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1.  Serum Apolipoproteins Are Associated With Systemic and Retinal Microvascular Function in People With Diabetes 
Diabetes  2012;61(7):1785-1792.
Serum apolipoprotein (apo)AI and -B have been shown to be associated with diabetic retinopathy, but the underlying mechanisms are unclear. We investigated whether apoAI and apoB levels are associated with measures of systemic and retinal microvascular function in patients with diabetes. We recruited 224 diabetic patients (85 type 1 and 139 type 2) and assessed serum lipids and lipoproteins from fasting blood, skin responses to sodium nitroprusside (endothelium independent) and acetylcholine (ACh) (endothelium dependent) iontophoresis, flicker-light–induced retinal vasodilatation, and retinal vascular tortuosity. After adjustment for age and sex, every SD increase in apoAI level was associated with ACh-induced skin perfusion (mean change 1.27%; P < 0.001 for apoAI) and flicker-light retinal arteriolar vasodilatation (0.33%; P = 0.003) and was associated inversely with arteriolar tortuosity (−2.83 × 10−5; P = 0.044). Each SD increase in apoB was associated with arteriolar tortuosity only (1.75 × 10−5; P = 0.050). These associations, except for apoB, remained in multivariate models. Serum apoAI was associated with increased vasomotor responsiveness to ACh and flickering light and inversely related to retinal vessel tortuosity—a characteristic that has both structural and functional dimensions. These findings provide additional insights into the potential mechanisms of apos in the pathogenesis of diabetic retinopathy and other diabetic microvascular complications.
PMCID: PMC3379684  PMID: 22511207
2.  Prevalence and Risk Factors for Epiretinal Membranes in a Multi-Ethnic United States Population 
Ophthalmology  2010;118(4):694-699.
To describe the prevalence of and risk factors for epiretinal membrane (ERM) in a multi-ethnic population and to evaluate possible racial/ethnic differences.
Cross-sectional study.
Participants of the Multi-Ethnic Study of Atherosclerosis (MESA), examined at the second visit of the MESA when retinal photography was performed.
Data on 5960 participants aged 45 to 84 years from MESA, including white, blacks, Hispanic and Chinese from six United States communities, were analysed. ERM was assessed from digital non-stereoscopic fundus photographs and defined as cellophane macular reflex (CMR) without retinal folds or pre-retinal macular fibrosis (PMF) with retinal folds. Risk factors were assessed from standardized interviews, clinical examinations, and laboratory investigations.
Main outcome measures
ERM prevalence by ethnic/racial group, and risk factors associated with ERM.
The prevalence of any ERM was 28.9%, of which 25.1% were CMR and 3.8% were PMF. The prevalence of ERM was significantly higher in Chinese (39.0%), compared to Hispanics (29.3%), whites (27.5%), and blacks (26.2%), p<0.001. In multivariable models, increasing age (odds ratio [OR] 1.19, 95% confidence intervals [CI], 1.06, 1.34, per year increase in age), diabetes (OR 1.92, 95% CI, 1.39, 2.65) and hypercholesterolemia (OR 1.33, 95% CI, 1.04, 1.69) were significantly associated with CMR.
This study showed that ERM was significantly more common in Chinese persons compared to whites, blacks and Hispanics. Risk factors for epiretinal membrane were increasing age, presence of diabetes and hypercholesterolemia.
PMCID: PMC3070851  PMID: 21035863
3.  Serum Apolipoprotein AI and B Are Stronger Biomarkers of Diabetic Retinopathy Than Traditional Lipids 
Diabetes Care  2011;34(2):474-479.
To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy.
This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) from a diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non–HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed.
Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16–0.94], highest versus lowest quartile; Ptrend = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59–0.98]), whereas apoB (per SD increase, 1.31 [1.02–1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13–1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%.
ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures.
PMCID: PMC3024371  PMID: 21270203
4.  Is early age‐related macular degeneration related to carotid artery stiffness? The Atherosclerosis Risk in Communities Study 
Atherosclerosis and vascular stiffness have been implicated in the pathogenesis of age‐related macular degeneration (AMD). The association of carotid artery stiffness, a measure of arterial elasticity reflecting early atherosclerosis, with early AMD, was examined in this study.
A population‐based, cross‐sectional study of 9954 middle‐aged people (age range 51–72 years). The presence of AMD signs was determined from fundus photographs according to the Wisconsin grading protocol. Carotid arterial stiffness was measured from high‐resolution ultrasonic echo tracking of the left common carotid artery, and was defined as an adjusted arterial diameter change (AADCμ). A smaller AADC reflects greater carotid artery stiffness. The associations of pulse pressure and carotid artery intima–media thickness (IMT) with early AMD signs were also analysed.
In the study population, 454 (4.6%) had early AMD. The mean (SD) AADC was 403 (127) μ. After adjusting for age, sex, race/centre, education, cigarette smoking, fasting glucose, lipid profile and inflammatory markers, a smaller AADC was found to be not associated with early AMD (odds ratio 0.94; 95% confidence interval, 0.71 to 1.25) or its component lesions. Other measures of arterial stiffness (pulse pressure) and atherosclerosis (carotid IMT) were also not associated with early AMD.
