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Kathryn P. Burdon, Rhys Fogarty, Mark Daniell, Sotoodeh Abhary, Mark Gillies, Rohan W. Essex, Alicia Jenkins, Johanna Hadler, Matthew A. Brown, Jamie E. Craig; Identification Of Loci For Blinding Diabetic Retinopathy In A Genome Wide Association Scan. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2258.
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Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus. It is known to have a strong genetic component independent of duration of diabetes and extent of diabetic control, but to date, very few genes have been reliably identified. Further understanding of the molecular pathogenesis is required in order to develop better strategies for prevention and treatment of DR.
Patients with type 1 or type 2 diabetes mellitus of at least 5 years duration, and on medical treatment for diabetes were recruited through eye and endocrine clinics in multiple hospitals in Australia. DR gradings were classified according to ETDRS criteria and relevant clinical details were collected. A genome-wide association study was conducted using 629 patients with potentially blinding DR defined as proliferative DR, severe non-proliferative DR or clinically significant macular edema, compared to 800 diabetic controls with no DR. Genotyping was performed on Illumina OmniExpress arrays. Population stratification was assessed with Eigenstrat and outliers removed. Association analysis was conducted in Plink and included adjustment for principal components and clinical covariates.
The univariate association analysis revealed two loci reaching genome-wide significance (p<5x10-8) for association with blinding DR. The highest ranked variant was located within a protein coding gene on chromosome 2q32 (p=9.6x10-9) and also reached genome-wide significance in an analysis of proliferative DR alone. The second ranked variant was located in an intergenic region on chromosome 3p22.3. Both loci reached significance in the subset of participants with type 2 diabetes alone (467 cases vs 618 controls). An additional locus of interest was identified in the subset of patients with macular edema onchromosome 5p15 (p=7.18x10-9). Adjustment for HbA1c, hypertension, nephropathy, duration of diabetes and sex revealed an additional locus on chromosome 2q22 in the blinding DR group (p=5.9x10-8).
This study has identified several candidate loci for blinding diabetic retinopathy and specific subtypes of proliferative retinopathy and macular edema. These loci and other highly ranked variants are undergoing genotyping in an independent sample set for replication analysis and results will be presented.
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