abstract: Purpose: Current knowledge of ethnic variability in the epidemiology of major eye diseases in Asia is limited. This report summarizes the rationale and study design of the Singapore Indian Chinese Cohort (SICC) Eye Study, a population-based study of ethnic South Asian (Indians) and East Asian (Chinese) older adults in Singapore.Methods: The SICC examined a population-based cross-sectional sample of 3,300 ethnic Indians and 3,300 ethnic Chinese aged 40–80+ years residing in the South-Western part of Singapore. Results: From two lists of 12,000 names of each ethnic group provided by the Ministry of Home Affairs, age-stratified random sampling was used to select 6,350 names in each group, with a target sample size of 3,300. Invitations were sent to attend a central clinic using letters, telephone calls and home visits. Examination procedures included interviews, measurement of blood pressure, anthropometry, presenting and best-corrected visual acuity, subjective refraction, ocular biometry, Goldmann applanat...
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University of Washington1, National University of Singapore2, Cedars-Sinai Medical Center3, National Institutes of Health4, Erasmus University Rotterdam5, University of Newcastle6, University of Wisconsin-Madison7, University of Iceland8, University of Texas Health Science Center at Houston9, University of Melbourne10, University of Sydney11, Boston University12, University of Auckland13, Group Health Cooperative14, University of Amsterdam15, Singapore National Eye Center16, Agency for Science, Technology and Research17, University of California, San Francisco18, University of Michigan19, Harvard University20
TL;DR: This genome-wide association study of retinopathy in individuals without diabetes showed little evidence of genetic associations and further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
Abstract: Background
Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
805 citations
Cites result from "Methodology of the Singapore Indian..."
...We also examined the SNP and locus transferability of our findings to cohorts of other ethnicities including Singapore Asian Indians from the Singapore Indian Eye Study (SINDI) [37] and African Americans in the MESA cohort....
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...We tested the transferability of this SNP and locus (other SNPs in the HDAC9 gene) in a cohort of Singapore Asian Indians (SINDI) and a cohort of African Americans in MESA....
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...We also examined the SNP and locus transferability of our findings to cohorts of other ethnicities including Singapore Asian Indians from the Singapore Indian Eye Study (SINDI) [37] and African Americans in the MESA cohort....
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...First we looked at the SNP transferability to the SINDI and MESA cohorts using a significance level of 0.05....
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TL;DR: A collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry, identifies 19 loci associated at P < 5 × 10−8, which show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis.
Abstract: Age-related macular degeneration (AMD) is a common cause of blindness in older individuals To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry We identified 19 loci associated at P < 5 × 10(-8) These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined Our findings provide new directions for biological, genetic and therapeutic studies of AMD
745 citations
TL;DR: The results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism–associated TKI resistance.
Abstract: Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.
537 citations
National Institutes of Health1, University of Cambridge2, National University of Singapore3, Ealing Hospital4, Imperial College London5, University of Oklahoma6, University of Oxford7, University of Geneva8, Aga Khan University9, The Heart Research Institute10, Indian Council of Medical Research11, Heart of England NHS Foundation Trust12, University of Birmingham13, Singapore National Eye Center14, National Health Service15, King's College London16, Agency for Science, Technology and Research17, University of Kelaniya18, Wellcome Trust Sanger Institute19, University of Melbourne20, Beijing Genomics Institute21, University of Michigan22, Queen Mary University of London23, University of Exeter24, University of Colombo25, University of Oklahoma Health Sciences Center26, University of California, San Francisco27, Baker IDI Heart and Diabetes Institute28, National Institute for Health Research29, Wellcome Trust Centre for Human Genetics30, Imperial College Healthcare31
TL;DR: A genome-wide association study of type-2 diabetes in individuals of South Asian ancestry provides additional insight into mechanisms underlying T2D and shows the potential for new discovery from genetic association studies in South Asians.
Abstract: John Chambers and colleagues report a genome-wide association study for type 2 diabetes in individuals of south Asian ancestry. They identify six loci newly associated with type 2 diabetes.
513 citations
TL;DR: The LV, which represents the anterior portion of the lens, is a novel parameter independently associated with angle closure after adjusting for age, gender, ACD, and LT.
304 citations
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TL;DR: The EuroQol instrument is intended to complement other forms of quality of life measures, and it has been purposefully developed to generate a cardinal index of health, thus giving it considerable potential for use in economic evaluation.
5,362 citations
TL;DR: A genome-wide screen for polymorphisms associated with age-related macular degeneration revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402 in the complement factor H gene.
Abstract: Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. We report a genome-wide screen of 96 cases and 50 controls for polymorphisms associated with AMD. Among 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene ( CFH ) is strongly associated with AMD (nominal P value -7 ). In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (95% confidence interval 2.9 to 19). Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies.
4,459 citations
TL;DR: The LOCS III is an improved LOCS system for grading slit-lamp and retroillumination images of age-related cataract and contains an expanded set of standards that were selected from the Longitudinal Study of Cataract slide library.
Abstract: • Objective. —To develop the Lens Opacities Classification System III (LOCS III) to overcome the limitations inherent in lens classification using LOCS II. These limitations include unequal intervals between standards, only one standard for color grading, use of integer grading, and wide 95% tolerance limits. Design and Results. —The LOCS III contains an expanded set of standards that were selected from the Longitudinal Study of Cataract slide library at the Center for Clinical Cataract Research, Boston, Mass. It consists of six slitlamp images for grading nuclear color (NC) and nuclear opalescence (NO), five retroillumination images for grading cortical cataract (C), and five retroillumination images for grading posterior subcapsular (P) cataract. Cataract severity is graded on a decimal scale, and the standards have regularly spaced intervals on a decimal scale. The 95% tolerance limits are reduced from 2.0 for each class with LOCS II to 0.7 for nuclear opalescence, 0.7 for nuclear color, 0.5 for cortical cataract, and 1.0 for posterior subcapsular cataract with the LOCS III, with excellent interobserver agreement. Conclusion. —The LOCS III is an improved LOCS system for grading slit-lamp and retroillumination images of age-related cataract.
2,540 citations
TL;DR: DNA resequencing of the complement factor H gene within this haplotype revealed a common coding variant that significantly increases the risk for AMD with odds ratios between 2.45 and 5.57, which likely explains ∼43% of AMD in older adults.
Abstract: Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in the elderly whose etiology remains largely unknown. Previous studies identified chromosome 1q32 as harboring a susceptibility locus for AMD. We used single-nucleotide polymorphisms to interrogate this region and identified a strongly associated haplotype in two independent data sets. DNA resequencing of the complement factor H gene within this haplotype revealed a common coding variant, Y402H, that significantly increases the risk for AMD with odds ratios between 2.45 and 5.57. This common variant likely explains approximately 43% of AMD in older adults.
2,463 citations
TL;DR: This review describes a scheme for diagnosis of glaucoma in population based prevalence surveys that makes provision for diagnosing glauca in eyes with severe visual loss where formal field testing is impractical, and for blind eyes in which the optic disc cannot be seen because of media opacities.
Abstract: This review describes a scheme for diagnosis of glaucoma in population based prevalence surveys. Cases are diagnosed on the grounds of both structural and functional evidence of glaucomatous optic neuropathy. The scheme also makes provision for diagnosing glaucoma in eyes with severe visual loss where formal field testing is impractical, and for blind eyes in which the optic disc cannot be seen because of media opacities.
2,004 citations