Carotid artery stiffness was not associated with signs of early AMD in this middle‐aged population. These data provide no evidence of a link between age‐related elastoid changes and early atherosclerotic processes in the carotid arteries and early AMD.
PMCID: PMC1994729  PMID: 17035267
5.  Combined Effects of Complement Factor H Genotypes, Fish Consumption, and Inflammatory Markers on Long-Term Risk for Age-related Macular Degeneration in a Cohort 
American Journal of Epidemiology  2008;169(5):633-641.
At baseline in 1992–1994, the authors assessed the combined effects of complement factor H (CFH) genotypes with smoking, fish consumption, and inflammatory markers on the risk of age-related macular degeneration (AMD) in 3,654 persons aged ≥49 years. They reexamined 75% of the survivors after 5 and 10 years, confirming incident AMD by side-by-side photographic grading. Of the 2,452 persons followed in the Blue Mountains Eye Study, 1,881 were genotyped (rs1061170), with CC, CT, and TT identified in 13.6%, 46.7%, and 39.7%, respectively. AMD risk increased with each additional C allele (early AMD: age- and sex-adjusted relative risk (RR) = 1.6, 95% confidence interval (CI): 1.2, 1.9; late AMD: RR = 2.3, 95% CI: 1.5, 3.6). Late AMD risk among current smokers with the CC/CT genotypes (RR = 10.7, 95% CI: 3.4, 33.9) was 5-fold that for genotypically similar nonsmokers (RR = 2.2, 95% CI: 0.9, 5.5) versus current nonsmokers with TT genotypes. Weekly compared with less than weekly consumption of fish was associated with reduced late AMD risk in participants with the CC genotype (RR = 0.15, 95% CI: 0.03, 0.8) but not the CT (RR = 0.7, 95% CI: 0.3, 2.0) or TT (RR = 1.3, 95% CI: 0.2, 7.2) genotypes. This study documents joint contributions from genetic and systemic factors in determining the progression of AMD.
PMCID: PMC2732972  PMID: 19074778
cohort studies; complement factor H; environmental exposure; genetics; macular degeneration; seafood; smoking
6.  Is Nuclear Magnetic Resonance Lipoprotein Subclass related to Diabetic Retinopathy? The Multi-Ethnic Study of Atherosclerosis 
To examine associations between nuclear magnetic resonance (NMR) defined lipoproteins and diabetic retinopathy (DR) in a population-based sample of adults with type 2 diabetes.
Research Design and Methods
921 persons with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) were included. DR was assessed from retinal photographs. Lipoproteins were measured by NMR spectroscopy.
After controlling for age, race/ethnicity, study center and diabetes and vascular risk factors, no consistent patterns of associations between NMR defined lipoprotein particle concentrations and subclass with DR were evident.
The lack of association between NMR defined lipoproteins and DR does not support clinical use of NMR spectroscopy for management of patients with DR.
PMCID: PMC2757060  PMID: 19156628
lipoprotein; NMR-lipids; diabetic retinopathy; retinal photography
7.  The LOC387715 Polymorphism, Inflammatory Markers, Smoking, and Age-Related Macular Degeneration 
Ophthalmology  2007;115(4):693-699.
To assess combined effects on the risk of age-related macular degeneration (AMD) by the LOC387715 polymorphism, smoking, and inflammatory or hemostatic factors.
Population-based case–control study.
Two hundred seventy-eight AMD cases (224 early, 54 late) and 557 controls matched for age, gender, and smoking, drawn from the Blue Mountains Eye Study cohort.
Subjects were genotyped for the LOC387715 Ala69Ser polymorphism (rs# 10490924). Smoking was self-reported. Serum high-sensitivity C-reactive protein (CRP), interleukin 6 (IL-6), soluble intercellular adhesion molecule 1 (sICAM-1), fibrinogen, homocysteine, plasminogen activator inhibitor 1 (PAI-1), von Wille-brand factor, and white cell count (WCC) were measured. Combined effects of this genetic variant plus any of these study factors on AMD risk were assessed using logistic regression models, adjusted for age and smoking. We defined interaction if the influence of 2 factors departed from the multiplicative scale, confirmed by a statistically significant interaction term. Otherwise, the combined effect was used.
Main Outcome Measures
Age-related macular degeneration was graded using the Wisconsin grading system.
Combined effects on the likelihood of early or late AMD were demonstrated for the LOC387715 Ala69Ser G/T and T/T genotypes with the markers high-sensitivity CRP (odds ratios [ORs], 1.2 for the highest tertile alone, 1.6 for G/T and T/T genotypes alone, and 2.2 for both G/T and T/T genotypes plus the highest tertile, compared with the G/G genotype with the 2 lower tertiles), IL-6 (corresponding ORs, 1.1, 1.6, and 2.2), sICAM-1 (ORs, 1.0, 1.5, and 2.3, respectively), and PAI-1 (ORs, 1.3, 1.7, and 2.3, respectively), but not with WCC, fibrinogen, homocysteine, and von Willebrand factor. Findings were similar for early and late AMD separately. Current smokers with G/T and T/T genotypes had strong combined effects on late AMD risk compared with those who never smoked or past smokers with the G/G genotype (ORs, 1.2 for current smokers alone, 1.8 for G/T and T/T genotypes alone, and 6.1 for current smokers plus G/T and T/T genotypes).
