Article:Candidate gene studies of diabetic retinopathy in human (5102952)

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This page is the ScienceSource HTML version of the scholarly article described at Its title is Candidate gene studies of diabetic retinopathy in human and the publication date was 2016-12-01. The initial author is Petra Priščáková.

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Journal Information

Title: Molecular Biology Reports

Candidate gene studies of diabetic retinopathy in human

  • Petra Priščáková
  • Gabriel Minárik
  • Vanda Repiská

Publication date (epub): 10/2016

Publication date (pmc-release): 10/2016

Publication date (ppub): /2016


Diabetic retinopathy (DR) is a multifactorial disease with complex pathophysiology. It is the main cause of blindness among the people in productive age. The purpose of this literature review is to highlight recent achievements in the genetics of diabetic retinopathy with particular focus on candidate gene studies. We summarized most of the available published data about candidate genes for diabetic retinopathy with the goal to identify main genetic aspects. We conclude that genetic studies reported contradictory findings and no genetic variants meet criteria of a diagnostic marker, or significantly elucidate the root of DR development. Based on these findings it is important to continue with the research in the field of DR genetics, mainly due to the fact that currently new possibilities and approaches associated with utilization of next-generation sequencing are available.



Diabetes mellitus (DM) is one of the most significant health problems worldwide. It is a metabolic disorder in which elevated blood sugar levels are present as a result of the inability to produce a sufficient amount of insulin (type 1) or because of cellular insulin resistance (type 2). Both types of diabetes are associated with hyperglycaemia, oxidative stress, inflammation and macrovascular (coronary artery disease, atherosclerosis, hypertension and stroke) and microvascular complications such as retinopathy, nephropathy and neuropathy [[1]].

The number of patients with diabetes mellitus is rapidly increasing every year. Global mortality resulting from diabetes in adults was estimated to be 1.5 million deaths in 2012 (World Health Organization). It is estimated that there will be 418 million patients with impaired glucose tolerance and 380 million patients with T2DM by 2025 [[2]].

Diabetic retinopathy (DR) is a leading cause of visual impairment in patients at productive age. These alarming numbers highlight the necessity of optimization of diagnostic methods that will allow early identification of diabetic patients with significantly elevated risk of DR development that will help start optimal prevention and intervention. DR has an overall prevalence of 22–37 % in individuals with known diabetes. It leads to damage of the retina microvasculature as a result of prolonged exposure to metabolic changes induced by diabetes. If left untreated, it may lead to blindness on account of continuous blood leakage due to the loss of retinal pericytes and fenestration [[1]]. DR is classified into two categories based on severity, namely less-severe nonproliferative diabetic retinopathy (NPDR) and severe proliferative diabetic retinopathy (PDR). The key changes of the retina in NPDR, as a result of hypoxia and venous bleading, are microaneurysms, vascular leakage, hard exudates, intraretinal microvascular abnormalities and cotton wool spots (Fig. 1). Retinal neovascularization induced by ischemia is the main characteristic of PDR [[3]].

Fig. 1

Symptoms and pathological processies typical for diabetic retinopathy leading to vision lost. EBM endothelial basal membrane, BRB blood retinal barrier, EC endothelial cell

The aetiology of this complex disease remains unclear and poorly understood. It is associated with both environmental and genetic factors. The possibility of developing and progression of DR is closely related to the duration of DM [[1]]. Almost all patients with T1DM and >60 % of patients with T2DM are anticipated to have some type of retinopathy within the first 10 years of diabetes being diagnosed. The Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) clinical trials have also confirmed significant association between chronic hyperglycaemia and development and progression of DR, however, the fundamentals of how hyperglycaemia causes microvascular changes in the retina has not been fully elucidated [[4]]. Involvement of several biochemical pathways which can elucidate the role of hyperglycaemia in DR pathophysiology has been proposed, including activation of diacyl-glycerol (DAG)-PKC pathway, accelerated formation of advanced glycation endproducts (AGE), increased polyol pathway flux, increased expression of growth factors (VEGF, IGF-1), haemodynamic changes, renin-angiotensine-aldosterone system (RAAS), leukostasis, subclinical inflammation, and oxidative stress that leads to increased expression of several proinflammatory genes (NF-κB, TGF-β, NOX4, Nrf2, etc.). Other risk contributors for DR development are dyslipidemia [[5]] and possibly blood pressure, but studies are contradictory about these risk modifiers [[4], [6]]. Pathways contributing to DR pathologies alongside with relevant genes are summarized in Fig. 2. In summary, increased vascular permeability, haemostatic abnormalities, endothelial dysfunction, increased tissue ischemia, angiogenesis and neovascularization is typical for overall DR pathophysiology [[1]].

Fig. 2

Putative roles of genes identified by candidate genes studies in pathophysiological processies during diabetic retinopathy. RAAS renin–angiotensin–aldosterone system, AGE advanced glycation end-product, IO intraoccular, EBM endothelial basal membrane, BRB blood retinal barrier

Genetic aspects of the diabetic retinopathy

The above mentioned risk factors are not solely responsible for susceptibility to DR. Clinical studies have revealed considerable variations in the retinopathy onset and severity that cannot be fully explained by known risk factors such as the duration of diabetes, the level of glycemic control, or concomitant vascular disease [[7]]. For instance, some people might have DR even when they have good glycemic control and duration of DM is short. In contrast, other patients have poor glycemic control and prolonged duration of DM and yet may not develop DR. The probability of DR development also depends on the ethnicity; the Hispanics, the individuals of African descent and the Asians are more susceptible to DR [[8], [9]]. A study from 2008 reported retinopathy symptoms, including retinal microaneurysms, in nondiabetic patients with an optimal glucose level (glycosylated haemoglobin levels <5.0 %) [[10]] and these microvascular changes were indistinguishable from lesions in diabetic DR. Therefore there is evidence that additional risk factors and genetic predispositions have a part in the development and progression of DR and that these factors are independent of DM.

This is a solid confirmation of genetic contribution to the development and progression of DR. Over the past several years, progress has been made in identifying some of the susceptibility loci associated with DR through twin studies, family studies, candidate gene studies, linkage studies and small-scale GWAS (genome-wide association study). Twin and family studies have demonstrated that risk of DR emergence is three times higher for patients with a family history of DR than in patients without it for both T1DM and T2DM. Concordance is dramatically higher among monozygotic twins when compared to dizygotic twins [[11]]. One of the first twin studies has reported DR concordance of 68 % in T1DM and 95 % in T2DM [[12]]. Heritability score increases with the severity of DR, and has been estimated to be 18 and 52 % for DR and PDR, respectively [[13]].

Candidate genes studies

Our knowledge of pathophysiology of DR allows us to propose possible candidate genes, which could play a role in the development and progression of DR. Candidate gene studies compare the frequency of a particular genetic variant in subjects with or without DR. This approach has revealed several genes with a possible key role in DR. These genes are part of different physiological and pathophysiological processes in organism, often associated with inflammation, such as RAAS (renin–angiotensine–aldosterone system), glucose induced pathways, remodeling of extracellular matrix (ECM), vascular endothelial dysfunction, and angiogenesis. It has been proposed that a great number of factors and genes with modest effect, as a part of different biochemical pathways, invoke pathological processes leading to DR.

Polyol pathway and its role in DR

Polyol pathway represents the main metabolic link between hyperglycaemia and damages caused by DM. Aldose reductase (ALR2) is the essentialenzyme in the pathway. ALR2 converts glucose to sorbitol in an NADPH-dependent reaction. During the hyperglycaemia sorbitol accumulates in cells and induces osmotic stress and cellular damage. The above mentioned process leads to the destruction of retinal cells, microaneurysms, thickening of the basement membrane and loss of pericytes in animal models, which are also typical symptoms of DR in humans [[14]]. Three DR-associated ALR2 polymorphisms have been identified in different populations (see Table 1). The first polymorphism located at the 5′ end of the gene, the Z-2 allele of the (CA)n microsatellite located at the 5′ end of the gene increases risk of DR. In contrast, Z + 2 and Z alleles show protective effect against DR [[15]]. Another polymorphism, rs759853, has shown association with DR where T allele confers protection against DR in T1DM [[15], [16]]. However, the use of AKR (aldo–keto reductase) inhibitors did not confirm expected results in clinical trials and they could not prevent progression of the disease [[17]]. But these clinical trials disregarded the genetic variants in the AKR2 gene which could have had negative impact on the function of AKR inhibitors. Another enzyme in the polyol pathway, sorbitol dehydrogenase (SDH) converts sorbitol into fructose in NAD+-dependent reaction. Amano et al. found that SDH overexpression potentiated glucose toxicity to cultured retinal pericytes, thus leading to acceleration of pericyte loss, a typical trait of DR [[18]]. Polymorphisms rs2055858 and rs3759890 were identified in Polish, Japanese and Caucasian-Brazilian population and it is possible that they could affect the promoter activity of the SDH gene and have role in onset of DR [[18], [19]].

