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Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene


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]

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Copyright 2015 Springer-Verlag

DOI: doi:10.1007/s00125-015-3697-2


Aims/hypothesis: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.

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 Details

Item Type:Refereed Article
Keywords:blinding retinopathy, diabetic complications, genetic risk factors, genome-wide association study, Muller cell, proliferative retinopathy
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Burdon, KP (Professor Kathryn Burdon)
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:102331
Year Published:2015
Web of Science® Times Cited:49
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-08-13
Last Modified:2018-12-07
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