We found no significant interaction but combined effects for the LOC387715 genotypes with 3 inflammatory markers and PAI-1 on the risk of early or late AMD, and with current smoking on the risk of late AMD.
PMCID: PMC2561271  PMID: 17675241
8.  Is Renal Function associated with Early Age-Related Macular Degeneration? 
Age-related macular degeneration (AMD) and chronic kidney disease both involve immune dysregulation and may share underlying pathophysiologic changes to systemic homeostasis. Hence we aim to evaluate associations between impaired kidney function and early AMD, in a search for urinary biomarkers for AMD.
A population-based, cross-sectional analysis of persons aged 45-84 years was conducted with renal function measured using serum creatinine and cystatin C levels and the estimated glomerular filtration rate (eGFR) calculated. AMD status was ascertained from retinal photographs.
Of 5,874 participants, 221 had early AMD. High serum cystatin C and low eGFR (≤60ml/min/1.73m2) were not associated with early AMD in our multivariate analyses. Among normotensive persons, however, highest versus other deciles of cystatin C were associated with an increased prevalence of early AMD (odds ratio 1.80, 95% confidence interval 1.00-3.23).
Results could not confirm an association between kidney function and early AMD. The borderline association between cystatin C and early AMD in normotensives require further verification.
PMCID: PMC4111798  PMID: 24879085
age-related macular degeneration; kidney; renal function
9.  Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma 
Nature genetics  2014;46(10):1120-1125.
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 advanced POAG cases and 1,992 controls. Association of the top SNPs from the discovery stage was investigated in two Australian replication cohorts (total 932 cases, 6,862 controls) and two US replication cohorts (total 2,616 cases, 2,634 controls). Meta-analysis of all cohorts revealed three novel loci associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493 [G] OR=1.31, P= 2.1 × 10-19), within AFAP1 (rs4619890 [G] OR=1.20, P= 7.0 × 10-10) and within GMDS (rs11969985 [G] OR=1.31, and P= 7.7 × 10-10). Using RT-PCR and immunolabelling, we also showed that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
PMCID: PMC4177327  PMID: 25173105
10.  Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma 
Nature genetics  2014;46(10):1120-1125.
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 advanced POAG cases and 1,992 controls. Association of the top SNPs from the discovery stage was investigated in two Australian replication cohorts (total 932 cases, 6,862 controls) and two US replication cohorts (total 2,616 cases, 2,634 controls). Meta-analysis of all cohorts revealed three novel loci associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493 [G] OR=1.31, P= 2.1 × 10−19), within AFAP1 (rs4619890 [G] OR=1.20, P= 7.0 × 10−10) and within GMDS (rs11969985 [G] OR=1.31, and P= 7.7 × 10−10). Using RT-PCR and immunolabelling, we also showed that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
PMCID: PMC4177327  PMID: 25173105
11.  Lens Status Influences the Association between CFH Polymorphisms and Age-Related Macular Degeneration: Findings from Two Population-Based Studies in Singapore 
PLoS ONE  2015;10(3):e0119570.
To determine the differential effects of genetic polymorphism in CFH and ARMS2 on risk of age-related macular degeneration (AMD) between phakic vs. pseudophakic/aphakic eyes.
9,529 eyes of 4,918 participants from the Singapore Malay Eye Study and Singapore Indian Eye Study were analyzed. Participants had detailed eye examinations, including slit-lamp examinations and dilated fundus photography. AMD grading was performed according to the Wisconsin age-related maculopathy grading system. Lens status was defined. Single nucleotide polymorphisms (SNPs) rs10801555 (Y402H) within CFH and rs3750847 in ARMS2 were assessed. The main outcome measure was early AMD or any AMD.
No significant associations between the CFH Y402H genotypes and early AMD were found in phakic individuals. In contrast, among pseudophakic/aphakic individuals, the CFH Y402H risk genotypes were significantly associated with higher odds of early AMD, with an OR of 1.57 (95% CI: 1.07–2.29) for GA genotype and 2.40 (95% CI: 1.25–4.61) for AA genotype, compared to those with GG genotype. There was significant interaction between pseudophakic/aphakic status and CFH Y402H variant on risk of early AMD (p = 0.037), adjusting for age, gender, and the first 5 genetic principal components. No significant interaction was found between lens status and ARMS2 rs3750847.
CFH genetic polymorphism and pseudophakic/aphakic status may have a potential synergistic effect on early AMD, suggesting roles for the complement system and related pathways in the pathogenesis of AMD in eyes after cataract surgery.
PMCID: PMC4364964  PMID: 25786237
12.  Retinal vascular caliber and the development of hypertension: a meta-analysis of individual participant data 
Journal of hypertension  2014;32(2):207-215.
Microvascular dysfunction has been suggested to be a major pathogenic factor for the development of hypertension. We examined the association between retinal vascular caliber, a marker of systemic microvascular dysfunction, and incident hypertension on a meta-analysis of individual participant data.