Table 1

Summary of genes identified by candidate genes studies with possible role in pathophysiology of DR

Gene symbol Gene name Function/cellular role Polymorphism Ch. Type of DM Population Comments Ref.
AKR1B1/ALR2 Aldose reductase gene Polyol pathway—conversion of glucose to sorbitol rs35839483 [(CA)n dinucleotide repeats] 7 1 and 2 Chinese, Japanese, Indians, Chileans, Brazilians z-2 microsatellite confers risk in all DR, z2 microsatellite against all DR [[20][27]]
rs759853 (c. C-106T) 7 2 Euro-Brazilian, Mainland Chinese, Han Chinese, Japanese T allele protective against DR but according to some studies it is weak association [[25], [26], [28][30]]
rs9640883 7 2 Australian Association with onset of diabetes [[25]]
SDH Sorbitol dehydrogenase Polyol pathway—conversion of sorbitol to fructose rs2055858 (c. C-1214G) 15 2 Poland Weak associations; polymorphism possibly affect promoter activity [[18], [19]]
rs3759890 (c. G-888C) 15 2 Japan, Poland, Caucasian-Brazilians Inconsistent finding, polymorphism possibly affect promoter activity [[18], [31]]
ALDH2 Mitochondrial aldehyde dehydrogenase 2 Polyol pathway—transformation from acetaldehyde to acetic acid, prevents creation of AGE ALDH2*2 12 2 Japanese Associated with protective effect against DR [[32]]
VEGF Vascular endothelial growth factor Stimulation of angiogenesis and vasculogenesis rs2010963 (c. C-634G) 6 2 Japanese, Indian, Caucasian C allele confers risk for NPDR in T2DM [[33][41]]
(c. C-460T) 6 1 and 2 Caucasian Possible association with DR [[42], [43]]
rs25648 6 2 Multi-ethnic T allele increase risk of DR but finding inconsistent [[33], [34], [37]]
rs1570360 (c. A-116G) 6 2 Multi-ethnic Inconsistent finding [[33], [34], [42]]
rs3095039 6 2 Multi-ethnic T allele increase risk of DR but finding inconsistent [[33][36]]
rs35569394 6 1 and 2 Multi-ethnic (− 2549) DEL increases risk but finding inconsistent [[33]]
rs699947(c. A-2578C) 6 2 Multi-ethnic A allele increases risk but finding inconsistent [[33], [36], [40], [43][46]]
rs13207351 (c. A-152G) 6 1 and 2 Caucasian Associated with PDR in some of the studies [[34], [42], [46]]
rs735286 (c. C4618T) 6 1 and 2 Caucasian Haplotype-tagged SNP associated with severity of DR [[42]]
rs2146323 (c. C5092A) 6 1 and 2 Caucasian Haplotype-tagged SNP associated with severity of DR, associated with early progression of DR [[42], [44], [47]]
rs833061 (c. C-1498T) 6 2 Chinese Inconsistent finding and weak association [[34], [37], [39], [46]]
rs3025021 6 2 Chinese Inconclusive [[33], [46]]
rs10434 6 1 and 21 and 2 Caucasian G allele associated with blinding DR [[33]]
rs833068 6 1 and 2 Caucasian G allele confers risk in DR [[33]]
rs833070 6 1 Japanese Associated with early progression of DR but weak association [[44]]
rs3025039 (c. C+936T) 6 2 Caucasian T allele increases risk [[48]]
bFGF/FGF2 Basic fibroblast growth factor/fibroblast growth factor 2 Stimulation of angiogenesis and tissue repair rs41456044 4 2 Multi-ethnic A allele increases risk but weak associations [[15]]
rs308395 4 2 Multi-ethnic G allele increases risk but finding inconsistent [[15]]
c. C-754G 4 2 Slovak C allele increases level of bFGF [[49]]
c. T − 553 Ac. T−834A 4 2 Caucasian AT genotype could be risk factor for PDR during T2DM [[50]]
IGF-1 Insulin-like growth factor 1 Stimulation of cell growth and proliferation, inhibition of apoptosis (CA)n 4 2 Southern Indian 18-repeat of (CA) increases risk of DR [[51]]
EPO Erythropoietin Control of erythropoiesis, stimulation of proliferation, migration and angiogenesis in hypoxic cells rs1617640, rs507392, rs551238 7 1 and 2 Multi-ethnic, European American, Australian TTA allele associated with PDR in European American, meta-analysis hasn´t found significant association; GCC haplotype associated with DR in Australian [[15], [52], [53]]
RAGE Advanced glycosylation end product-specific receptor Activation of pro-inflammatory genes rs1800624 (c. T-374A) 6 2 Indian, Chinese, African-Brazilian, Caucasian - Scandinavian Inconsistent finding and weak association, may be interacting with glycosylated hemoglobin [[15], [54][56]]
rs1800625 (c. T-429C) 6 2 Caucasian, Indians, Danish Inconsistent finding and weak association, functional studies show differences in polymorphic receptor activity [[55][60]]
rs2070600 (p. G82S) 6 2 Caucasian, Indian, Chinese, Malaysian Associated with DR, no association in Malaysian [[15], [58], [61]]
ACE I Angiotensin-I converting enzyme Component of the renin-angiotensin system—activation of angiotensin II rs4646994 (c. G2350A)-INS/DEL at intron 16 17 1 and 2 Caucasian - Slovene, Danish; Japanese, Multi-ethnic, Iranian, Japanese, Chinese, Pakistani D allele possibly associated with DR in T2DM in Chinese, but inconsistentfinding and weak association in other populations, associated with NPDR in Pakistani [[62][66]]
GSTT1 Glutathione S-transferase T1 Detoxifying enzyme—conjugation of reduced glutathione to a compounds Null genotype 22 2 Caucasian - Slovenian Greater risk of DR [[67]]
GSTM1 Glutathione S-transferase M1 Detoxifying enzyme—conjugation of reduced glutathione to a compounds Null genotype 1 2 Caucasian - Slovenian Lower risk of DR [[67]]
SOD2/MnSOD Mitochondrial manganese superoxide dismutase Decrease of ROS production (transformation to to peroxide and oxide) rs4880 (c. C47T, p. A16V) 6 1 and 2 Slovene (Caucasian), Finnish, Indian C allele reduces risk of DR, not confirmed in Indian population [[15], [36], [56], [65], [68], [69]]
eNOS3 Endothelial nitric oxide synthases Synthesis of nitric oxide (vasodilatation) rs3138808 (27 VNTR intron 4 a/b) 7 2 Indians, West African, Caucasian - Brazilian 4a allele protective effect against DR [[15], [37], [70][73]]
rs1799983 (c. C894T) 7 2 Caucasian—Brazilian, Danish, Multi-ethnic G allele increases risk but weak association [[15], [37], [50], [60], [72], [74]]
rs41322052 (c. T-784C) 7 1&2 Caucasian—Brazilian, Multi-ethnic Inconsistent finding and weak association [[37], [71], [72], [75]]
rs2297518 (c. G-954C) 7 2 Caucasian Protective factor against NPDR [[48]]
RXRA Retinoid X receptor alpha Nuclear receptor—retinoic acid-mediated gene activation(antoxidants properties) rs3132300 9 1 African American Associated with progression of DR [[76], [77]]
RXRG Retinoid X receptor gamma nuclear receptor—retinoic acid-mediated gene (antiproliferative effects) rs3818569 9 Taiwanese G allele associated with development of DR [[78]]
UCP1 Uncoupling protein-1 Mitochondrial anion carrier protein (thermogenesis), protection againt oxidative stress rs1800592 (c. A-3826G) 4 1 and 2 Brazilian, Chinese, Danish G allele associated with increased risk of PDR [[60], [75], [79]]
UCP2 Uncoupling protein-2 Mitochondrial anion carrier protein (thermogenesis), control of ROS production rs660339 (p. A55V, 45 bp INS/DEL) 11 1 and 2 Brazilian Risk factor for PDR [[77], [80]]
TLR4 Toll-like receptor 4 Pathogen recognition and activation of innate immunity rs10759931, rs1927914 9 2 Indian, Chinese A,T alleles positively modulate the risk of DR, rs1927914 associated with susceptibility to DR in a Han Chinese population [[3], [55]]
rs4986790, rs4986791 (p. D299G) 9 2 Polish G allele associated with early onset of DR [[81]]
CFH Complement factor H Regulator of complement activation rs800292 (p. I62V) 1 2 Chinese Associated with DR [[82]]
CFB Complement factor B Regulator of complement activation rs1048709 6 2 Chinese Associated with DR [[82], [83]]
MCP-1/CCL2 Monocyte chemoattractant protein-1 Cytokine—activation of monocytes, macrophages and lymphocytes rs1024611 (c. A-2518G) 17 2 Chinese, Korean, Japanese G allele associated with susceptibility to DR and specifically PDR in Koreans [[84][86]]
TGF-β1 Transforming growth factor-beta 1 Control of cell growth, proliferation, differentiation and apoptosis c. T869C (p. L10P) 19 2 Multi-ethnic Potential protect factor against DR [[15], [83]]
c. G915C (p. R25P) 19 2 Slovak Strong risk factor for PDR [[87]]
ICAM1 Intercellular adhesion molecule 1 Stabilization of cell–cell interactions and facilitation of leukocyte endothelial transmigration rs13306430 19 2 Multi-ethnic G allele confers protection [[15], [77]]
rs5498 (p. K469E) 19 2 Chinese, Indian, Japanese, Caucasian - Slovene Inconsistent finding, discrepancy maybe caused by ethnicities [[55], [88][93]]
SLC2A1/GLUT1 Solute carrier family 2, member 1 Transport of glucose across the plasma membranes rs841846 (c. A26177G) 1 1 and 2 African American, Malaysian Significant associations with severe DR, associated with progression of DR, not confirmed in Malaysian [[77], [94]]
rs841853 1 1 Malaysian, Multi-ethnic Weak association [[77], [94]]
SLC2A11 Solute carrier family 2, member 11 Transport of glucose across the plasma membranes rs4822441 22 1 African American Associated with progression of DR [[77]]
SLC24A3 Solute carrier family 24, member 3 Sodium-calcium exchanger rs2294895 20 1 African American Associated with progression of DR [[77]]
