Burdon, KP and Fogarty, RD and Shen, W and Abhary, S and Kaidonis, G and Appukuttan, B and Hewitt, AW and Sharma, S and Daniell, M and Essex, RW and Chang, JH and Klebe, S and Lake, SR and Pal, B and Jenkins, A and Govindarjan, G and Sundaresan, P and Lamoureux, EL and Ramasamy, K and Pefkianaki, M and Hykin, PG and Petrovsky, N and Brown, MA and Gillies, MC and Craig, JE, Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene, Diabetologia, 58, (10) pp. 2288-2297. ISSN 0012-186X (2015) [Refereed Article]
Copyright 2015 Springer-Verlag
Methods: Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot.
Results: The top ranked variant was rs3805931 with p = 2.66 × 10−7, but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10−5) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10−8). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina.
Conclusions/interpretation: Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.
|Item Type:||Refereed Article|
|Keywords:||blinding retinopathy, diabetic complications, genetic risk factors, genome-wide association study, Muller cell, proliferative retinopathy|
|Research Division:||Medical and Health Sciences|
|Research Group:||Ophthalmology and Optometry|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Hearing, Vision, Speech and Their Disorders|
|Author:||Burdon, KP (Associate Professor Kathryn Burdon)|
|Author:||Hewitt, AW (Professor Alex Hewitt)|
|Web of Science® Times Cited:||17|
|Deposited By:||Menzies Institute for Medical Research|
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