Abstract
Diabetes mellitus is the fastest growing disease in the world that is estimated to reach nearly half a billion in 2045, and a third of them would have microvascular complication like diabetic retinopathy (DR). Hyperglycemia, hypertension, and dyslipidemia are some of the controllable risk factors. DR is classified into nonproliferative, proliferative, and macular edema types. Many molecular factors like VEGF, ALR2, eNOS, MTHFR, ACE, IGF, and RAGE and its associated single nucleotide polymorphisms play a critical role in the process of neovascularization. Some of the drug discovery and newer treatment regimens are based on these molecular factors. More research by the clinicians, epidemiologists, and vision scientists is necessary to reduce the visual morbidity and disease burden of DR in the community.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
28.1 Introduction
28.1.1 Prevalence of Diabetes Mellitus (DM) and Diabetic Retinopathy (DR)
Diabetes mellitus (DM), a noncommunicable complexly origin disease, is considered as one of the most challenging health problems rising at a tremendous pace globally. DM is estimated to rise to 629 million by 2045 from 425 million in 2017 [1]. According to IDF 2017 report, 159 million in Western Pacific and 82 million in Southeast Asian adults are living with DM [1]. China, India, Indonesia, and Pakistan represent 48% of the global burden [1]. With the incidence of DM increasing at an alarming rate, the number of people with diabetic retinopathy (DR), a microvascular complication, is expected to surge from 126.6 million in 2010 to 191.0 million by 2030 [2]. DR ranks the fifth most common cause of global blindness (moderate and severe vision impairment) [3] accounting for 4.8% of the cases of blindness throughout the world [4]. It is one of the leading causes of visual impairment and blindness in the working-age population (24–70 years) in both developing and developed countries [5].
A pooled analysis of 22,896 people with DM from 35 population-based studies in the USA, Australia, Europe, and Asia (between 1980 and 2008) showed that the overall prevalence of any DR in T1DM (type 1 diabetes mellitus) and T2DM (type 2 diabetes mellitus)) was 34.6% (95%CI 34.5–34.8), with 10.2% having vision-threatening diabetic retinopathy (VTDR) [6].
The prevalence of DR appears to be higher in patients with T1DM than in those with T2DM [3]. Nearly all persons suffering from T1DM develop retinopathy, while more than 77% of persons with T2DM may develop retinopathy after 20 years’ duration of diabetes [5], and approximately 25% of persons with DR may develop macular edema [7]. In India, the overall crude prevalence of DM is 4.7% in urban and 1.9% in rural areas [8], and 7.3–26.2% of these develop DR [9]. In a population-based door-to-door survey in the urban slums of Western India, we reported the DR prevalence of 1.41% in general population and 15.4% in type 2 DM [10]. The prevalence of severe retinopathy in patients with T1DM has diminished over the past 35 years due to improved medical care [11], but the recent epidemic of T2DM requires a new understanding of the biology of DM. The growing number of diabetic patients and the longer life span in aging population imply an increase in patients suffering from DR, which not only affects the quality of life of the individuals and their families but also increases the medical and economic burden of the society.
28.1.2 Social Burden and Health Economics
DM and its complications like DR impose a huge economic burden on the global healthcare. According to the International Diabetes Federation (IDF) estimation, globally USD 727 billion is spent for DM (20–79 years age group), whereas USD 850 billion was spent (19–99 years age group) in 2017. The expenditure on diabetes is projected to reach USD 776 billion (20–79 years age group) and USD 958 billion (18–99 years age group) by 2045 [1]. A recently published study from India estimated that the total annual expenditure on DM care was, on an average, INR (Indian rupee) 10,000 (USD 154) in urban areas and INR 6260 (USD 96.42) in rural areas [12]. Patients with DM having retinal complication spent approximately INR 13922 (USD 214.38) per month [12]. For a chronic disease like DM and hence DR, there is an unmet urgency for development of a cost-effective therapy that is dependent on a basic understanding of the pathophysiological progression of DR.
28.2 Patho-mechanisms and Biology of Retinopathy
Retinopathy is a slow-progressing disease, mainly characterized by damage of the microvasculature of the retina. The onset and progression of retinopathy are triggered by numerous factors including extended duration of diabetes, poor control of blood glucose, elevated blood pressure, and dyslipidemia [13,14,15,16].