PPARγ Peroxisome proliferator-activated receptor γ Nuclear receptor—regulation of fatty acid storage and glucose metabolism, role in vascular permeability, inflammation, angiogenesis, neovascularization, and insulin resistance rs1801282 (c. C34G, p. P12A) 3 1 and 2 Caucasian - Poland; Chinese, Danish, Multi-ethnic G allele confers protection against DR in Caucasian but finding inconsistent - protective effect against only PDR during T2DM in Pakistan population, not for Asian patients [[60], [79], [95], [96]]
rs10510419 3 1 African American Associated with progression of DR [[15], [95]]
TCF7L2/TCF4 Transcription factor 7-like 2 Transcription factor for several genes (Wnt signaling pathway), vascular development rs7903146, rs7901695, rs12255372 10 2 Caucasian—Italian, Chinese, Multi-ethnic Associated with DR, cardiovascular disease and coronary artery disease, rs7903146 associated with DR risk in Caucasian [[15], [79], [96][98]]
OPG/OCIF Osteoprotegerin/osteoclastogenesis inhibitory factor Cytokine receptor rs2073618, rs3134069 8 2 Caucasian - Slovenian CA haplotype increase risk of DR [[99]]
PAI-1 Plasminogen activator inhibitor-1 Serine protease inhibitor—inhibitor of plasminogen activation, tissue repair and remodeling rs1799768 (4G/5G INS/DEL) 7 2 Indian, Caucasian, Euro-Brazilian, Multi-ethnic, Pakistani 4G/5G allele increases risk but finding inconsistent, ethnicity discrepancies [[28], [55], [66], [100], [101]]
MMP-2 Matrix metalloproteinase-2 Breakdown of extracellular matrix c. C-1306T 16 2 Chinese T allele associated with PDR [[7]]
ANGPT1 Angiopoietin 1 Vascular development and angiogenesis rs1283649 8 1 African American Significant associations with severe DR [[77]]
APOE Apolipoprotein E Transportation of lipoproteins, fat-soluble vitamins, and cholesterol E2/E3/E4 19 1 and 2 Mexicans, Multi-ethnic Inconsistent finding and weak association [[102], [103]]
BBS2 Bardet-Biedl syndrome 2 protein Unknown function and link to DR rs4784675 16 1 African American Significant associations with severe DR [[15]]
CPVL/CHN2 Carboxypeptidase, vitellogenic-like; chimerin 2 Carboxypeptidase—unknown function/regulation of a cell growth, proliferation, and migration rs39059 7 2 Chinese Increases risk of DR, significant in meta-analysis [[77], [104]]
rs1002630 7 2 Taiwanese Associated with DR and NPDR [[142]]
CTSH Cathepsin H Lysosomal cysteine proteinase - degradation of lysosomal proteins, putative role in microcirculation changes rs3825932 15 1 Danish T allele associated with reduced risk of progression to PDR [[60]]
DRD2 Dopamine receptor D2 Dopamine receptor—regulation of vasodilatation, aldosterone production and insulin secretion rs7131056 11 1 African American Significant associations with severe DR [[77]]
EDN1 Endothelin-1 Vasoconstriction rs5370 (p. K198N) 6 2 Chinese Reduced risk in Chinese [[77], [105]]
ENPP1 Ectonucleotide pyrophosphatase/phosphodiesterase 1 Insulin resistance, interaction with integrins rs1409181 6 1 African American Significant associations with severe DR [[77]]
ERBB3/HER3 Human epidermal growth factor receptor 3 Protein-tyrosine kinase—activation of downstream signaling pathways, unknown link to DR rs2292239 12 1 Danish T allele associated with reduced risk of progression to PDR [[60]]
FLT1/VEGFR1 FMS-like tyrosine kinase 1/vascular endothelial growth factor receptor 1 Protein-tyrosine kinase—control of cell proliferation and differentiation rs622227 13 1 African American Associated with progression of DR [[77]]
FRMD3 FERM domain containing 3 Maintaining cellular shape, putative TSG, unknown link to DR rs10868025 9 2 Chinese Weak association with DR [[104]]
HLA-B Major histocompatibility complex, class I, B Regulation of the immune system—presenting peptides on the cell surface rs2523608 6 1 African American Significant associations with severe DR, associated with progression of DR [[77]]
HTR1B Serotonin receptor 1B GPCR for serotonin—regulation of the serotonin, dopamine, and acetylcholine release, putative regulator of retinal blood flow rs1228814 6 1 African American Significant associations with severe DR [[77]]
HTRA1/ARMS2 HtrA serine peptidase 1/age-related maculopathy susceptibility 2 Serine protease—regulation of insulin-like growth factors, putative regulator of cell growth and neovascularization rs11200638, rs10490924 10 2 Indian Marginal association with DR [[55]]
IL-10 Interleukin-10 Cytokine—pleiotropic effects in immunoregulation and inflammation n. A-1082G 1 2 Indian G allele is risk factor for PDR [[113]]
INSR Insulin receptor Activation of the insulin signaling pathway rs10500204 19 1 African American Associated with progression of DR [[77]]
ITGA2B1 Integrin α2β1 Cell–cell and cell-extracellular matrix interactions RFLP - Bgl II 5/10 2 Japanese, Caucasian Risk factor for DR [[15], [106], [143]]
ITGB5 Integrin β5 Cell–cell and cell-extracellular matrix interactions rs9865359 3 1 African American Associated with progression of DR [[15]]
MTHFR Methylenetetrahydrofolate reductase Remethylation of homocysteine to methionine rs1801133 (c. C677T) 1 2 Japanese, Euro-Brazilian, Multi-ethnic, Turkish Controversial findings, T allele possible increases risk of DR because of hyperhomocysteinemia [[28], [77], [107], [108]]
NPY Neuropeptide Y (p. L7P) Vasoconstriction, angiogenesis rs16139 7 2 Finnish C allele increases risk but weak association [[144]]
OLR1 Oxidited low-density lipoprotein (lectin-like) receptor 1 Recognition, internalization and degradation of oxidized low-density lipoprotein, putative regulator of Fas-induced apoptosis rs2742115 12 1 African American Associated with progression of DR [[77]]
PEDF/SERPINF1 Pigment epithelium derived factor/serpin peptidase inhibitor, clade F member 1 (alpha-2 antiplasmin) Antioxidative properties, inhibition of angiogenesis, neurotrophic factor (neuronal differentiation in retinoblastoma cells) rs12150053, rs12948385, rs8697961, rs1126287 17 2 Multi-ethnic Not associated with DR [[8], [15]]
PON1 Paraoxonase 1 Cellular antioxidant—inhibition of HDL oxidation rs662 (p. Q192R) 7 2 Multi-ethnic Inconsistent finding and weak association [[15], [109]]
rs854560 (p. L55M) 7 1 and 2 Multi-ethnic Associated with DR [[109]]
PON2 Paraoxonase 2 Cellular antioxidant, hydrolytic activity—a putative role in defense responses to pathogenic bacteria rs7493 (p. S311C) 7 1 and 2 Multi-ethnic Inconsistent and weak association [[77]]
s12026 (p. A148G) 7 1 and 2 Multi-ethnic Inconsistent and weak association [[109]]
PROS1 Protein S Cofactor for the anticoagulant protease rs13062355 3 1 African American Significant associations with severe DR [[77]]
PSMD9 Proteasome 6S subunit, non-ATPase, 9 Part of multicatalytic proteinase complex (proteasome) rs74421874, rs14259, rs3825172 12 2 Italian Associated with DR [[110]]
ROBO2 Roundabout, axon guidance receptor, homologue 2 Axon guidance and cell migration, unknown link to DR rs10865559 3 1 African American Significant associations with severe DR [[77]]
ROCK2 Rho-associated, coiled-coil containing protein kinase 2 Serine/threonine kinase—regulation of cytokinesis, smooth muscle contraction, the formation of actin stress fibers and focal adhesions, and the activation of the c-fos serum response element p. T431N, p. R83K 2 1 and 2 Turkish No association [[15], [111]]
Romo-1 Reactive oxygen species modulator 1 Mitochondrial membrane protein—increase of the level of reactive oxygen species in cells rs6060566 20 2 Caucasian Independent risk factor for DR [[112]]
TF Transferrin Transportation iron from the intestine, reticuloendothelial system, and liver parenchymal cells to all proliferating cells in the body rs3811647 3 1 Associated with progression of DR [[77]]
TNF-α Tumor necrosis factor-alfa Multifunctional proinflammatory cytokine (cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation) rs361525 (c. G-238A), rs1800629 (c. G-308A), rs1799724 (c. C-857T) 6 2 Indian, Caucasian - Brazilians AA genotype of rs361525 confers risk for pathogenesis of PDR in Indian, rs1800629 associated with PDR in Caucasian - Brazilians [[113][115]]
TNF-β/LTA Tumor necrosis factor-beta (lymphotoxin-alpha) Cytokine— inflammatory, immunostimulatory, and antiviral responses, the formation of secondary lymphoid organs, apoptosis NcoI 6 2 Caucasian - Slovak β2 allele is genetic factor for incidence of PDR in T2DM [[15], [116]]
(GT)n microsatellite 6 2 Asian Indian Allele 4 (103 bp) is a low risk for developing retinopathy, allele 8 (111 bp) is associated with PDR [[114], [115]]
VDR Vitamin D receptor Nuclear hormone receptor for vitamin D3, associated with insulin secretion and sensitivity, anti-proliferative and anti-angiogenic effect, regulator of apoptoses rs10735810 12 1 and 2 Multi-ethnic T allele increases risk but weak association [[15]]
rs2228570 12 2 Han Chinese T allele increases risk of DR onset [[117]]
rs1544410 12 2 Polish, Korean Protective effect against DR in Korean [[118], [119]]

