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Potential biomarker for diabetic retinopathy uncovered through genome-wide mRNA analysis

Researchers based at the Institute of Ophthalmology, Conde de Valenciana, Mexico City, have published the results of a genome wide mRNA screen which suggest a potential link between alternative splice forms of the TUBD1 gene, and a risk for developing diabetic retinopathy (DR). While the study was performed on a relatively small number of diabetic patients, the initial results may present a diagnostic opportunity to highlight those diabetic patients at a higher risk of developing a retinopathy as time progresses. Given that an estimated 30% of all diabetic patients will develop an ophthalmic complication, the earlier a diagnosis can be made the more opportunities there may be to introduce preventative and management strategies to improve patient care.


The Mexican research team designed their studies to explore the potential contribution of alternative gene splicing events in DR development. Alternative splicing is a well-documented process that occurs across multiple species whereby several protein outputs may arise from alternative concatentation of gene exons from within a single gene transcript. Depending on how specific sections of a gene are spliced together prior to translation, alternate polypeptide sequences may be translated. The process is a post-transcriptional regulatory mechanism that determines the inclusion/exclusion of certain exons into mature mRNAs, giving rise to multiple protein isoforms that increase the overall proteome diversity. The researchers compared alternative splicing detected in blood-derived samples of RNA from both DR subjects and from non-DR controls (patients diagnosed with diabetes but with as yet no ocular comorbidity). 95 RNA samples, 67 from patients with bilateral DR and 28 from diabetic patients without DR (but with type 2 diabetes) were compared in a genome-wide transcriptome analysis, covering an estimated ~33,500 coding transcripts of annotated genes. In addition, microarray data analysis and cDNA sequencing showed up differential splicing events in the TUBD1 gene (Tubulin, Delta-1). Co-expression of particular TUBD1 isoforms was significantly associated with non-proliferative DR risk (p=0.039, OR (CI 95%): 8.1 (1.0 – 72.7)).


The team looked at what function might be carried out by the TUBD1 gene in the retina by analyzing signal pathways involving TUBD1 and found that HIF-1 (hypoxia inducible factor 1) may be involved in regulation of TUBD1. As HIF1 is also known to play an important role in DR pathology, the new research may have identified a piece of the map critical to the molecular pathology of DR. The association of particular isoforms in those with DR compared to those without DR, the discovery may provide a means to use this molecular knowledge to see if it might flag up DR patients that are clinically pre-symptomatic. Such a tool in the diagnostic kit could have a significant impact on diagnosis, prevention and care of DR. The researchers concluded that “our results indicate that the absence of co-expression of TUBD1 a and b (Vab) isoforms is significantly associated with the risk of developing DR, specifically proliferative retinopathy, whereas the co-expression of TUBD1 isoforms a, b, and d (Vabd) is associated with risk for developing non-proliferative retinopathy.” If the finding holds true on much larger populations of diabetic patients, then transfer to clinical utility will be the next challenge.