We performed a systematic review with relevant studies identified through a search of electronic databases, a review of reference lists, and correspondence with experts. Studies were included if participants were selected from a general population, retinal vascular caliber was measured from photographs using computer-assisted methods at baseline, and individuals were followed up to ascertain the incidence of hypertension. Prespecified individual recorded data from six population-based prospective cohort studies were included. Discrete time proportional odds models were constructed for each study with adjustment for hypertension risk factors. Log odds ratios (ORs) per 20-μm difference were pooled using random-effects meta-analysis.
Among 10 229 participants without prevalent hypertension, diabetes, or cardiovascular disease, 2599 developed new-onset hypertension during median follow-up periods ranging from 2.9 to 10 years. Both narrower retinal arterioles [pooled multivariate-adjusted OR per 20-μm difference 1.29, 95% confidence interval (CI) 1.20–1.39] and wider venules (OR per 20-μm difference 1.14, 95% CI 1.06–1.23) were associated with an increased risk of hypertension. Each 20 μm narrower arterioles at baseline were associated with a 1.12 mmHg (95% CI 0.25–1.99) greater increase in SBP over 5 years.
Retinal arteriolar narrowing and venular widening were independently associated with an increased risk of hypertension. These findings underscore the importance of microvascular remodeling in the pathogenesis of hypertension.
PMCID: PMC4120649  PMID: 24322199
hypertension; meta-analysis; microvascular dysfunction
13.  Association of Open-Angle Glaucoma Loci With Incident Glaucoma in the Blue Mountains Eye Study 
American Journal of Ophthalmology  2015;159(1):31-36.e1.
To determine if open-angle glaucoma (OAG)-associated single nucleotide polymorphisms (SNPs) are associated with incident glaucoma and if such genetic information is useful in OAG risk prediction.
Case-control from within a population-based longitudinal study.
study population: Individuals aged over 49 years of age living in the Blue Mountains region west of Sydney and enrolled in the Blue Mountains Eye Study. observation: Cases for this sub-study (n = 67) developed incident OAG between baseline and 10-year visits, in either eye, while controls (n = 1919) had no evidence for OAG at any visit. All participants had an ocular examination and DNA genotyped for reported OAG risk SNPs. main outcome measure: Incident OAG.
Two loci also known to be associated with cup-to-disc ratio as well as OAG (9p21 near CDKN2B-AS1 and SIX1/SIX6) were both significantly associated with incident OAG in the Blue Mountains Eye Study cohort (P = .006 and P = .004, respectively). The TMCO1 locus was nominally associated (P = .012), while the CAV1/CAV2 and 8q22 loci were not associated. Multivariate logistic regression and neural network analysis both indicated that the genetic risk factors contributed positively to the predictive models incorporating traditional risk factors.
This study shows that previously reported genetic variations related to OAG and cup-to-disc ratio are associated with the onset of OAG and thus may become useful in risk prediction algorithms designed to target early treatment to those most at risk of developing glaucoma.
PMCID: PMC4265734  PMID: 25242315
14.  An Update on the Molecular Actions of Fenofibrate and Its Clinical Effects on Diabetic Retinopathy and Other Microvascular End Points in Patients With Diabetes 
Diabetes  2013;62(12):3968-3975.
The drug fenofibrate has received major attention as a novel medical treatment for diabetic retinopathy (DR) and other diabetes-induced microvascular complications. This interest stems from two recent large, well-designed clinical trials that demonstrated large reductions in the progression of DR and the need for laser intervention, in addition to a reduction in renal and neurological outcomes, in patients with type 2 diabetes. In both trials, the greatest benefit on DR progression was observed in those patients with DR at baseline. Originally considered a lipid-modifying drug, it now appears that multiple mechanisms may underpin the benefit of fenofibrate on diabetic microvascular end points. Fenofibrate regulates the expression of many different genes, with a range of beneficial effects on lipid control, inflammation, angiogenesis, and cell apoptosis. These factors are believed to be important in the development of DR regardless of the underlying diabetes etiology. Cell experiments have demonstrated improved survival of retinal endothelial and pigment epithelial cells in conjunction with reduced stress signaling under diabetic conditions. Further, fenofibrate improves retinal outcomes in rodent models of diabetes and retinal neovascularization. Given the results of these preclinical studies, further clinical trials are needed to establish the benefits of fenofibrate in other forms of diabetes, including type 1 diabetes. In DR management, fenofibrate could be a useful adjunctive treatment to modifiable risk factor control and regular ophthalmic review. Its incorporation into clinical practice should be continually revised as more information becomes available.
PMCID: PMC3837039  PMID: 24264394
15.  Prediction of Age-related Macular Degeneration in the General Population 
Ophthalmology  2013;120(12):2644-2655.
Prediction models for age-related macular degeneration (AMD) based on case-control studies have a tendency to overestimate risks. The aim of this study is to develop a prediction model for late AMD based on data from population-based studies.
Three population-based studies: the Rotterdam Study (RS), the Beaver Dam Eye Study (BDES), and the Blue Mountains Eye Study (BMES) from the Three Continent AMD Consortium (3CC).
People (n = 10106) with gradable fundus photographs, genotype data, and follow-up data without late AMD at baseline.