Ch. chromoseme, Ref. references, Multi-ethnic findings of studies regardless of ethnicity or from meta-analyses, TSG tumor suppressor gene, GPCR G protein-coupled receptor

The mitochondrial aldehyde dehydrogenase 2 (ALDH2), expressed in vasculature, detoxifies reactive aldehydes formed from glucose and lipids, also prevents creation of AGE (advanced glycation end products) [[32]]. Morita et al. have reported a substantial relation between the ALDH2*2 allele and the incidence of DR in their study.

Growth factors with role in DR

Vascular endothelial growth factor (VEGF) is one of the major factors in angiogenesis and influences vascular permeability of endothelial cells. VEGF is activated by microvascular changes induced by hypoxia during DM and also by hyperglycaemia [[120]]. Activation of VEGF leads to the destruction of the blood retinal barrier (BRB), the development of diabetic macular oedema and neovascularization typical for PDR. At the same time, elevated serum and vitreous levels of VEGF have also been described in eyes of patients with PDR [[121]]. Anti-VEGF therapies have led to the improvement of the patients´ condition and to the deceleration of retinal vessels proliferation [[122]]. Studies have revealed several polymorphisms in the VEGF promoter (rs2010963, rs25648, rs1570360, rs3095039, rs35569394, rs699947, rs13207351, rs735286, rs2146323, rs833061, rs302502, rs10434, rs833068 and rs833070) with possible associations with DR [[15], [33], [42], [44]]. Rs2010963 (−634C/G) has been associated with DR in Japanese and Indian populations [[34], [35]] whereas G allele of rs2010963 has significant protective effect against NPDR in patients with T2DM. Rs2010963 is also associated with higher risk of macular oedema in Japanese population [[123]]. There are constantly emerging studies identifying new polymorphisms in VEGF gene with possible connections to DR which underlines importance of this gene in the development of DR.

Other growth factors with a possible function in the pathology of DR are the basic fibroblast growth factor (bFGF) and insulin-like growth factor 1 (IGF-1). The bFGF is important for tissue repair and is angiogenic factor. Studies have revealed increased level of bFGF in patients with PDR and it seems to stimulate VEGF production. IGF-1 regulates the proliferation and differentiation of several cell types. Levels of intravitreal IGF-1 were found to be significantly increased in the eyes of patients with PDR compared to those of controls [[124]]. Variants identified to date are summarized in the Table 1.

Erythropoietin (EPO) plays an important role in stimulation of bone marrow stem cells, erythropoiesis, proliferation, migration, and angiogenesis in hypoxic vascular endothelial cellsStudy has reported a elevated concentration of EPO in the vitreous of DM and PDR patients compared to controls [[52]]. There are two studies which have reported the association of rs1617640, rs507392, and rs551238 with the development of DR, but these studies report different findings. Tong et al. have determined the TTA haplotype as a risk contributor in European American population, whereas Abhary et al. have associated the GCC haplotype with DR in Australian population [[52], [53]].

Interaction of various growth factors, cytokines, cell signalling molecules and extracellular matrix are essential for angiogenesis during DR [[125]] while VEGF plays crucial part [[126]] (Fig. 3).

Fig. 3

Genes harboring DNA polymorphisms involved in angiogenesis during diabetic retinopathy (DR). AS angiostatin, ES endostatin, BRB blood retinal barrier, ECM extracellular matrix, • inhibition

Receptor for advanced glycation end products and cytokines

Hyperglycaemia causes nonenzymatic glycation of proteins and lipids and the creation of AGE. Accumulation of AGE leads to tissue damage by the formation of a covalent crosslinks between proteins, which alter structure and function of proteins. Another feature of AGE is its ability to interact with different surface receptors, such as the receptor for advanced glycation end products (RAGE). RAGE is a immunoglobulin and its activation leads to cytokine secretion. Cytokines accelerate the advance of diabetic complications by supporting proinflammatory processes and increasing endothelial permeability [[127]]. AGEs are found in the retinal vessels of diabetic patients where their levels correlate with those in the serum as well as with severity of retinopathy [[128]]. The c. T–374A (rs1800624), p. Gly82Ser (rs2070600) and c. T-429C (rs1800625) polymorphisms in the RAGE gene are associated with DR in Caucasians and Asian Indians [[54], [57], [129], [130]], but the association was not confirmed in Chinese [[131]].

Dysregulation of RAAS system

The rennin-angiotensin-aldosterone system (RAAS) is an endocrine system involved in the regulation of blood pressure and fluid balance. Patients with diabetes show dysregulation of RAAS system, namely angiotensin converting enzymes I and II (ACEI, ACEII) and angiotensin receptors which are upregulated in retina during PDR independently of blood pressure [[132]]. ACE converts angiotensin I (ATI) to angiotensin II (ATII) which mediates its haemodynamic effects through the angiotensin receptor ANGTR1 and ANGTR2. ATII in the eye regulates promotion of capillary growth, cell growth, intraocular blood flow and pressure,, enhances vascular permeability, increases oxidative stress and via the expression of several growth factors including VEGF, IGF-1 and PDGF [[15]]. ACE inhibitors, angiotensin receptor blockers prevents neovascularization, reduce the incidence and progression of DR in T1DM. Studies have proposed that ACEII is also involved in PKC activation [[133]]. Meta-analysis suggested that ACE I/D polymorphism (insertion/deletion of a 287 bp Alu sequence in intron 16) may be associated with PDR [[62]].

The other polymorphisms modulating risk of DR

The retina is very sensitive to damage by oxidative stress. Oxidative stress is strongly implicated in the pathogenesis of DR, therefore the role of detoxifying enzymes, such as glutathione S-transferases (GST), was considered in the development of DR. Studies have shown that GSTT1-null genotype is found more frequently in the cases with DR in Caucasians patients with T2DM compared to controls, so the GSTT1-null genotype can be a risk factor for DR The individuals homozygous for the GSTT1-null allele had more generalized vasculopathy that leads to increased risk of sight threatening DR. In contrast, the GSTM1-null genotype may confer protection against development of DR in people with T2DM [[67]], but at the same time this polymorphism confers elevated risk for lung cancer [[134]]. There are reports that deficiency in GSTM1 leads to slower excretion of isothiocyanates. Isothiocyanates also suppress expression of VEGF which is the main inductor of retinal neovascularization in diabetes [[67]].

Oxidative stress induces a large amount of ROS and is assumed to damage the mitochondrial DNA. Mitochondrial manganese superoxide dismutase (MnSOD) prevents an excessive production of ROS by dismutation of superoxide radicals into hydrogen peroxide and hence defends the retinal endothelial cells from oxidative damage. The polymorphism rs4880 (c. C47T, p. A16V) affects a mitochondrial processing efficiency under oxidative stress and has been associated with DR in some studies [[36], [68], [69]].

Regarding PDR, presence of the 4a/4a genotype of the VNTR polymorphism for endothelial nitric oxide synthase (eNOS) has been associated with 3.4 times increased risk of PDR in Caucasian patients with T2DM [[135]]. In contrast, other studies have proposed that the 4a allele has a protective effect against DR [[70], [71]]. NO synthesized by eNOS is an endogenous vasodilator and has a role in induction of angiogenesis and regulation of VEGF expression. NO levels are significantly elevated in PDR patients relative to nondiabetic subject.

A study in 2008 revealed that retinoid-X receptor alpha (RXRA) possessess antioxidants properties and is associated with the development of DR [[76]]. Polymorphism rs3132300 has been linked with a progression of DR in T2DM in African American population. Also, polymorphism rs3818569 of the retinoid-X receptor gamma (RXRG) has been found to be connected with an increased DR risk in the Taiwanese population [[78]].

Uncoupling protein 1 (UCP 1) is the mitochondrial inner membrane electron carrier that has a part in protection against oxidative stress. It has been proposed that UCP 1 and its product play role in insulin resistance when oxidative stress pathways are activated. SNP rs1800592, which is located in the promoter of the UCP1, has been shown to be associated with glucose homeostasis, adiposity and obesity, as well as changes in the body mass index (BMI) and body weight, resulting from metabolic disorders. UCP 1 has been implicated as a candidate marker for a risk factor of DR and the rs1800592 (c. A-3826G) polymorphism has been associated with PDR [[75], [79]]. Uncoupling protein 2 (UCP2) regulates production of reactive oxygen species (ROS) by mitochondria. Overproduction of ROS is associated with diabetic retinopathy (DR), thereby UCP2 gene polymorphisms can be involved in the development of this complication. rs660339 can be a relevant risk factor associated with PDR in both type 2 and 1 of diabetes [[77], [80]].

The inflammatory processes are a major part of the DR pathophysiology. They are often regulated by inadequate activation of members of the immune system. Toll-like receptor 4 (TLR4) takes part in the activation of a pro-inflammatory response by the ligand-depended activation of the nuclear factor-κB (NF-κB) pathway. Any deregulation of TLR4 signaling due to single nucleotide polymorphisms (SNPs) in the extracellular domain of TLR4 may alter the ligand binding capacity and hence disturb the balance of pro- and anti-inflammatory cytokines [[81]]. It has been reported that rs4986790, rs4986791, rs10759931 and rs1927914 in TLR4 positively modulate the risk of DR [[3], [81], [136]].

There is increasing evidence from in vitro and in vivo studies that suggests a pathogenic role of the complement system in the development of diabetic angiopathy. In these studies, increased expression of several complement factors, namely, complement factor H (CFH), complement factor B (CFB), component 3 (C3), and component 5 (C5), has been observed in the vitreous of DR patients. CFH and CFB (an antagonist of CFH) contribute to the regulation of the activation of complement cascade. Polymorphism rs800292 (p.I62V) in CFH affects protein-binding affinity with C3b and subsequently activation of the complement alternative pathway. A synergy effect between CFH rs800292 and CFB rs1048709 conferring a significantly increased risk for DR has been identified in the study of Wang [[82]].

Studies have reported significantly increased levels of monocyte chemotactic protein 1 (MCP-1) in aqueous and vitreous conditions in DR patients. MCP-1 has an ability to activate monocytes, macrophages and lymphocytes. Hyperglycaemia accelerates MCP-1 production in vascular endothelial cells and retinal epithelial cells which can lead to neovascularization and increased permeability of retinal vessels typical for PDR. Moreover rs1024611 polymorphism has been associated with DR in the Japanese, Korean, and Chinese populations [[84][86]].

