Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

Type 2 Diabetes Genetic Variants and Risk of Diabetic Retinopathy.

PURPOSE: Genetic association studies to date have not identified any robust risk loci for diabetic retinopathy (DR). We hypothesized that individuals with more diabetes genetic risk alleles have a higher risk of developing DR. DESIGN: Case-control genetic association study. PARTICIPANTS: We evaluated the aggregate effects of multiple type 2 diabetes-associated genetic variants on the risk of DR among 1528 participants with diabetes from the Singapore Epidemiology of Eye Diseases Study, of whom 547 (35.8%) had DR. METHODS: Participants underwent a comprehensive ocular examination, including dilated fundus photography. Retinal photographs were graded using the modified Airlie House classification system to assess the presence and severity of DR following a standardized protocol. We identified 76 previously discovered type 2 diabetes-associated single nucleotide polymorphisms (SNPs) and constructed multilocus genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on DR. Two GRSs were generated: an overall GRS that included all 76 discovered type 2 diabetes-associated SNPs, and an Asian-specific GRS that included a subset of 55 SNPs previously found to be associated with type 2 diabetes in East and/or South Asian ancestry populations. Associations between the GRSs with DR were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under the receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES: Odds ratios on DR. RESULTS: Participants in the top tertile of the overall GRS were 2.56-fold more likely to have DR compared with participants in the lowest tertile. Participants in the top tertile of the Asian-specific GRS were 2.00-fold more likely to have DR compared with participants in the bottom tertile. Both GRSs were associated with higher DR severity levels. However, addition of the GRSs to traditional risk factors improved the AUC only modestly by 3% to 4%. CONCLUSIONS: Type 2 diabetes-associated genetic loci were significantly associated with higher risks of DR, independent of traditional risk factors. Our findings may provide new insights to further our understanding of the genetic pathogenesis of DR.

Analysis of competency in phacoemulsification trainees using the cumulative sum analysis.

PURPOSE: To determine the number of cases required to achieve competency in phacoemulsification in terms of the posterior capsule rupture rate. SETTING: Singapore National Eye Centre, Singapore. DESIGN: Retrospective cohort study. METHODS: The posterior capsule rupture rate of the first 300 phacoemulsification cases performed by each trainee in the Singapore National Eye Centre (2004 to 2012) was charted using cumulative sum graphs. Competency was primarily defined as a posterior capsule rupture rate of 2% or lower and secondarily as 5% or lower. RESULTS: Twenty trainees fulfilled the inclusion criteria. Four trainees (20%) and 19 trainees (95%) achieved a posterior capsule rupture rate of 2% and 5%, respectively. At least 41 cases were required to achieve a 5% posterior capsule rupture rate (mean 106, median 83). CONCLUSIONS: There was considerable variation in the trainees' abilities. Only 20% of the trainees achieved a posterior capsule rupture rate of 2% or lower and required at least 212 cases.

Prevalence and risk factors for epiretinal membrane: the Singapore Epidemiology of Eye Disease study.

AIM: To examine prevalence and risk factors of epiretinal membrane (ERM) in a large, contemporary, multiethnic Asian population. METHODS: Combined analysis of three population-based studies of eye diseases, with a total of 9799 Chinese, Malays and Indians residing in the general communities of Singapore. A comprehensive ophthalmic examination, interviews and laboratory blood tests were performed to assess potential risk factors. Digital retinal photographs were used to assess ERM according to a standardised protocol. ERM was classified into cellophane macular reflex (CMR) and/or preretinal macular fibrosis (PMF), and also as primary or secondary (in eyes with other retinal pathology or a history of cataract surgery). RESULTS: The age-standardised and ethnicity-standardised prevalence was 12.1% for any ERM, 6.8% for CMR, 6.7% for PMF and 2.8% for bilateral ERM. ERM prevalence was higher in Chinese (13.0%) compared with Malays (7.9%) or Indians (8.7%). In multivariate analysis, significant factors associated with primary ERM were older age (OR 1.08 per year increase; p<0.01), Chinese ethnicity (OR 1.60 vs Indians; p<0.01; OR 1.39 vs Malays; p<0.01), smoking (OR 0.70; p=0.01), longer axial length (OR 1.07 per mm increase; p=0.03) and cataract (OR 0.64; p<0.01). Significant factors independently associated with secondary ERM were older age (OR 1.05; p<0.01), cataract surgery (OR 10.6; p<0.01) and diabetic retinopathy (OR 2.48; p<0.01). CONCLUSIONS: ERM is common in Asians, particularly among Chinese. Older age is the most consistent risk factor for any ERM, and previous cataract surgery and diabetic retinopathy are the strongest risk factors for secondary ERM.

Incidence and risk factors of symptomatic dry eye disease in Asian Malays from the Singapore Malay Eye Study.

PURPOSE: To evaluate the incidence of symptomatic dry eye disease (SDED) and associated risk factors in a well-characterized cohort of ethnic Malays in Singapore. METHODS: We included 1682 participants (mean age [SD]: 57 [10]years; 55.4% female) without SDED from the Singapore Malay Eye Study (SiMES), a population-based longitudinal study with baseline examination (SiMES-1) conducted between 2004 and 2006, and follow-up examination (SiMES-2) conducted between 2010 and 2013. SDED was considered to be present if a participant answered "often" or "all the time" to any of the six questions from the Salisbury Eye Evaluation Study dry eye questionnaire. Age-standardized incidence of SDED was calculated as the crude 6-year cumulative incidence standardized to Singapore's population census. Gender-stratified multivariable log-binomial regression models were utilized to determine the independent risk factors of incident SDED. RESULTS: At the 6-year follow-up, 86 of 1682 participants had developed SDED, which was equivalent to an age-standardized 6-year incidence of 5.1% (95% CI 4.1-6.4%). There were no differences in the incidence of SDED between men and women (P = 0.9). Multivariable models revealed that presence of glaucoma and poorer self-rated health were independently associated with incident SDED in men (P = 0.003 and 0.03, respectively), while contact lens wear (P = 0.002), history of thyroid disease (P = 0.03), and having had cataract surgery (P = 0.02) were predictive of incident SDED in women. CONCLUSION: One in twenty adult Malays developed SDED over a 6-year period. Risk factors for incident SDED were different between men and women. Future studies and public health interventions should consider this gender-specific difference in risk factors.