Histological studies, using postmortem retinas of diabetic patients, have revealed several cellular changes: selective endothelial and mural cell loss (including pericytes), presence of mural cell ghosts, endothelial clusters, acellularity and microaneurysms [17, 18], basement membrane thickening, presence of hemorrhage in the inner nuclear layer (INL) and outer plexiform layer (OPL), as well as eosinophilic exudates in the OPL [18] .
Further, immunological and immunohistochemical studies have shown hypertrophy of Müller cells throughout the inner and outer diabetic retina and increased apoptosis [19]; expression of pro- and antiapoptotic molecules in ganglion and glial cells, respectively [20]; and elevated levels of vascular endothelial growth factor (VEGF) in retinal blood vessels of diabetic patients with pre-proliferative or no retinopathy stages [21]. Alternation in several other factors, including somatostatin [22], cortistatin [23], 𝛼A- and 𝛼B-crystallins, advanced glycation end products (AGEs), and receptor for AGE (RAGE) [24], as well as apolipoprotein A1 (ApoA1) [25], was also observed in the postmortem tissues.
Advanced molecular studies revealed abnormal levels of expression of mRNA and proteins of various chemokines [26, 27], cytokines [26,27,28,29], inflammatory markers [29,30,31], and angiogenic factors [27, 29, 30, 32] in aqueous humor, serum, or urine from diabetic patients. Although these morphological and molecular studies provide a better picture of the pathogenesis of DR at a cell and molecular level, they failed to provide mechanistic biological pathway. However, based on these observations, several mechanisms and interlinked biological pathways such as hyperglycemia and oxidative stress-mediated AGE products and inflammation, endoplasmic stress (ES)-mediated unfolded protein response (UPR) and apoptosis, hypoxia- and ischemia-mediated angiogenesis, activation of protein kinase C, polyol production, and hexosamine pathways have been postulated to be responsible for retinopathy complications in DM [33,34,35,36]. As these mechanisms and pathways are interlinked [37], the strategies to prevent the development/progression of this complication become complicated.
28.3 Clinical Diagnosis and Classification of DR
From a clinical standpoint, it is clear that the primary driving factors in DR pathogenesis are uncontrolled hyperglycemia, hypertension, and dyslipidemia. However, recent evidences have also suggested neurodegeneration as an early event in the pathogenesis of DR [38].
The diagnosis of DR essentially remains clinical in nature, the gold standard being dilated eye exam and serial fundus images. DR is classified as either nonproliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) based on the presence of neovascularization that typifies the proliferative form [13]. Nonproliferative features of retinopathy, include microaneurysms, intraretinal hemorrhage, hard exudates, venous beading, and intraretinal microvascular anomalies (IRMAs), and the proliferative form features the neovascularization (NV) that bleeds easily resulting in vitreous hemorrhage, subsequent fibrosis, and tractional retinal detachment [39, 40]. DME characterized by increased vascular permeability and deposition of hard exudate at the central retina secondary to lipoproteins leaking from retinal capillaries into the extracellular space of the retina [41] is also a major cause of vision loss and can occur at any stage of DR.
IDF estimates globally 64% of people are living with DME, while 58% with DR face difficulties in performing daily activities [1]. Vision loss results from retinal detachment if patients are left untreated. Several emerging automated technologies have demonstrated promise in assisting with the diagnosis of sight-threatening DR leading to prompt referral for the timely management of the treatable conditions.
28.4 Genetics and Epigenetics of DR
DR is a complex disease, strongly influenced by both genetics and environment. Single nucleotide polymorphisms in genes encoding for the molecules and other enzymes, cytokines, and growth factors involved in DR pathophysiology have been associated with risk for DR in various populations. Among the candidate genes studied for variations and association with DR, VEGF, aldose reductase (ALR2), endothelial nitric oxide synthase (eNOS), methylene tetrahydrofolate reductase (MTHFR), and RAGE have been widely studied in various populations (Table 28.1).
Elevated serum and vitreous VEGF levels have been associated with PDR suggesting possible increase in VEGF gene expression in DR. The C(−634)G promoter VEGF polymorphism has been associated with risk for DR [67] and DME in Japanese cohorts [68], similarly G(−1154)A and C(− 7)T, and T(−1498)C polymorphisms are reported to be associated with risk for DR in Caucasian [69] and South Indian populations [70], respectively. VEGF-460C variation might accelerate the pathogenesis of retinal neovascularization in T2DM patients as suggested by association studies in Indian population [59]. In Chinese patients with T2DM, SNPs rs699947, rs833061, and rs13207351 at the promoter region of the VEGF gene might have association with predisposition DR [71].