Transforming growth factor β1 (TGF-β1) has an important role in angiogenesis, endothelial cell proliferation, adhesion and the deposition of extracellular matrix. The TGF-β1 gene may be involved in the development of DR through induction of angiogenesis and BRB breakdown. C. T869C (p. L10P) polymorphism has been associated with a protective effect against DR [[15], [83]].

Intercellular adhesion molecule-1 (ICAM-1) has a major role in mediating the adhesion of circulating leukocytes to the blood vessel wall and transendothelial migration to the vascular intima. The increased retinal expression of ICAM-1 is thought to play a key role in leukostasis-mediated BRB breakdown, capillary occlusion and endothelial cell damage in DR [[88]]. Polymorphisms of ICAM-1 gene might have a role in modulation of its own gene expression but findings about p. K469E polymorphism (rs5498) are inconsistent across multiple studies [[55], [88][91]]. The G allele of rs13306430 could confer protection against DR in T2DM patients [[15]].

Solute carrier family 2(SLC2A1), also known as facilitated glucose transporter (GLUT1) is expressed in endothelial cells of the BRB where SLC2A1 is the prevalent glucose transporter. Functional loss of BRB is typical for DR and studies have shown that patients with DR have high expression of GLUT1 in endothelial cells. SLC2A1 c. A26177G polymorphism has been associated with DR in a study of Ng [[94]].

The role of peroxisome proliferator-activated receptor γ (PPARγ) in DR pathogenesis has come to forefront mainly because of the protein’s role in vascular permeability, inflammation, angiogenesis, neovascularization, and insulin resistance, all of which contribute to the onset and severity of DR. However, the studies describing associations of PPARγ polymorphisms and DR have been inconsistent [[15], [95]].

Transcription factor 7-like 2 (TCF7L2/TCF4) is a key component in the regulation of fundamental processes such as vascular development. It has been found to mediate pathological neovascularization in PDR. Common variant rs7903146 in TCF7L2 has been reported to be strongly associated with T2DM and also with PDR in Caucasian [[96]]. An Italian study observed associations between TCF7L2 variants (rs7903146, rs7901695 and rs12255372) and DR, cardiovascular disease and coronary artery disease [[97]].

Osteoprotegerin (OPG), also called the osteoclastogenesis inhibitory factor (OCIF), is an important regulatory molecule in the vasculature. Rs2073618, rs3134069 polymorphisms have been linked with DR [[99]].

Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of plasminogen activation and is involved in tissue repair and remodeling. PAI-1 plays a crucial part in the regulation of intravascular fibrinolysis which is part of DR pathophysiology. Studies have investigated the connection between PAI-1 4G/5G and DR risk but findings have been inconsistent, maybe due to ethnicity discrepancies [[15], [100], [101]].

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix (ECM) components. MMPs also regulate cell proliferation, neovasculogenesis and tissue remodelling because degradation of the extracellular matrix (ECM) proteins of the basement membrane is necessary for endothelial cells to migrate, proliferate, and to form capillaries. Increased expression of MMP-2 may expedite degradation of the type IV collagen and the gap junction protein, accelerating the vascular complications of diabetes. It has been reported that c. C-1306T polymorphism seems to be genetic susceptibility factor for the development of DR [[7]].

In this review, we discussed candidate genes and polymorphisms with the highest genetic association with DR, or those most frequently analysed in studies in different population. The other genes and their polymorphisms associated with DR are summarized in Table 1 in alphabetical order. Studies concerning these genes have reported very weak or borderline associations, had small sample sizes and most of them have failed replication in other populations [[137]]. We did not include studies and polymorphisms that have been done on only one population and showed no associations with DR. None of the polymorphisms identified by candidate gene studies have achieved widespread acceptance as a marker of high risk of diabetic retinopathy. In part, this may be because of the complexity of DR which probably has more multifactorial, polygenic and environmental contributors to its pathophysiology.

In our review, we have included a number of genes in which multiple alleles or nearby SNPs have varying strengths of association or significance in relation to diabetic retinopathy. Possible explanation for this is variable association between the SNPs themselves with the causative change depended also on populations.

Another one of the possible reasons for the setback of the gene candidate approach is focusing on single SNPs when the linkage disequilibrium does not have to manifest [[16]]. It would be potentially useful to focus on haplotypes associated with DR instead of solely on SNPs. In addition, insufficient sample sizes to detect the modest effect of polymorphisms, incomplete coverage of variation in candidate genes and incorrect hypotheses about genes in the pathophysiology of DR are some of the reasons for controversial success of candidate genes studies. Based on these weaknesses of standard candidate gene studies, two recent studies have examined a higher number of candidate genes for DR in sample sizes larger than those used previously, in an approach that mimics a genome-wide approach [[77], [138]]. The first study, which examined 193 candidate genes with DR of type 1 diabetic African-Americans, found genetic associations in 13 genes with progression of DR and the polymorphisms are listed in Table 1 [[77]]. Identified genes are involved in pathways related to glucose metabolism, inflammatory processes, angiogenesis/vascular permeability, insulin signalling, retinal development, or blood pressure regulation. The second study, the Candidate gene Association Resource (CARe) has not confirmed connection between previously associated gene from numerous previous independent studies and DR [[138]]. The most interesting findings from this study are the variants in the P-selectin (SELP) (rs6128) and in the iduronidase (rs6856425) that have shown to be significantly linked with DR in European Americans, but were not seen in African-Americans, Hispanic Americans, or Asian Americans.

It is possible that the potential success of candidate gene studies lies in better characterization and definition of clinical phenotypes of DR, represented by specific patterns of severity and progression of DR. Only then, studies of candidate genes are worth pursuing, involving appropriately well-defined subgroups of patients [[139]]. Furthermore, it would be worthwhile to expand studies to those genes mutations in which are known to initiate hyperglycaemia [[140]] and indirectly lead to development of DM and DR.


DR remains to be one of the most complex, heterogeneous, multifactorial disorders in any genetic studies. It is one of the leading causes of blindness and visual impairment in the world and treatments options are limited. Research worldwide is focused on understanding the pathogenic mechanisms in DR with the key goal to prevent this disease and developing new drugs for treatments. There is a common consensus that the susceptibility to DR is contingent to a great amount of relatively common allelic variants with a modest effect, and how these genes interact among themselves and with environmental influences. Each of the allelic variants increased risk of DR by a small portion in overall susceptibility. The identification of genetic susceptibility loci for DR by genetic studies has not proved notably successful thus far, given the often contradictory and inconclusive results. It is obvious that the study of the DR genetics is still poorly developed and stands against numerous challenges. The most common approaches in studying this complex disease are insufficient for elucidating pathology of DR. At the same time, most studies of new possible treatments disregarded genetic background of the patietns, which could contribute to the treatment setback. Possible new NextGen sequencing methods and approaches based on interconnection of various omics, such as genomics, especially pharmacogenetics, transcriptomics, proteomics and metabolomics, will bring new breakthrough findings in the future. At this time, we can surely state that there is a long way ahead to fully understand this complex disease.


The authors acknowledge the funding provided by Research and Development Operational Programme ITMS 26240120038, 2013/4.1/04-SORO.