Systemic, Ocular and Genetic Risk Factors for Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Singaporeans.

To examine the association of systemic, ocular and genetic risk factors in neovascular age-related macular degeneration (nAMD) in a large cohort of Asian patients, and to further compare risk factors between those with typical AMD and polypoidal choroidal vasculoapthy (PCV) subtypes. We recruited 456 cases and 1,824 controls matched for age, gender and ethnicity. Data on systemic and ocular risk factors were collected on questionnaires. In a subgroup of subjects, we included genetic data on four AMD-associated single nucleotide polymorphisms (SNPs). Risk factors for nAMD and subtypes were analyzed. Systemic risk factors for nAMD included older age, male gender, higher BMI and higher HDL-cholesterol. Ocular risk factors included pseudophakic and shorter axial length. Risk factors common to both typical AMD and PCV subtypes included age, BMI and HDL-cholesterol. Shorter axial length was only associated with PCV, while male gender and pseudophakia were only associated with typical AMD. In the subgroup with genotype data, ARMS2 rs10490924 and CFH rs800292 were associated with nAMD. None of the risk factors were significantly different between PCV and typical AMD. Systemic, ocular and genetic risk factors were largely similar for typical AMD and PCV subtypes in this Asian population based in Singapore.

Inter-Relationships Between Retinal Vascular Caliber, Retinal Nerve Fiber Layer Thickness, and Glaucoma: A Mediation Analysis Approach.

PURPOSE: The purpose of this study was to explore the interrelationships among retinal vascular caliber, retinal nerve fiber layer (RNFL), and glaucoma; in particular, whether the relationship between narrower retinal vascular caliber and glaucoma is mediated by thinning of RNFL. METHODS: A total of 9407 participants, including 253 glaucoma and 195 primary open-angle glaucoma (POAG) cases from the Singapore Epidemiology of Eye Diseases Study were included in this study. All participants underwent standardized examinations. Glaucoma was defined according to International Society for Geographical and Epidemiologic Ophthalmology criteria. Logistic regression analyses were used to determine the total direct effects of retinal vascular calibers on glaucoma. Regression-based mediation analyses were used to evaluate the indirect effects of retinal vascular caliber on glaucoma through RNFL thinning. RESULTS: After we adjusted for relevant covariates, narrower retinal arteriolar caliber (per standard deviation [SD], 15.1-µm decrease) was associated with glaucoma (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.06-1.38) and POAG (OR, 1.23; 95% CI, 1.06-1.43). Similarly, narrower retinal venular caliber (per SD, 21.6µm decrease) was associated with glaucoma (OR, 1.51; 95% CI, 1.32-1.73) and POAG (OR, 1.64; 95% CI, 1.41-1.91). In addition, there were significant indirect effects of retinal vascular narrowing on glaucoma through thinning of RNFL (all P < 0.001), with mediated proportion of 36.9% and 12.9% in retinal arteriole- and venule-related analysis, respectively. CONCLUSIONS: Mediation analyses indicated that the effect of retinal vascular narrowing on glaucoma was partially the result of thinning of RNFL. These findings provide additional mechanistic insights linking retinal vascular narrowing and glaucoma.

Choroidal Thickness Changes in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy: A 12-Month Prospective Study.

PURPOSE: To describe 12-month changes in choroidal thickness after anti-vascular endothelial growth factor (anti-VEGF) therapy for typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). DESIGN: Prospective, consecutive, noninterventional, longitudinal case series. METHODS: This study included patients with typical AMD and PCV who received anti-VEGF therapy over a 12-month period. We used spectral-domain optical coherence tomography with enhanced depth imaging mode to measure choroidal thickness. RESULTS: Of the 163 patients, 77 had typical AMD and 86 had PCV. Patients with PCV were younger (67.6 vs 72.5 years, P < .01) and received fewer anti-VEGF injections (3.9 vs 5.6, P = .02) than patients with typical AMD. Baseline subfoveal choroidal thickness was not significantly different between PCV and typical AMD eyes, and was thicker in the study eye compared to fellow eye in the typical AMD group (223.1 vs 208.8 µm, P < .01). Subfoveal choroidal thickness decreased significantly in both typical AMD (213.7 µm to 190.3 µm, P < .001) and PCV (240.8 µm to 213.4 µm, P < .01) eyes, but no significant change was noted in fellow unaffected eyes. Reduction in choroidal thickness was associated with elevated C-reactive protein (odds ratio [OR]: 1.4, P = .04) and smoking (OR: 7.6, P = .03) at baseline, but not with age, refractive error, diagnosis of typical AMD or PCV, number or type of anti-VEGF injections, PDT therapy, or baseline choroidal thickness. CONCLUSIONS: A significant reduction in subfoveal choroidal thickness was noted after anti-VEGF therapy in typical AMD and PCV. Choroidal thickness changes were similar despite differences in number of anti-VEGF treatment.