Features of AMD were graded on fundus photographs using the 3CC AMD severity scale. Associations with known genetic and environmental AMD risk factors were tested using Cox proportional hazard analysis. In the RS, the prediction of AMD was estimated for multivariate models by area under receiver operating characteristic curves (AUCs). The best model was validated in the BDES and BMES, and associations of variables were re-estimated in the pooled data set. Beta coefficients were used to construct a risk score, and risk of incident late AMD was calculated using Cox proportional hazard analysis. Cumulative incident risks were estimated using Kaplan–Meier product-limit analysis.
Main Outcome Measures
Incident late AMD determined per visit during a median follow-up period of 11.1 years with a total of 4 to 5 visits.
Overall, 363 participants developed incident late AMD, 3378 participants developed early AMD, and 6365 participants remained free of any AMD. The highest AUC was achieved with a model including age, sex, 26 single nucleotide polymorphisms in AMD risk genes, smoking, body mass index, and baseline AMD phenotype. The AUC of this model was 0.88 in the RS, 0.85 in the BDES and BMES at validation, and 0.87 in the pooled analysis. Individuals with low-risk scores had a hazard ratio (HR) of 0.02 (95% confidence interval [CI], 0.01–0.04) to develop late AMD, and individuals with high-risk scores had an HR of 22.0 (95% CI, 15.2–31.8). Cumulative risk of incident late AMD ranged from virtually 0 to more than 65% for those with the highest risk scores.
Our prediction model is robust and distinguishes well between those who will develop late AMD and those who will not. Estimated risks were lower in these population-based studies than in previous case-control studies.
PMCID: PMC3986722  PMID: 24120328
16.  Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci 
PLoS ONE  2014;9(9):e107110.
Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10−8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10−11) and 8q12 (minimum p value 1.82×10−11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. “Replication-level” association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.
PMCID: PMC4169415  PMID: 25233373
17.  Complete Blood Count and Retinal Vessel Calibers 
PLoS ONE  2014;9(7):e102230.
The influence of hematological indices such as complete blood count on microcirculation is poorly understood. Retinal microvasculature can be directly visualized and vessel calibers are associated with a range of ocular and systemic diseases. We examined the association of complete blood count with retinal vessel calibers.
Cross-sectional population-based Blue Mountains Eye Study, n = 3009, aged 49+ years. Complete blood count was measured from fasting blood samples taken at baseline examination, 1992–4. Retinal arteriolar and venular calibers were measured from digitized retinal photographs using a validated semi-automated computer program.
All analyses adjusted for age, sex, systolic blood pressure, diabetes, smoking and fellow vessel caliber. Higher hematocrit, white cell count and platelet count were associated with narrower arteriolar caliber (p = 0.02, 0.03 and 0.001 respectively), while higher hemoglobin, hematocrit, red cell count, white cell count and platelet count were associated with wider venular caliber (p<0.0001 for all). Each quintile increase in hematocrit, white cell count and platelet count was associated with approximately 0.5 µm narrower arteriolar caliber; whereas each quintile increase in all of the complete blood count components was associated with approximately 1–2 µm wider venular caliber.
These associations show that elevated levels of hematological indices can have adverse effects on the microcirculation.
PMCID: PMC4103855  PMID: 25036459
18.  Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error 
Human Molecular Genetics  2013;22(13):2754-2764.
Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (‘Cooperative Health Research in the Region of Augsburg’); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10−9) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.
PMCID: PMC3674806  PMID: 23474815
19.  A genome-wide association study of intra-ocular pressure suggests a novel association in the gene FAM125B in the TwinsUK cohort 
Human Molecular Genetics  2014;23(12):3343-3348.
Glaucoma is a major cause of blindness in the world. To date, common genetic variants associated with glaucoma only explain a small proportion of its heritability. We performed a genome-wide association study of intra-ocular pressure (IOP), an underlying endophenotype for glaucoma. The discovery phase of the study was carried out in the TwinsUK cohort (N = 2774) analyzing association between IOP and single nucleotide polymorphisms (SNPs) imputed to HapMap2. The results were validated in 12 independent replication cohorts of European ancestry (combined N = 22 789) that were a part of the International Glaucoma Genetics Consortium. Expression quantitative trait locus (eQTL) analyses of the significantly associated SNPs were performed using data from the Multiple Tissue Human Expression Resource (MuTHER) Study. In the TwinsUK cohort, IOP was significantly associated with a number of SNPs at 9q33.3 (P = 3.48 × 10−8 for rs2286885, the most significantly associated SNP at this locus), within the genomic sequence of the FAM125B gene. Independent replication in a composite panel of 12 cohorts revealed consistent direction of effect and significant association (P = 0.003, for fixed-effect meta-analysis). Suggestive evidence for an eQTL effect of rs2286885 was observed for one of the probes targeting the coding region of the FAM125B gene. This gene codes for a component of a membrane complex involved in vesicular trafficking process, a function similar to that of the Caveolin genes (CAV1 and CAV2) which have previously been associated with primary open-angle glaucoma. This study suggests a novel association between SNPs in FAM125B and IOP in the TwinsUK cohort, though further studies to elucidate the functional role of this gene in glaucoma are necessary.