  1. D PetrovičCandidate genes for proliferative diabetic retinopathyBiomed Res Int2013201354041624066292
  2. S van DierenJW BeulensYT van der SchouwDE GrobbeeB NealThe global burden of diabetes and its complications: an emerging pandemicEur J Cardiovasc Prev Rehabil2010171S3S820489418
  3. K SinghS KantVK SinghNK AgrawalSK GuptaK SinghToll-like receptor 4 polymorphisms and their haplotypes modulate the risk of developing diabetic retinopathy in type 2 diabetes patientsMol Vis20142070471324883015
  4. DR MatthewsIM StrattonSJ AldingtonRR HolmanEM KohnerRisks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69Arch Ophthalmol20041221631164015534123
  5. LS LimTY WongLipids and diabetic retinopathyExpert Opin Biol Ther2012129310522122357
  6. EY ChewWT AmbrosiusMD DavisRP DanisS GangaputraCM GrevenEffects of medical therapies on retinopathy progression in type 2 diabetesN Engl J Med201036323324420587587
  7. J YangXH FanYQ GuanY LiW SunXZ YangMMP-2 gene polymorphisms in type 2 diabetes mellitus diabetic retinopathyInt J Ophthalmol2010313714022553537
  8. TY WongR KleinFM IslamMF CotchAR FolsomBE KleinDiabetic retinopathy in a multi-ethnic cohort in the United StatesAm J Ophthalmol200614144645516490489
  9. X ZhangJB SaaddineCF ChouMF CotchYJ ChengLS GeissPrevalence of diabetic retinopathy in the United States, 2005–2008JAMA201030464965620699456
  10. TY WongG LiewRJ TappMI SchmidtJJ WangP MitchellRelation between fasting glucose and retinopathy for diagnosis of diabetes: three population-based cross-sectional studiesLancet200837173674318313502
  11. JZ KuoTY WongJI RotterChallenges in elucidating the genetics of diabetic retinopathyJAMA Ophthalmol20141329610724201651
  12. RD LeslieDA PykeDiabetic retinopathy in identical twinsDiabetes19823119216759208
  13. HC LookerRG NelsonE ChewR KleinBE KleinWC KnowlerGenome-wide linkage analyses to identify loci for diabetic retinopathyDiabetes2007561160116617395753
  14. JH KinoshitaA thirty year journey in the polyol pathwayExp Eye Res1990505675732115448
  15. S AbharyAW HewittKP BurdonJE CraigA systematic meta-analysis of genetic association studies for diabetic retinopathyDiabetes2009582137214719587357
  16. DPK NgHuman genetics of diabetic retinopathy: current perspectivesJ Ophthalmol2010
  17. Q MohamedMC GilliesTY WongManagement of diabetic retinopathy: a systematic reviewJAMA2009298902916
  18. S AmanoSI YamagishiY KodaM TsuneokaM SoejimaT OkamotoPolymorphisms of sorbitol dehydrogenase (SDH) gene and susceptibility to diabetic retinopathyMed Hypotheses20036055055112615520
  19. JP SzaflikI MajsterekM KowalskiP RusinA SobezukAI BoruckaJ SzaflikJ BlasiakAssociation between sorbitol dehydrogenase gene polymorphisms and type 2 diabetic retinopathyExp Eye Res20088664765218289528
  20. BC KoKS LamNM WatSS ChungAn (A-C)n dinucleotide repeat polymorphic marker at the 5′ end of the aldose reductase gene is associated with early-onset diabetic retinopathy in NIDDM patientsDiabetes1995447277327789640
  21. T FujisawaH IkegamiY KawaguchiE YamatoY NakagawaGQ ShenLength rather than a specific allele of dinucleotide repeat in the 5′ upstream region of the aldose reductase gene is associated with diabetic retinopathyDiabet Med1999161044104710656235
  22. F IchikawaK YamadaS Ishiyama-ShigemotoX YuanK NonakaAssociation of an (A-C)n dinucleotide repeat polymorphic marker at the 5′-region of the aldose reductase gene with retinopathy but not with nephropathy or neuropathy in Japanese patients with type 2 diabetes mellitusDiabet Med19991674474810510950
  23. Y IkegishiM TawataK AidaT OnayaZ-4 allele upstream of the aldose reductase gene is associated with proliferative retinopathy in Japanese patients with NIDDM, and elevated luciferase gene transcription in vitroLife Sci1999652061207010579460
  24. SC LeeY WangGT KoJA CritchleyMC NgPC TongAssociation of retinopathy with a microsatellite at 5′ end of the aldose reductase gene in Chinese patients with lateonset type 2 diabetesOphthalmic Genet200122636711449315
  25. Y WangMC NgSC LeeWY SoPC TongCS CockramPhenotypic heterogeneity and associations of two aldose reductase gene polymorphisms with nephropathy and retinopathy in type 2 diabetesDiabetes Care2003262410241512882871
  26. S AbharyKP BurdonKJ LaurieS ThorpeJ LandersL GooldAldose reductase gene polymorphisms and diabetic retinopathy susceptibilityDiabetes Care2010331834183620424224
  27. F RichetiRM NoronhaRT WaetgeJP de VasconcellosOF de SouzaB KneippN AssisMN RochaLE CalliariCA LonguiO MonteMB de MeloEvaluation of AC(n) and C(–106)T polymorphisms of the aldose reductase gene in Brazilian patients with DM1 and susceptibility to diabetic retinopathyMol Vis20071374074517563730
  28. KG SantosB TschiedelJ SchneiderK SOutoI RoisenbergDiabetic retinopathy in Euro-Brazilian type 2 diabetic patients: relationship with polymorphisms in the aldose reductase, the plasminogen activator inhibitor-1 and the methylenetetrahydrofolate reductase genesDiabetes Res Clin Pract20036113313612951282
  29. N KatakamiH KanetoM TakaharaTA MatsuokaK ImamuraF IshibashiAldose reductase C-106 T gene polymorphism is associated with diabetic retinopathy in Japanese patients with type 2 diabetesDiabetes Res Clin Pract201192e57e6021420193
  30. ZD SongY TaoN HanYZ WuAssociation of the aldose reductase-106TT genotype with increased risk for diabetic retinopathy in the Chinese han population: an updated meta-analysisCurr Eye Res20151815
  31. FN FerreiraD CrispimLH CananiJL GrossKG dos SantosAssociation study of sorbitol dehydrogenase–888G >C polymorphism with type 2 diabetic retinopathy in Caucasian-BraziliansExp Eye Res201311514014323850972
  32. K MoritaJ SaruwatariH MiyagawaY UchiyashikiK OnikiM SakataA KajiwaraA YoshidaH JinnouchiK NakagawaAssociation between aldehyde dehydrogenase 2 polymorphisms and the incidence of diabetic retinopathy among Japanese subjects with type 2 diabetes mellitusCardiovasc Diabetol20131213224028448
  33. S AbharyKP BurdonA GuptaCommon sequence variation in the VEGFA gene predicts risk of diabetic retinopathyInvest Ophthalmol Vis Sci2009505552555819553626
  34. T AwataK InoueS KuriharaT OhkuboM WatanabeK InukaiA common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetesDiabetes2002511635163911978667
  35. S UthraR RamanBN MukeshSA RajkumarKR PadmajaPG PaulAssociation of VEGF gene polymorphisms with diabetic retinopathy in a south Indian cohortOphthalmic Genet200829111518363167
  36. T Kangas-KontioS VavuliSJ KakkoJ PennaER SavolainenLiinamaaPolymorphism of the manganese superoxide dismutase gene but not of vascular endothelial growth factor gene is a risk factor for diabetic retinopathyBr J Ophthalmol20099314011406
  37. B SuganthalakshmiR AnandR KimR MahalakshmiS KarthiprakashP NamperumalsamyAssociation of VEGF and eNOS gene polymorphisms in type 2 diabetic retinopathyMol Vis20061233634116636650
  38. M BuraczynskaP KsiazekI Baranowicz-GaszczykL JozwiakAssociation of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetes patientsNephrol Dial Transplant20072282783217121786
  39. JP SzaflikT WysockiM KowalskiI MajsterekAI BoruckaJ BlasiakJ SzaflikAn association between vascular endothelial growth factor gene promoter polymorphisms and diabetic retinopathyGraefes Arch Clin Exp Ophthalmol2008246394317849138
  40. S NakamuraN IwasakiH FunatsuS KitanoY IwamotoImpact of variants in the VEGF gene on progression of proliferative diabetic retinopathyGraefes Arch Clin Exp Ophthalmol2009247212618709380
  41. M QiuW XiongH LiaoF LiVEGF–634G >C polymorphism and diabetic retinopathy risk: a meta-analysisGene201351831031523353010
  42. AJ ChurchillJG CarterC RamsdenSJ TurnerA YeungPE BrenchleyVEGF polymorphisms are associated with severity of diabetic retinopathyInvest Ophthalmol Vis Sci2008493611361618441306
  43. JY GongYH SunAssociation of VEGF gene polymorphisms with diabetic retinopathy: a meta-analysisPloS One2013884069
  44. K NakanishiC WatanabeSingle nucleotide polymorphisms of vascular endothelial growth factor gene intron 2 are markers for early progression of diabetic retinopathy in Japanese with type 1 diabetesClin Chim Acta200940217117519263526
  45. MY ChunHS HwangHY ChoHJ ChunJT WooKW LeeAssociation of vascular endothelial growth factor polymorphisms with nonproliferative and proliferative diabetic retinpathyJ Clin Endocrinol Metab2010953547355120444917
  46. X YangY DengH GuA LimA AltankhuyagW JiaPolymorphisms in the vascular endothelial growth factor gene and the risk of diabetic retinopathy in Chinese patients with type 2 diabetesMol Vis2011173088309622162628
  47. Y ZengF DaiK YangY TangM XuY ZhouAssociation between a vascular endothelial growth factor gene polymorphism (rs2146323) and diabetic retinopathy: a meta-analysisBMC Ophthalmol20151516326553067
  48. MD PorojanA CătanăRA PoppDL DumitrascuC BalaThe role of NOS2A–954G/C and vascular endothelial growth factor +936C/T polymorphisms in type 2 diabetes mellitus and diabetic nonproliferative retinopathy risk managementTher Clin Risk Manag2015111743174826664124
  49. M BeránekP KolarS TschoplovaK KankovaA VaskuGenetic variation and plasma level of the basis fibroblast growth factor in proliferative diabetic retinopathyDiabetes Res Clin Pract20087936236717997184
  50. MG PetrovičM KrkovičJ OsredkarM HawlinaD PetrovičPolymorphisms in the promoter region of the basic fibroblast growth factor gene and proliferative diabetic retinopathy in Caucasians with type 2 diabetesClin Experiment Ophthalmol20083616817218279437
