Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy

Ung, Cindy; Sanchez, Angie V.; Shen, Lishuang; Davoudi, Samaneh; Ahmadi, Tina; Navarro-Gómez, Daniel; Chen, Ching J.; Hancock, Heather; Penman, Alan D.; Hoadley, Suzanne; Consugar, Mark; Restrepo, Carlos Martín; Shah, Vinay; Arboleda‐Velásquez, Joseph F.; Sobrin, Lucia; Gai, Xiaowu; Kim, Leo A.

doi:10.1016/j.visres.2017.03.007

Cited by 34 publications

(23 citation statements)

References 52 publications

(40 reference statements)

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“…WES including 107 Saudi-Arabian individuals with T2D found enrichment of rare variants in those without DR in the NME3, LOC728699, and FASTK genes (p<5×10 -8 ) [35]. Another WES including 70 individuals of mixed ethnicity and mainly T2D, suggested six genes with rare variants in DR cases and reduced gene expression in human retinal endothelial cells, when cultured under high glucose [36]. However, findings from both studies require replication for validation of the association.…”

Section: Diabetic Retinopathy (Dr)mentioning

confidence: 98%

Genetic basis of diabetic kidney disease and other diabetic complications

Sandholm

Groop

2018

Current Opinion in Genetics & Development

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Diabetic kidney disease and other long-term complications are common in diabetes, and comprise the main cause of co-morbidity and premature mortality in individuals with diabetes. While familial clustering and heritability have been reported for all diabetic complications, the genetic background and the molecular mechanisms remain poorly understood. In recent years, genome-wide association studies have identified a few susceptibility loci for the renal complications as well as for diabetic retinopathy, diabetic cardiovascular disease and mortality. As for many complex diseases, the genetic factors increase the risk of complications in concert with the environment, and certain associations seem specific for particular conditions, for example, SP3-CDCA7 associated with end-stage renal disease only in women, or MGMT and variants on chromosome 5q13 associated with cardiovascular mortality only under tight glycaemic control. The characterization of the phenotypes is one of the main challenges for genetic research on diabetic complications, in addition to an urgent need to increase the number of individuals with diabetes with high quality phenotypic data to be included in future genetic studies.

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Section: Diabetic Retinopathy (Dr)mentioning

confidence: 98%

Genetic basis of diabetic kidney disease and other diabetic complications

Sandholm

Groop

2018

Current Opinion in Genetics & Development

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“…DM is characterized by high blood glucose and leads to multiple complications including diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy (Baba and Ishizaki, 1992;Chen et al, 2017;Hung et al, 2017;Ung et al, 2017). Moreover, silymarin administration attenuated myocardial fibrosis and collagen deposition through decreased TGF-b1 and p-Smad2/3 levels but increased the level of Smad7 in the hearts of DM rats.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, silymarin administration attenuated myocardial fibrosis and collagen deposition through decreased TGF-b1 and p-Smad2/3 levels but increased the level of Smad7 in the hearts of DM rats. DM is characterized by high blood glucose and leads to multiple complications including diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy (Baba and Ishizaki, 1992;Chen et al, 2017;Hung et al, 2017;Ung et al, 2017). Of these, DCM is a major complication, causing high morbidity and mortality (Frati et al, 2017;Gilca et al, 2017;Hu et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Silymarin ameliorates diabetic cardiomyopathy via inhibiting TGF‐β1/Smad signaling

Meng

Yang

Wang

et al. 2018

Cell Biology International

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Diabetic cardiomyopathy (DCM) is the leading cause of morbidity and mortality in diabetes mellitus (DM) patients. Previous studies have shown that the transforming growth factor-beta 1 (TGF-b1)/Smad signaling pathway plays a key role in the development of myocardial fibrosis in DCM. Silymarin (SMN) is used clinically to treat liver disorders and acts by influencing TGF-b1. However, the possible effects of silymarin on DCM remain to be elucidated. In our study, the DM animal model was induced by streptozotocin (STZ) injection. Fasting blood glucose level was measured, and the structure and function of the heart were measured by hematoxylin and eosin (H&E) and Masson staining, echocardiography, and transmission electron microscopy (TEM). Western blot was used to detect the expression of TGF-b1, Smad2/3, phosphorylation Smad2/3(p-Smad2/ 3), and Smad7. Our results showed that silymarin downregulated blood glucose level and significantly improved cardiac fibrosis and collagen deposition in DM rats detected by H&E, Masson staining, and TEM assays. The echocardiography results showed that silymarin administration attenuated cardiac dysfunction in DM rats. Additionally, compared with untreated DM rats, levels of TGF-b1 and p-Smad2/3 were decreased, whereas Smad7 was increased following silymarin administration. These data demonstrate that silymarin ameliorates DCM through the inhibition of TGF-b1/Smad signaling, suggesting that silymarin may be a potential target for DCM treatment.

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“…Recently, the WES approach has been used to identify the genetic variants associated with DR in two independent studies (see Table 3) [89,90]. Shtir and colleagues based their study on an 'extreme' phenotype design to search for 'protective' gene variants in a Saudi population, hypothesizing that using stringent criteria for study controls would enhance the probability to yield robust candidate variants [89].…”

Section: Whole Exome Sequencingmentioning

confidence: 99%

“…More recently, Ung and colleagues used a similar approach to analyze an African American (AA) Type 2 diabetic cohort from the African American Proliferative Diabetic Retinopathy Study and a mixed ethnicity (ME) cohort that included Type 1 and Type 2 diabetic participants of African American, Caucasian, and Hispanic backgrounds [90]. The DR phenotype under study was PDR and these cases were compared to the AA Type 2 diabetic control cohort which had a duration of diabetes for a minimum of 10 years.…”

Section: Whole Exome Sequencingmentioning

confidence: 99%

Do Genomic Factors Play a Role in Diabetic Retinopathy?

Cabrera

Monickaraj

Rangasamy

et al. 2020

JCM

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Although there is strong clinical evidence that the control of blood glucose, blood pressure, and lipid level can prevent and slow down the progression of diabetic retinopathy (DR) as shown by landmark clinical trials, it has been shown that these factors only account for 10% of the risk for developing this disease. This suggests that other factors, such as genetics, may play a role in the development and progression of DR. Clinical evidence shows that some diabetics, despite the long duration of their diabetes (25 years or more) do not show any sign of DR or show minimal non-proliferative diabetic retinopathy (NPDR). Similarly, not all diabetics develop proliferative diabetic retinopathy (PDR). So far, linkage analysis, candidate gene studies, and genome-wide association studies (GWAS) have not produced any statistically significant results. We recently initiated a genomics study, the Diabetic Retinopathy Genetics (DRGen) Study, to examine the contribution of rare and common variants in the development of different phenotypes of DR, as well as their responsiveness to anti-VEGF treatment in diabetic macular edema (DME). Our preliminary findings reveal a novel set of genetic variants involved in the angiogenesis and inflammatory pathways that contribute to DR progression or protection. Further investigation of variants can help to develop novel biomarkers and lead to new therapeutic targets in DR.

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Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy

Cited by 34 publications

References 52 publications

Genetic basis of diabetic kidney disease and other diabetic complications

Genetic basis of diabetic kidney disease and other diabetic complications

Silymarin ameliorates diabetic cardiomyopathy via inhibiting TGF‐β1/Smad signaling

Do Genomic Factors Play a Role in Diabetic Retinopathy?

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