Among Chinese Han individuals with T2DM, polymorphism -634G/C of the VEGF gene was not correlated with NPDR or PDR; however, polymorphism-460C/T of the VEGF gene was correlated with NPDR, and C allele was associated with lower NPDR risk than T allele [72].
The gene ALR2 that codes for aldose reductase, the rate-limiting enzyme of the polyol pathway, has a particular Z-2 promoter microsatellite repeat which has not only been associated with genetic susceptibility to DR in Caucasian [48, 73] and Asian Indian populations [47] with T2DM but also has been shown through functional studies to enhance gene expression in response to hyperglycemia. Also an association was observed between DR and the C-106 T, CC genotype in the T2DM patients in Iranian [42] and Japanese population [74] but not in Chinese population [44]. Kaur et al. reported significant association of AKR1B1 -106C > T polymorphism (homozygous recessive TT genotype) with retinopathy in North Indian patients [75]. Studies from Asia, South America, Europe, and Australia showed an association between C(−106)T polymorphism and the risk of DR in T1DM but not type 2 DM [45]. The Z-4 allele was significantly associated with patients with proliferative retinopathy in Japanese population. While the same study reported an association of Z + 2 allele with patients without retinopathy [53], a South Indian study reported an association of Z + 2 allele with risk for DR [54]. Results on Z + 2 allele from T1DM white ancestors were comparable to Japanese study [48].
Increased production of nitric oxide by downregulation of eNOS has been shown to result in angiogenesis in animal models [76]. The intron4 27-bp (VNTR) has been consistently associated with risk for DR in Japanese [77], German, and Caucasian [78] populations.
Ser82 allele in the RAGE gene is a low-risk allele for developing DR in Asian Indian patients with T2DM [54, 79], whereas Vanita V. showed significant association of p.Gly82Ser polymorphism in RAGE with DR in T2DM patients [80]. However, studies from Malaysia, the USA, Europe, and Asia reported no associations between RAGE polymorphisms and DR [45]. Lindholam (2006) reported an association between RAGE(−374 T/A) polymorphism and type 1 diabetes [57].
Saleem et al. (2015) observed a significant association between insertion deletion polymorphism rs4646994 in intron 16 and DR and NPDR, but not with PDR in Pakistani cohort [62]. Matsumoto reported significant association in Japanese population between the presence of the D allele polymorphism in the ACE gene and advanced diabetic retinopathy (ADR) in Japanese subjects with T2DM [81].
An 18-repeat polymorphism in the promoter of IGF-1 gene is a susceptibility genotype for DR, and its clinical severity in a Southern Indian cohort is found by Uthra et al. [66] who also reported lack of association of PRKCB1 gene promoter polymorphisms and moderate protective association of PEDF gene polymorphism with DR in the same cohort [65].
Monocyte chemoattractant protein-1 (MCP-1) is a chemokine specific for monocytes and basophils. MCP-1 rs1024611 (−2518 A/G) AA genotype was significantly associated with PDR in T2DM in Korean patients. On the other hand, the G allele of the same polymorphism in Han Chinese patients was significantly associated with high-risk PDR in T2DM. A study in Japanese patients with T2DM also reported that the G allele was significantly associated with DR [45].
Single gene association studies have not been comprehensively informative about the role of the DNA polymorphisms in disease pathogenesis, and hence approaches like haplotype analysis, linkage disequilibrium, and functional studies are expected to throw more light in this area.
Analysis of a handful of genetic variations is often insufficient to understand the genetic etiopathology of polygenic disease as DR. Hence, researchers now rely on robust technologies such as genome-wide association studies. Imperatore et al. (1998), in their study on Pima Indians with T2DM, showed some evidence of linkage to chromosomes 3 (LOD = 1.36) and 9 (LOD = 1.46) for diabetic retinopathy, although the evidence was insufficient for genome-aide studies [82]. Looker et al. (2007) performed a genome-linkage analysis for DR and found evidence of linkage to chromosome 1p (LOD = 3.1 by single-point analysis and 2.58 by multipoint analysis) [83]. Similarly, another study on Mexican Americans with T2DM revealed suggestive linkage on chromosome 3 (LOD = 3.41) and chromosome 12 (LOD = 2.47) [84]. However, fine mapping of critical genomic regions, which harbor possible susceptibility genes, has not yet been reported. Genome-wide meta-analysis performed by Grassi et al. (2011) identified an intragenic SNP on chromosome 6 rs227455, located more than 200 kb from two undesignated genes LOC728275 and LOC728316, and rs10521145 in strong linkage disequilibrium with copy number variation CNVR6685.1 on chromosome 16 to have strong association with risk for sight-threatening DR [85]. A genome-wide association study on Taiwanese population reported a risk association of SNPs located in five novel chromosomal regions in and around MYSM1, PLXDC2, HS6ST3, and ARHGAP22 genes; the latter two found to have significant role in endothelial cell angiogenesis and increased capillary permeability [86]. A three-stage genome-wide association study carried out in a Japanese cohort revealed a borderline significance of association of an intronic SNP in long intragenic noncoding RNA RP1-90 L14 adjacent to KIAA1009/QN1/CEP162 gene, suggesting a possible role of ciliary-associated genes in the pathogenesis of DR due to the involvement of CEP162 gene [87].