  51. J KytnarovaK VeselaB ZlatohlavkovaA DohnalovaM FedorovaM KrsekCytosine-adenosine (CA)n repeats polymorphim in IGF-I gene and early growth in infants born appropriate and small for gestational ageNeuro Endocrinol Lett20093050150520010501
  52. S AbharyKP BurdonRJ CassonM GogginNP PetrovskyJE CraigAssociation between erythropoietin gene polymorphisms and diabetic retinopathyArch Ophthalmol201012810210620065225
  53. Z TongZ YangS PatelH ChenD GibbsX YangPromoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complicationsProc Natl Acad Sci USA20081056998700318458324
  54. BI HudsonMH SticklandTS FutersPJ GrantEffects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathyDiabetes2001501505151111375354
  55. S BalasubbuP SundaresanA RajendranK RamasamyG GovindarajanN PerumalsamyAssociation analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathyBMC Med Genet20101115821067572
  56. V VanitaAssociation of RAGE (p.Gly82Ser) and MnSOD (p.Val16Ala) polymorphisms with diabetic retinopathy in T2DM patients from north IndiaDiabetes Res Clin Pract201410415516224529564
  57. G KumaramanickavelVL RamprasadS SripriyaNK UpadyayPG PaulT SharmaAssociation of Gly82Ser polymorphism in the RAGE gene with diabetic retinopathy in type II diabetic Asian Indian patientsJ Diabetes Complications20021639139412477623
  58. L YangQ WuY LiX FanY HaoH SunAssociation of the receptor for advanced glycation end products gene polymorphisms and circulating RAGE levels with diabetic retinopathy in Chinese populationJ Diabetes Res2013201326457924303504
  59. M Globocnik PetrovicK SteblovnikB PeterlinD PetrovicThe –429T/C and –374T/A gene polymorphisms of the receptor of advanced glycation end products gene are not risk factors for diabetic retinopathy in Caucasians with type 2 diabetesKlin Monbl Augenheilkd200322087387614704946
  60. SU ThorsenK SandahlLB NielsenR BroeML RasmussenT PetoJ GrauslundML AndersenHB MortensenF PociotBS OlsenC BrorssonPolymorphisms in the CTSH gene may influence the progression of diabetic retinopathy: a candidate-gene study in the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987)Graefes Arch Clin Exp Ophthalmol20152531959196526245339
  61. ZX NgUR KuppusamyR PohI TajunisahA KoayK FongLack of association between Gly82Ser, 1704G/T and 2184A/G RAGE gene polymorphisms and retinopathy susceptibility in Malaysian diabetic patientsGenet Mol Res20121145546122427038
  62. JB ZhouJK YangAngiotensin-converting enzyme gene polymorphism is associated with proliferative diabetic retinopathy: a meta-analysisActa Diabetol Suppl20101187193
  63. Y LuY GeQ HuY ShiC XueY ShiAssociation between angiotensin-converting enzyme gene polymorphism and diabetic retinopathy in the Chinese populationJ Renin Angiotensin Aldosterone Syst20121328929522249557
  64. S LiangM PanN HuYY WuH ChenJ ZhuAssociation of angiotensin-converting enzyme gene 2350 G/A polymorphism with diabetic retinopathy in Chinese Han populationMol Biol Rep20134046346823065222
  65. A NikzamirA RashidiA EsteghamatiM NakhjavaniT GolmohammadiO KhalilzadehThe relationship between ACE gene insertion/deletion polymorphism and diabetic retinopathy in Iranian patients with type 2 diabetesOphthalmic Genet20103110811320565247
  66. S SaleemA AzamSI MaqsoodI MuslimS BashirN FazalRole of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic RetinopathyPLoS One201510e014455726658948
  67. I CilenšekS MankočMG PetrovičD PetrovičGSTT1 null genotype is a risk factor for diabetic retinopathy in Caucasians with type 2 diabetes, whereas GSTM1 null genotype might confer protection against retinopathyDis Markers201232939922377702
  68. MG PetrovičI CilenšekD PetrovičManganese superoxide dismutase gene polymorphism (V16A) is associated with diabetic retinopathy in Slovene (Caucasians) type 2 diabetes patientsDis Markers200824596418057537
  69. C TianS FangX DuC JiaAssociation of the C47T polymorphism in SOD2 with diabetes mellitus and diabetic microvascular complications: a meta-analysisDiabetologia20115480381121181397
  70. BS CheemaHS KohliR SharmaA BhansaliM KhullarEndothelial nitric oxide synthase gene polymorphism and type 2 diabetic retinopathy among Asians IndiansActa Diabetol20124948148823085930
  71. S ZhaoT LiB ZhengZ ZhengNitric oxide synthase 3 (NOS3) 4b/a, T-786C and G894T polymorphisms in association with diabetic retinopathy susceptibility: a meta-analysisOphthalmic Genet201233200200722506535
  72. KG SantosD CrispimLH CananiPT FerrugemJL GrossI RoisenbergRelationship of endothelial nitric oxide synthase (eNOS) gene polymorphisms with diabetic retinopathy in Caucasians with type 2 diabetesOphtalmic Genet2012332327
  73. Y ChenH HuangJM ZhouA DoumateyK LashleyG ChenPolymorphism of the endothelial nitric oxide synthase gene is associated with diabetic retinopathy in a cohort of West AfricansMol Vis20072621422147
  74. JT BazzazMM AmoliV PravicaR ChandrasecaranAJ BoultonB LarijaniIV HutchinsoneNOS gene polymorphism association with retinopathy in type 1 diabetesOphthalmic Genet20103110310720565248
  75. LA BrondaniBM de SouzaGCK DuarteLM KliemannJF EstevesAS MarconThe UCP1–3826A/G polymorphism is associated with diabetic retinopathy and increased UCP1 and MnSOD2 gene expression in human retinaInvest Ophthalmol Vis Sci2012537449745723033381
  76. D ChaiB WangL ShenJ PuXK ZhangB HeRXR agonists inhibit high-glucose-induced oxidative stress by repressing PKC activity in human endothelial cellsFree Radic Biol Med2008441334134718206668
  77. M RoyM HallmanY FuM MachadoCL HanisAssesment of 193 candidate genes for retinopathy in African Americans with type 1 diabetesArch Ophthalmol200912760561219433708
  78. CH HsiehD PeiYJ HungFC HsiaoAssociation between retinoid-X receptor-gamma genetic polymorphisms and diabetic retnopathyGenet Mol Res2011103545355122180072
  79. Y ZhangN MengZ LvH LiY QuThe gene polymorphisms of UCP1 but not PPARγ and TCF7L2 are associated with diabetic retinopathy in Chinese type 2 diabetes mellitus casesActa Ophthalmol201593e223e22925274455
  80. D CrispimNJ FaqundesKG dos SantosJ RheinheimerAP BouçasBM de SouzaPolymorphisms of the UCP2 gene are associated with proliferative diabetic retinopathy in patients with diabetes mellitusClin Endocrinol201072612619
  81. M BuraczynskaI Baranowicz-GaszczykJ TarachA KsiazekToll-like receptor 4 gene polymorphism and early onset of diabetic retinopathy in patients with type 2 diabetesHum Immunol20097012112419135114
  82. J WangMM YangYB LiGD LiuY TengXM LiuAssociation of CFH and CFB gene polymorphisms with retinopathy in type 2 diabetic patientsMediators Inflamm2013201374843523864767
  83. L LiuJ JiaoY WangJ WuD HuangW TengTGF-beta1 gene polymorphism in association with diabetic retinopathy susceptibility: a systematic review and meta-analysisPLoS One20149e9416024710116
  84. N KatakamiM MatsuhisaH KanetoTA MatsuokaK ImamuraF IshibashiMonocyte chemoattractant protein-1 (MCP-1) gene polymorphism as a potentional risk factor for diabetic retinopathy in Japanese patients with type 2 diabetesDiabetes Res Clin Pract201089e9e1220488574
  85. HJ JeonHJ ChoiBH ParkYH LeeT OhAssociation on monocyte chemoattractant protein-1(MCP-1) 2518A/G with proliferative diabetic retinopathy in Korean type 2 diabetesYonsei Med J20135462162523549806
  86. L DongXY IvBJ WangYQ WangH MuZL FengAssociation of monocyte chemoattractant protein-1 (MCP-1) 2518A/G polymorphism with proliferative diabetic retinopathy in nirthern Chinese type 2 diabetesGraefes Arch Clin Exp Ophtalmol201425219211926
  87. M BeránekK KankováP BenesL Izakovicová-HolláV ZnojilD HájekPolymorphism R25P in the gene encoding transforming growth factor-beta (TGF-beta1) is a newly identified risk factor for proliferative diabetic retinopathyAm J Med Genet200210927828311992481
  88. H SunX CongR SunC WangX WangY LiuAssociation between the ICAM-1K469E polymorphism and diabetic retinopathy in type 2 diabetes mellitus: a meta-analysisDiabetes Res Clin Pract20141044649
  89. L LiuQ YuH WangSX ZhangC HuangX ChenAssociation of intercellular adhesion molecule 1 polymorphisms with retinopathy in Chinese patients with type 2 diabetesDiabet Med20062364364816759306
  90. MG PetrovičJ OsredkarM Saraga-BabićD PetrovičK469E polymorphism of the intracellular adhesion molecule 1 gene is associated with proliferative diabetic retinopathy in Caucasians with type 2 diabetesClin Experiment Ophthalmol20083646847218942221
  91. J ZhuSH GaoXD ChiYS ZhangXZ LaiWL ZhongRelationship between diabetic retinopathy and K469E gene polymorphism of intracellular adhesion molecule-1J Fujian Med Univ201044190193
  92. X SuX ChenL LuiX ChangX YuK SunIntracellular adhesion molecule-1K469E gene polymorphim and risk of diabetic microvascular complications: a meta-analysisPloS One20138e6994023922864
  93. Z LvY LiY WuY QuAssociation of ICAM-1 and HMGA1 gene variants with retinopathy in type 2 diabetes mellitus among Chinese individualsCurr Eye Res20153015
  94. ZX NgUR KuppusamyI TajunisahKCS FongKH ChuaInvestigation of SLC2A1 26177A/G gene polymorphism via high resolution melting curve analysis in Malaysian patients with diabetic retinopathyJ Diabetes Complications20122638839222795339
  95. K TariqSB MalikSH AliSE MaqsoodA AzamI MuslimAssociation of Pro12Ala polymorphism in peroxisome proliferator activated receptor gamma with proliferative diabetic retinopathyMol Vis20131971071723559865
  96. J LuoL ZhaoAY ChenX ZhangJ ZhuJ ZhaoTCF7L2 variation and proliferative diabetic retinopathyDiabetes20136272613261723434931
