Genome-wide association study (GWAS) in diabetic retinopathy indicates association near the GRB2 gene on human chromosome 17

Research, led by scientists at Flinders University, Adelaide, Australia, has reported the first association of a genetic locus on human chromosome 17 with diabetic retinopathy. The study, supported by the National Health and Medical Research Council (NHMRC) of Australia and the Ophthalmic Research Institute of Australia, was aimed at identifying novel genetic risk loci for diabetic retinopathy in patients of European descent with type 2 diabetes. In addition, the research aimed to leverage other genetic studies to underscore any association in patients of the same ethnicity with type 1 and type 2 diabetes and in an Indian type 2 diabetes cohort. A significant association was found in the proximity of the GRB2 gene (Growth Factor Receptor-Bound Protein 2), a viable gene candidate for involvement in diabetic retinopathy given its potential role in insulin pathways and VEGF signaling. While the overall GWAS numbers may be small, future larger studies and further meta-analyses will be important in extending the finding.

 

The research study was conducted on 442 diabetic retinopathy (DR) cases and 582 controls, from which principal components analysis excluded 69 participants as ethnic outliers while a further 111 subjects were excluded due to missing clinical covariate measurements. From the remaining 336 DR cases and 508 controls, computational analyses showed that the marker, rs9896052 (p=6.55Å~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 research team additionally reported that study-wide meta-analysis reached genome-wide significance (p=4.15Å~10−8). The GRB2 gene is located downstream of the rs9896052 marker and a mouse model of retinopathy analysed by the research group showed increased GRB2 expression in the retina.

 

While poor glycaemic control is a known risk factor for diabetic retinopathy it is also recognized that regular and tight control does not automatically prevent the disease and, according to the research group, intensive diabetic control can result in increased mortality. As such, it is important to uncover any other factors that may contribute to diabetic retinopathy which might then be addressed at a therapeutic level. While the study recognized previous GWAS projects that had aimed at revealing genetic associations, many such studies did not meet the statistical thresholds for genome-wide significance. The suspected GRB2 gene product is understood to bind phosphorylated insulin receptor substrate 1 and subsequently activate the MAPK pathway via Ras in response to insulin. This protein is also understood to be involved in vascular endothelial growth factor (VEGF) signalling and angiogenesis, both of which are characteristic of proliferative diabetic retinopathy. The GRB2 gene has been shown to encode two transcripts in humans, one is expressed in most human tissues while the other appears to be either absent from most cells or expressed at far lower levels. According to the Australian research team, the GRB2 protein was observed in all layers of the human and mouse retina and, most importantly, it was demonstrated that retinal stress in a rodent model that leads to neovascular retinopathy results in an increase in GBR2 expression suggesting an active role for the gene in the pathology of diabetic retinopathy. GRB2 response to retinal stress was also demonstrated in the retina of transgenic models of selective Müller cell ablation, further strengthening a putative role for the transcript in DR patients.