Centre for Eye Research Australia (CERA) - Research Publications
Permanent URI for this collection
Search Results
1 - 6 of 6
-
ItemNo Preview AvailableGenetic Loci for Retinal Arteriolar Microcirculation(PUBLIC LIBRARY SCIENCE, 2013-06-12)Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5Ć10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-valueā=ā2.11Ć10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
-
ItemGenome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4(SPRINGER, 2013-06)AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with pā<ā1āĆā10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p metaā=ā2.6āĆā10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p metaā=ā2.3āĆā10(-10)) and a population of European descent (pā=ā8.6āĆā10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
-
ItemNo Preview AvailableGenome-Wide Association Study of Retinopathy in Individuals without Diabetes(PUBLIC LIBRARY SCIENCE, 2013-02-05)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. METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3Ā±0.23 (beta Ā± standard error), pā=ā6.6Ć10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (ā¼2%), the quality of the imputation was moderate (r(2) ā¼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
-
ItemNo Preview AvailableSeven new loci associated with age-related macular degeneration(NATURE PORTFOLIO, 2013-04)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 Ć 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 Ć 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.
-
ItemNo Preview AvailableShort Sleep Duration Is Associated with Risk of Future Diabetes but Not Cardiovascular Disease: a Prospective Study and Meta-Analysis(PUBLIC LIBRARY SCIENCE, 2013-11-25)Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak Pā=ā1.5Ć10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (Pā=ā4.3Ć10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; Pā=ā1.1Ć10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; Pā=ā8.9Ć10(-6)) and upstream of GLI2 (rs6721654; Pā=ā6.5Ć10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; Pā=ā3.5Ć10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
-
ItemHypertensive retinopathy: comparing the Keith-Wagener-Barker to a simplified classification(LIPPINCOTT WILLIAMS & WILKINS, 2013-05)PURPOSE: This study assessed the interobserver and intraobserver grading reliability of the Keith-Wagener-Barker (KWB) system to the proposed Mitchell-Wong 'simplified' three-grade classification for hypertensive retinopathy. METHODS: Digital retinal images of normal and hypertensive human fundii (nā=ā50 per group) were randomly graded by an optometrist and an ophthalmologist using the two systems. Interobserver agreement was compared to a 'gold standard' research grader. Intraobserver agreement was assessed through a repeat grading after 6 months. Cohen's kappa coefficients were used to assess the degree of agreement. RESULTS: Both clinicians demonstrated a good level of agreement with the KWB and simplified classification compared with a 'gold standard' grader; there was no significant difference in the level of agreement for either of the two classification methods for either observer. The simplified classification was found to be equally as efficacious as the KWB system with respect to interobserver and intraobserver agreement for both practitioners. CONCLUSION: These findings indicate that the simplified classification of hypertensive retinopathy is both reliable and repeatable. The advantage of the simplified method over the KWB system in correlating retinal microvascular signs to incident cardiovascular risk supports its adoption in clinical practice.