  97. C CiccacciD Di FuscoL CacciottiR MorgantiC D´AmatoG NovelliTCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathyActa Diabetol201250578979922843023
  98. Y DingZ HuS YuanP XieQ LiuAssociation between transcription factor 7-like 2 rs7903146 polymorphism and diabetic retinopathy in type 2 diabetes mellitus: a meta-analysisDiab Vasc Dis Res20151243644426316572
  99. SM RamušT KumšeMG PetrovičD PetrovičI CilenšekSNP 2073618 of the osteoprotegerin gene is associated with diabetic retinopathy in Slovenian patients with type 2 diabetesBiomed Research Internat2013
  100. DK NagiLJ McCormackV Mohamed-AliJS YudkinWC KnowlerPJ GrantDiabetic retinopathy, promoter (4G/5G) polymorphism of PAI-1 gene, and PAI-1 activity in Pima Indians with type 2 diabetesDiabetes Care1997208130413099250459
  101. T ZhangC PangN LiE ZhouK ZhaoPlasminogen activator inhibitor-1 4G/5G polymorphism and retinopathy risk in type 2 diabetes: a meta-analysisBMC Med2013
  102. A SantosML SalgueroC GurrolaF MunozE Roig-MeloA PanduroThe epsilon4 allele of apolipoprotein E gene is a potential risk factor for the severity of macular edema in type 2 diabetic Mexican patientsOphthalmic Genet200223131911910554
  103. G LiewA ShankarJJ WangR KleinMS BrayDJ CouperApolipoprotein E gene polymorphisms are not associated with diabetic retinopathy: the atherosclerosis risk in communities studyAm J Ophthalmol200614210511116815257
  104. C HuR ZhangW YuJ WangC WangC PangCPVL/CHN2 genetic variant is associated with diabetic retinopathy in Chinese type 2 diabetic patientsDiabetes2011603085308921911749
  105. H LiJW LoueyKW ChoyDT LiuWM ChanYM ChanEDN1 Lys198Asn is associated with diabetic retinopathy in type 2 diabetesMol Vis2008141698170418806884
  106. Y MatsubaraM MurataT MaruyamaM HandaN YamagataG WatanabeT SarutaY IkedaAssociation between diabetic retinopathy and genetic variations in alpha2beta1 integrin, a platelet receptor for collagenBlood2000951560156410688808
  107. K YoshiokaT YoshidaY TakakuraA KogureT UmekawaH TodaT YoshikawaNo association between the MTHFR gene polymorphism and diabetic retinopathy in type 2 diabetic patients without overt nephropathyDiabetes Care2003261947194812766148
  108. M MaedaI YamamotoM FukudaM NishidaJ FujitsuS NonenT IgarashiT MotomuraM InabaY FujioJ AzumaMTHFR gene polymorphism as a risk for diabetic retinopathy in type 2 diabetic patients without serum creatinine elevationDiabetes Care200326547548
  109. J WangMM YangSS RongTK NgYB LiXM LiuAssociation of paraoxonase gene polymorphisms with diabetic nephropathy and retinopathyMol Med Rep201381845185124100645
  110. C GragnoliProteasome modulator 9 gene is linked to diabetic and non-diabetic retinopathy in T2DOphthalmic Genet20113222823021728808
  111. AT DemiryurekI ErbagciS OztuzcuB AlasehirliE OzkaraM SekerLack of association between the Thr431Asn and Arg83Lys polymorphisms of the ROCK2 gene and diabetic retinopathyCurr Eye Res2010351128113420961215
  112. MG PetrovičP KružliakD PetrovičThe rs6060566 of the reactive oxygen species modulator 1 (Romo-1) gene affects Romo-1 expression and the development of diabetic retinopathy in Caucasians with type 2 diabetesActa Ophthalmol201593e654e65725824963
  113. SK PaineA SenS ChoudhuriLK MondalIH CowdhuryA BasuAssociation of tumor necrosis factor α, interleukin 6, and interleukin 10 promoter polymorphism with proliferative diabetic retinopathy in type 2 diabetic subjectsRetina2012321197120322105495
  114. G KumaramanickavelS SripriyaRN VellankiNK UpadyaySS BadrinathT ArokiasamyTumor necrosis factor allelic polymorphim with diabetic retinopathy in IndiaDiabetes Res Clin Pract200154899411640992
  115. LF SestiD CrispimLH CananiER PolinaJ RheinheimerPS CarvalhoJL GrossKG SantosThe –308G> a polymorphism of the TNF gene is associated with proliferative diabetic retinopathy in Caucasian Brazilians with type 2 diabetesInvest Ophthalmol Vis Sci2015561184119025634985
  116. K KankováJ MuzíkJ KaráskováM BeránekD HájekV ZnojilDuration of non-insulin-dependent diabetes mellitus and the TNF-beta NcoI genotype as predictive factors in proliferative diabetic retinopathyOphtalmologica2001215294298
  117. DU Y Zhong XY LeiN LiuY GuoT PanEffects of vitamin D receptor gene polymorphism and clinical characteristics on risk of diabetic retinopathy in Han Chinese type 2 diabetes patientsGene201556621221625899017
  118. K CyganekB Mirkiewicz-SieradzkaMT MaleckiP WolkowJ SkupienJ BobrekM CzogalaT KlupaJ SieradzkiClinical risk factors and the role of VDR gene polymorphisms in diabetic retinopathy in Polish type 2 diabetes patientsActa Diabetol20064311411917211561
  119. YJ HongES KangMJ JiHJ ChoiT OhS-S KoongHJ JeonAssociation between Bsm1 polymorphism in vitamin D receptor gene and diabetic retinopathy of type 2 Diabetes in Korean populationEndocrinol Metab (Seoul)20153046947426790383
  120. O Simó-ServatC HernándezR SimóGenetics in diabetic retinopathy: current concepts and new insightsCurr Genomics20131428929924403848
  121. M SydorovaMS LeeVascular endothelial growth factor levels in vitreous and serum of patients with either proliferative diabetic retinopathy or proliferative vitreoretinopathyOphthalmic Res20053718819015990461
  122. MW StewartAflibercept (VEGF Trap-eye): the newest anti-VEGF drugBr J Ophthalmol2012961157115822446028
  123. T AwataS KuriharaN TakataT NedaH IizukaT OhkuboFunctional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macula rretinal thickness in type 2 diabetesBiochem Biophys Res Commun200533367968515963467
  124. F SemeraroA CancariniR dell´OmoS RezzolaMR RomanoC CostagliolaDiabetic retinopathy: vascular and inflammatory diseaseJ Diabetes Res Suppl20152015582060
  125. Y QuaziS MaddulaBK AmbatiMediators of ocular angiogenesisJ Genet20098849551520090210
  126. SF AbcouwerAngiogenic factors and cytokines in diabetic retinopathyJ Clin Cell Immunol2013
  127. JM TarrK KaulM ChopraEM KohnerR ChibberPathophysiology of diabetic retinopathyISRN Ophthalmol20122013343560
  128. H ZongM WardAW StittAGEs, RAGE, and diabetic retinopathyCurr Diabetes Rep201111244252
  129. E LindholmE BakhtadzeM SjogrenCM CilioE AgardhL GroopThe –374T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patientsDiabetologica20064927452755
  130. S RamprasadV RadhaRA MathiasPP MajumderMR RaoM RemaRage gene promoter polymorphisms and diabetic retinopathy in a clinic-based population from South IndiaEye20072139540116440015
  131. X JiXiongX BiLinY MingGongL ShuQin–429T/C and –374T/A polymorphisms of RAGE gene promoter are not associated with diabetic retinopathy in Chinese patients with type 2 diabetesDiabetes Care2003262696269712941744
  132. JL Wilkinson-BerkaAngiotensin and diabetic retinopathyInt J Biochem Cell Biol20063875276516165393
  133. AK SjølieR KleinM PortaT OrchardJ FullerHH ParvingEffect of candesartan on progression and regression ofretinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trialLancet20083721385139318823658
  134. T MatakovaM SivonovaE HalasovaD MistunaA DzianP BerzinecGene polymorphisms of biotransforming enzymes (GSTs) and their association with lung cancer in the Slovakian populationEur J Med Res Suppl200942759
  135. I CilenšekS MankocMG PetrovicD PetrovicThe 4a/4a genotype of the VNTR polymorphism for endothelial nitric oxide synthase (eNOS) gene predicts risk for proliferative diabetic retinopathy in Slovenian patients (Caucasians) with type 2 diabetes mellitusMol Biol Rep2012397061706722311033
  136. Y XuZ JiangJ HuangQ MenqP CohL TaoThe association between toll-like receptor 4 polymorphisms and diabetic retinopathy in Chinese patients with type 2 diabetesBr J Ophthalmol2015991301130525947554
  137. G LiewR KleinTY WongThe role of genetics in susceptibility to diabetic retinopathyInt Ophthalmol Clin2009493552
  138. L SobrinT GreenX SimRA JensenES TaiWT TayCandidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resources (CARE)Invest Ophthalmol Vis Sci2011527593760221873659
  139. J Cunha-VazL RibeiroC LoboPhenotypes and biomarkers of diabetic retinopathy. Personalized medicine for diabetic retinopathy: the Weisenfeld awardInvest Ophthalmol Vis Sci2014555412541925169433
  140. D GašperíkováND TribbleJ StaníkM HučkováN MišovicováM van de BuntIdentification of a novel β-cell glucokinase (GCK) promoter mutation (–71G>C) that modulates GCK gene expression through loss of allele-specific sp1 binding causing mild fasting hyperglycaemia in humansDiabetes2009581929193519411616
  141. HM ZhangLL ChenL WangYF LiaoZH WuF YeAssociation of 1704G/T and G82S polymorphisms in the receptor for advanced glycation end products gene with diabetic retinopathy in Chinese populationJ Endocrinol Invest20093225826219542745
  142. M ChenW LinC LuC ChenY HuangW LiaoF TsaiChimerin 2 genetic polymorphisms are associated with non-proliferative diabetic retinopathy in Taiwanese type 2 diabetic patientsJ Diabetes Complications20142846046324854763
  143. Petrovic MG, Hawlina M, Peterlin B, Petrovic D (2003) BglII gene polymorphism of the α2β1 integrin gene is a risk factor for diabetic retinopathy in Caucasians with type 2 diabetes. J Hum Genet 48(9):457–460
  144. Niskanen L, Voutilainen-Kaunisto R, Teräsvirta M, Karvonen MK, Valve R, Pesonen U, Laakso M, Uusitupa MIJ, Koulu M (2000) Leucine 7 to proline 7 polymorphism in the neuropeptide y gene is associated with retinopathy in type 2 diabetes. Exp Clin Endocrinol Diabetes 108(3):235–236
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