PMCID: PMC4030784  PMID: 24518671
20.  Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus 
Lu, Yi | Vitart, Veronique | Burdon, Kathryn P | Khor, Chiea Chuen | Bykhovskaya, Yelena | Mirshahi, Alireza | Hewitt, Alex W | Koehn, Demelza | Hysi, Pirro G | Ramdas, Wishal D | Zeller, Tanja | Vithana, Eranga N | Cornes, Belinda K | Tay, Wan-Ting | Tai, E Shyong | Cheng, Ching-Yu | Liu, Jianjun | Foo, Jia-Nee | Saw, Seang Mei | Thorleifsson, Gudmar | Stefansson, Kari | Dimasi, David P | Mills, Richard A | Mountain, Jenny | Ang, Wei | Hoehn, René | Verhoeven, Virginie J M | Grus, Franz | Wolfs, Roger | Castagne, Raphaële | Lackner, Karl J | Springelkamp, Henriët | Yang, Jian | Jonasson, Fridbert | Leung, Dexter Y L | Chen, Li J | Tham, Clement C Y | Rudan, Igor | Vatavuk, Zoran | Hayward, Caroline | Gibson, Jane | Cree, Angela J | MacLeod, Alex | Ennis, Sarah | Polasek, Ozren | Campbell, Harry | Wilson, James F | Viswanathan, Ananth C | Fleck, Brian | Li, Xiaohui | Siscovick, David | Taylor, Kent D | Rotter, Jerome I | Yazar, Seyhan | Ulmer, Megan | Li, Jun | Yaspan, Brian L | Ozel, Ayse B | Richards, Julia E | Moroi, Sayoko E | Haines, Jonathan L | Kang, Jae H | Pasquale, Louis R | Allingham, R Rand | Ashley-Koch, Allison | Mitchell, Paul | Wang, Jie Jin | Wright, Alan F | Pennell, Craig | Spector, Timothy D | Young, Terri L | Klaver, Caroline C W | Martin, Nicholas G | Montgomery, Grant W | Anderson, Michael G | Aung, Tin | Willoughby, Colin E | Wiggs, Janey L | Pang, Chi P | Thorsteinsdottir, Unnur | Lotery, Andrew J | Hammond, Christopher J | van Duijn, Cornelia M | Hauser, Michael A | Rabinowitz, Yaron S | Pfeiffer, Norbert | Mackey, David A | Craig, Jamie E | Macgregor, Stuart | Wong, Tien Y
Nature genetics  2013;45(2):155-163.
Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
PMCID: PMC3720123  PMID: 23291589
21.  Impact of Measurement Error on Testing Genetic Association with Quantitative Traits 
PLoS ONE  2014;9(1):e87044.
Measurement error of a phenotypic trait reduces the power to detect genetic associations. We examined the impact of sample size, allele frequency and effect size in presence of measurement error for quantitative traits. The statistical power to detect genetic association with phenotype mean and variability was investigated analytically. The non-centrality parameter for a non-central F distribution was derived and verified using computer simulations. We obtained equivalent formulas for the cost of phenotype measurement error. Effects of differences in measurements were examined in a genome-wide association study (GWAS) of two grading scales for cataract and a replication study of genetic variants influencing blood pressure. The mean absolute difference between the analytic power and simulation power for comparison of phenotypic means and variances was less than 0.005, and the absolute difference did not exceed 0.02. To maintain the same power, a one standard deviation (SD) in measurement error of a standard normal distributed trait required a one-fold increase in sample size for comparison of means, and a three-fold increase in sample size for comparison of variances. GWAS results revealed almost no overlap in the significant SNPs (p<10−5) for the two cataract grading scales while replication results in genetic variants of blood pressure displayed no significant differences between averaged blood pressure measurements and single blood pressure measurements. We have developed a framework for researchers to quantify power in the presence of measurement error, which will be applicable to studies of phenotypes in which the measurement is highly variable.
PMCID: PMC3901720  PMID: 24475218
22.  Replication and Meta-Analysis of Candidate Loci Identified Variation at RAB3GAP1 Associated With Keratoconus 
Keratoconus is a common complex corneal ectasia that can lead to severe visual impairment. Although a genetic component is well recognized, the genetic risk factors for keratoconus are yet to be fully elucidated. A recent genome-wide association study (GWAS) by Li et al. identified 15 potentially associated single nucleotide polymorphisms (SNPs). Here, we aimed to replicate these associations, and conduct a meta-analysis of the current and previous studies.
We genotyped the 15 reported associated SNPs in 524 Australian Caucasian cases with keratoconus and 2761 controls. Association analysis was conducted in PLINK. A meta-analysis of this study with the adjusted P values of the previously published GWAS was conducted using the method of Fisher to combine P values.
Our Australian cohort showed association (P < 0.003) at SNPs near RAB3GAP1, KCND3, IMMPL2, and in a gene desert on chromosome 13q33.3, providing evidence of replication of the published results. The meta-analysis showed SNP rs4954218 near RAB3GAP1 gene was associated significantly with keratoconus, with P = 9.26 × 10−9 passing the genome-wide significance level.
