Challenges in Elucidating the Genetics of Diabetic Retinopathy

Kuo, Jane Z.; Wong, Tien Yin; Rotter, Jerome I.

doi:10.1001/jamaophthalmol.2013.5024

Cited by 97 publications

(74 citation statements)

References 115 publications

(139 reference statements)

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“…Recent metabonomic studies have uncovered plasma and sera metabolic signatures associated with, or predictive of, impaired glucose tolerance and diabetes (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Furthermore, DR is a complex disease where findings from genomewide association studies have not been conclusive (23). We postulate that a distinct metabolic signature of DR exists and can be resolved from that of diabetes alone.…”

mentioning

confidence: 85%

Plasma Metabonomic Profiling of Diabetic Retinopathy

et al. 2016

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Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in working-age adults. Patients with diabetes often develop DR despite appropriate control of systemic risk factors, suggesting the involvement of other pathogenic factors. We hypothesize that the plasma metabolic signature of DR is distinct and resolvable from that of diabetes alone. A nested populationbased case-control metabonomic study was first performed on 40 DR cases and 40 control subjects with diabetes using gas chromatography-mass spectrometry. Eleven metabolites were found to be correlated with DR, and the majority were robust when adjusted for metabolic risk factors and confounding kidney disease. The metabolite markers 2-deoxyribonic acid; 3,4-dihydroxybutyric acid; erythritol; gluconic acid; and ribose were validated in an independent sample set with 40 DR cases, 40 control subjects with diabetes, and 40 individuals without diabetes. DR cases and control subjects with diabetes were matched by HbA 1c in the validation set. Activation of the pentose phosphate pathway was identified from the list of DR metabolite markers. The identification of novel metabolite markers for DR provides insights into potential new pathogenic pathways for this microvascular complication and holds translational value in DR risk stratification and the development of new therapeutic measures.Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in working-age adults worldwide (1,2). The global prevalence of diabetes is rising and the number of people with diabetes is projected to increase by 54% in 2030, compared with 2010 (3). The public health burden of diabetes and DR would thus increase correspondingly. The major risk factors of DR are poor glycemic control and hypertension, as well as the duration of diabetes (4,5), but their relative importance varies between studies (2,6). Although the risks of DR progression and vision loss are reduced with intensive control of risk factors (7,8), many patients with diabetes continue to develop complications despite tight glycemic and blood pressure control. There is increasing evidence to suggest that "metabolic memory" is responsible for this observation. The term metabolic memory refers to the persistent epigenetic modifications caused by early exposure to hyperglycemia that, in turn, predispose individuals to the development of diabetes complications even after good glycemic control

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confidence: 85%

Plasma Metabonomic Profiling of Diabetic Retinopathy

et al. 2016

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“…This assumption is supported by twin and family studies showing concordance for diabetic retinopathy [280]. As yet, no genetic markers are used in clinical practice in diabetes, and there are few genetic studies for diabetic retinopathy compared with the number of genetic studies for diabetes per se, diabetic nephropathy, or non-diabetic-related ocular diseases.…”

Section: Molecular Biomarkersmentioning

confidence: 99%

“…Earlier genetic studies, including twin and family studies, candidate gene and linkage studies, and small GWAS analyses are well reviewed and summarized by Kuo et al [280]. Genes related to pathways and other biomarkers implicated in retinopathy have been identified in some, but not all studies, including genes related to: Unlike candidate gene studies, a genome-wide association study (GWAS) provides an unbiased assessment of genes implicated in a disease process.…”

Section: Gwas and Snpsmentioning

confidence: 99%

Biomarkers in Diabetic Retinopathy

et al. 2015

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■ AbstractThere is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy.

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“…However, the results from candidate gene studies have been inconsistently replicated, as summarized in other articles [21][22][23]. Here, we will highlight some of the best powered candidate gene studies, and the more extensively examined candidate genes, including vascular endothelial growth factor (VEGF), erythropoietin (EPO), transcription factor 7-like 2 (TCF7L2), aldose reductase (ALR), receptor for advanced glycation end-products (RAGE) genes, and genes in the renin-angiotensin system [22].…”

Section: Candidate Gene Association Studiesmentioning

confidence: 99%

Novel Genetic Actors of Diabetes-Associated Microvascular Complications: Retinopathy, Kidney Disease and Neuropathy

Davoudi¹,

Sobrin²

2016

Rev Diabet Stud

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■ AbstractBoth type 1 and type 2 diabetes mellitus can lead to the common microvascular complications of diabetic retinopathy, kidney disease, and neuropathy. Diabetic patients do not universally develop these complications. Long duration of diabetes and poor glycemic control explain a lot of the variability in the development of microvascular complications, but not all. Genetic factors account for some of the remaining variability because of the heritability and familial clustering of these complications. There have been a large number of investigations, including linkage studies, candidate gene studies, and genome-wide association studies, all of which have sought to identify the specific variants that increase susceptibility. For retinopathy, several genomewide association studies have been performed in small or midsize samples, but no reproducible loci across the studies have been identified. For diabetic kidney disease, genomewide association studies in larger samples have been performed, and loci for this complication are beginning to emerge. However, validation of the existing discoveries, and further novel discoveries in larger samples is ongoing. The amount of genetic research into diabetic neuropathy has been very limited, and much is dedicated to the understanding of genetic risk factors only. Collaborations that pool samples and aim to detect phenotype classifications more precisely are promising avenues for a better explanation of the genetics of diabetic microvascular complications.

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Challenges in Elucidating the Genetics of Diabetic Retinopathy

Cited by 97 publications

References 115 publications

Plasma Metabonomic Profiling of Diabetic Retinopathy

Plasma Metabonomic Profiling of Diabetic Retinopathy

Biomarkers in Diabetic Retinopathy

Novel Genetic Actors of Diabetes-Associated Microvascular Complications: Retinopathy, Kidney Disease and Neuropathy

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