Although the mechanism of disease association is yet to be determined, SNP rs4954218 is associated consistently with keratoconus and likely tags a functional variant that contributes to disease susceptibility.
We describe the replication of published findings from a genome-wide association study of keratoconus. We show for the first time, to our knowledge, that SNPs near RAB3GAP1 are associated with keratoconus at genome-wide significance, and also provide further supportive evidence for association at other reported loci.
PMCID: PMC3729241  PMID: 23833071
keratoconus; cornea; genetics; genome-wide association study; meta-analysis
23.  Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function 
Chasman, Daniel I. | Fuchsberger, Christian | Pattaro, Cristian | Teumer, Alexander | Böger, Carsten A. | Endlich, Karlhans | Olden, Matthias | Chen, Ming-Huei | Tin, Adrienne | Taliun, Daniel | Li, Man | Gao, Xiaoyi | Gorski, Mathias | Yang, Qiong | Hundertmark, Claudia | Foster, Meredith C. | O'Seaghdha, Conall M. | Glazer, Nicole | Isaacs, Aaron | Liu, Ching-Ti | Smith, Albert V. | O'Connell, Jeffrey R. | Struchalin, Maksim | Tanaka, Toshiko | Li, Guo | Johnson, Andrew D. | Gierman, Hinco J. | Feitosa, Mary F. | Hwang, Shih-Jen | Atkinson, Elizabeth J. | Lohman, Kurt | Cornelis, Marilyn C. | Johansson, Åsa | Tönjes, Anke | Dehghan, Abbas | Lambert, Jean-Charles | Holliday, Elizabeth G. | Sorice, Rossella | Kutalik, Zoltan | Lehtimäki, Terho | Esko, Tõnu | Deshmukh, Harshal | Ulivi, Sheila | Chu, Audrey Y. | Murgia, Federico | Trompet, Stella | Imboden, Medea | Coassin, Stefan | Pistis, Giorgio | Harris, Tamara B. | Launer, Lenore J. | Aspelund, Thor | Eiriksdottir, Gudny | Mitchell, Braxton D. | Boerwinkle, Eric | Schmidt, Helena | Cavalieri, Margherita | Rao, Madhumathi | Hu, Frank | Demirkan, Ayse | Oostra, Ben A. | de Andrade, Mariza | Turner, Stephen T. | Ding, Jingzhong | Andrews, Jeanette S. | Freedman, Barry I. | Giulianini, Franco | Koenig, Wolfgang | Illig, Thomas | Meisinger, Christa | Gieger, Christian | Zgaga, Lina | Zemunik, Tatijana | Boban, Mladen | Minelli, Cosetta | Wheeler, Heather E. | Igl, Wilmar | Zaboli, Ghazal | Wild, Sarah H. | Wright, Alan F. | Campbell, Harry | Ellinghaus, David | Nöthlings, Ute | Jacobs, Gunnar | Biffar, Reiner | Ernst, Florian | Homuth, Georg | Kroemer, Heyo K. | Nauck, Matthias | Stracke, Sylvia | Völker, Uwe | Völzke, Henry | Kovacs, Peter | Stumvoll, Michael | Mägi, Reedik | Hofman, Albert | Uitterlinden, Andre G. | Rivadeneira, Fernando | Aulchenko, Yurii S. | Polasek, Ozren | Hastie, Nick | Vitart, Veronique | Helmer, Catherine | Wang, Jie Jin | Stengel, Bénédicte | Ruggiero, Daniela | Bergmann, Sven | Kähönen, Mika | Viikari, Jorma | Nikopensius, Tiit | Province, Michael | Ketkar, Shamika | Colhoun, Helen | Doney, Alex | Robino, Antonietta | Krämer, Bernhard K. | Portas, Laura | Ford, Ian | Buckley, Brendan M. | Adam, Martin | Thun, Gian-Andri | Paulweber, Bernhard | Haun, Margot | Sala, Cinzia | Mitchell, Paul | Ciullo, Marina | Kim, Stuart K. | Vollenweider, Peter | Raitakari, Olli | Metspalu, Andres | Palmer, Colin | Gasparini, Paolo | Pirastu, Mario | Jukema, J. Wouter | Probst-Hensch, Nicole M. | Kronenberg, Florian | Toniolo, Daniela | Gudnason, Vilmundur | Shuldiner, Alan R. | Coresh, Josef | Schmidt, Reinhold | Ferrucci, Luigi | Siscovick, David S. | van Duijn, Cornelia M. | Borecki, Ingrid B. | Kardia, Sharon L.R. | Liu, Yongmei | Curhan, Gary C. | Rudan, Igor | Gyllensten, Ulf | Wilson, James F. | Franke, Andre | Pramstaller, Peter P. | Rettig, Rainer | Prokopenko, Inga | Witteman, Jacqueline | Hayward, Caroline | Ridker, Paul M | Parsa, Afshin | Bochud, Murielle | Heid, Iris M. | Kao, W.H. Linda | Fox, Caroline S. | Köttgen, Anna
Human Molecular Genetics  2012;21(24):5329-5343.
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4–2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
PMCID: PMC3607468  PMID: 22962313
24.  Genome-wide meta-analyses of multi-ethnic cohorts identify multiple new susceptibility loci for refractive error and myopia 
Verhoeven, Virginie J.M. | Hysi, Pirro G. | Wojciechowski, Robert | Fan, Qiao | Guggenheim, Jeremy A. | Höhn, René | MacGregor, Stuart | Hewitt, Alex W. | Nag, Abhishek | Cheng, Ching-Yu | Yonova-Doing, Ekaterina | Zhou, Xin | Ikram, M. Kamran | Buitendijk, Gabriëlle H.S. | McMahon, George | Kemp, John P. | St. Pourcain, Beate | Simpson, Claire L. | Mäkelä, Kari-Matti | Lehtimäki, Terho | Kähönen, Mika | Paterson, Andrew D. | Hosseini, S. Mohsen | Wong, Hoi Suen | Xu, Liang | Jonas, Jost B. | Pärssinen, Olavi | Wedenoja, Juho | Yip, Shea Ping | Ho, Daniel W. H. | Pang, Chi Pui | Chen, Li Jia | Burdon, Kathryn P. | Craig, Jamie E. | Klein, Barbara E. K. | Klein, Ronald | Haller, Toomas | Metspalu, Andres | Khor, Chiea-Chuen | Tai, E-Shyong | Aung, Tin | Vithana, Eranga | Tay, Wan-Ting | Barathi, Veluchamy A. | Chen, Peng | Li, Ruoying | Liao, Jiemin | Zheng, Yingfeng | Ong, Rick T. | Döring, Angela | Evans, David M. | Timpson, Nicholas J. | Verkerk, Annemieke J.M.H. | Meitinger, Thomas | Raitakari, Olli | Hawthorne, Felicia | Spector, Tim D. | Karssen, Lennart C. | Pirastu, Mario | Murgia, Federico | Ang, Wei | Mishra, Aniket | Montgomery, Grant W. | Pennell, Craig E. | Cumberland, Phillippa M. | Cotlarciuc, Ioana | Mitchell, Paul | Wang, Jie Jin | Schache, Maria | Janmahasathian, Sarayut | Igo, Robert P. | Lass, Jonathan H. | Chew, Emily | Iyengar, Sudha K. | Gorgels, Theo G.M.F. | Rudan, Igor | Hayward, Caroline | Wright, Alan F. | Polasek, Ozren | Vatavuk, Zoran | Wilson, James F. | Fleck, Brian | Zeller, Tanja | Mirshahi, Alireza | Müller, Christian | Uitterlinden, Andre’ G. | Rivadeneira, Fernando | Vingerling, Johannes R. | Hofman, Albert | Oostra, Ben A. | Amin, Najaf | Bergen, Arthur A.B. | Teo, Yik-Ying | Rahi, Jugnoo S. | Vitart, Veronique | Williams, Cathy | Baird, Paul N. | Wong, Tien-Yin | Oexle, Konrad | Pfeiffer, Norbert | Mackey, David A. | Young, Terri L. | van Duijn, Cornelia M. | Saw, Seang-Mei | Wilson, Joan E. Bailey | Stambolian, Dwight | Klaver, Caroline C. | Hammond, Christopher J.
Nature genetics  2013;45(3):314-318.
Refractive error is the most common eye disorder worldwide, and a prominent cause of blindness. Myopia affects over 30% of Western populations, and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses including 37,382 individuals from 27 studies of European ancestry, and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in subjects of European ancestry, of which 8 were shared with Asians. Combined analysis revealed 8 additional loci. The new loci include genes with functions in neurotransmission (GRIA4), ion channels (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2, BMP2), and eye development (SIX6, PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for subjects with the highest genetic load. Our results, accumulated across independent multi-ethnic studies, considerably advance understanding of mechanisms involved in refractive error and myopia.
PMCID: PMC3740568  PMID: 23396134
25.  Mutations in the EPHA2 Gene Are a Major Contributor to Inherited Cataracts in South-Eastern Australia 
PLoS ONE  2013;8(8):e72518.
Congenital cataract is the most common cause of treatable visual impairment in children worldwide. Mutations in many different genes lead to congenital cataract. Recently, mutations in the receptor tyrosine kinase gene, EPHA2, have been found to cause congenital cataract in six different families. Although these findings have established EPHA2 as a causative gene, the total contribution of mutations in this gene to congenital cataract is unknown. In this study, for the first time, a population-based approach was used to investigate the frequency of disease causing mutations in the EPHA2 gene in inherited cataract cases in South-Eastern Australia. A cohort of 84 familial congenital or juvenile cataract index cases was screened for mutations in the EPHA2 gene by direct sequencing. Novel changes were assessed for segregation with the disease within the family and in unrelated controls. Microsatellite marker analysis was performed to establish any relationship between families carrying the same mutation. We report a novel congenital cataract causing mutation c.1751C>T in the EPHA2 gene and the previously reported splice mutation c.2826-9G>A in two new families. Additionally, we report a rare variant rs139787163 potentially associated with increased susceptibility to cataract. Thus mutations in EPHA2 account for 4.7% of inherited cataract cases in South-Eastern Australia. Interestingly, the identified rare variant provides a link between congenital and age-related cataract.
PMCID: PMC3754966  PMID: 24014202

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