However, identification of genes and genetic variations conferring risk for the development of DR and recognition of pre-symptomatic individuals would have tremendous impact in the treatment of the disease-related complications and could be useful in genetic counselling.
28.5 Recent Advances in Genetics/Epigenetics in Understanding and Management of DR
With the current use of inhibitors for growth factors involved in the DR pathology such as bevacizumab, ranibizumab, and aflibercept (VEGF-Trap) [88], significant genotype-specific personalized management strategies for patients could evolve. Gene therapy experiments targeting renin angiotensin system (RAS) pathway and antioxidant enzyme activities are also underway owing to the limitations of the current inhibitor-based treatments, which collectively hold promise in the effective management of diabetic microvascular complications in the retina [89].
28.6 Future Trends
Research in DR has to be a concerted effort between the ophthalmologist, the epidemiologist, and the vision scientist. Such efforts have led to the current knowledge that we have in the field.
However, further research is needed to identify molecular genetics and biological factors that could be applied as early genetic or biomarkers to identify the target population to reduce the burden of visual impairment or blindness in a community. Besides, such pathway analysis would also lead to the discovery of newer drugs that would reduce the morbidity or disease burden. Granting agencies should focus on these areas of research as DM is one of the rapidly rising diseases with epidemic proportions.
References
IDF. IDF Diabetes Atlas – 8th Edition; 2017.
Congdon N, Zheng Y, He M. The worldwide epidemic of diabetic retinopathy. Indian J Ophthalmol [Internet]. 2012;60(5):428. Available from: http://www.ijo.in/text.asp?2012/60/5/428/100542
Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis [Internet]. 2015;2(1):17. Available from: http://www.eandv.org/content/2/1/17
Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, et al. Policy and practice. Bull World Health Organ [Internet]. 2004;82(11):844–51. Available from: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=15640920&retmode=ref&cmd=prlinks%5Cnpapers2: //publication/uuid/BAA31E85-D8BD-4CD4-A484-651963213B14
World Health Organization. Prevention of blindness from diabetes mellitus. Geneva WHO [Internet]. 2005:1–48. Available from: http://search.who.int/search?q=Prevention+of+blindness+&ie=utf8&site=who&client=_en_r&proxystylesheet=_en_r&output=xml:no_dtd&oe=utf8&getfields=doctype
Yau JWY, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care [Internet]. 2012;35(3):556–64. Available from: http://care.diabetesjournals.org/cgi/doi/10.2337/dc11-1909
Cohen SR, Gardner TW. Diabetic retinopathy and diabetic macular Edema. Dev Ophthalmol [Internet]. 2016;55:137–46. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775164/
Mohan V, Pradeepa R. Epidemiology of diabetes in different regions of India. Heal Adm. 2009;22(1):1–18.
Gadkari S, Maskati Q, Nayak B. Prevalence of diabetic retinopathy in India: the all India ophthalmological society diabetic retinopathy eye screening study 2014. Indian J Ophthalmol [Internet]. 2016;64(1):38. Available from: http://www.ijo.in/text.asp?2016/64/1/38/178144
Sunita M, Singh AK, Rogye A, Sonawane M, Gaonkar R, Srinivasan R, et al. Prevalence of diabetic retinopathy in urban slums: the Aditya Jyot diabetic retinopathy in urban Mumbai slums study-report 2. Ophthalmic Epidemiol. 2017;24(5):303–10.
Hovind P, Tarnow L, Rossing K, Rossing P, Eising S, Larsen N, et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care. 2003;26(4):1258–64.
Kumar J. Economic burden of diabetes. Med Updat [Internet]. 2013:205–8. Available from: http://www.apiindia.org/medicine_update_2013/chap45.pdf
Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet (London, England). 2010;376(9735):124–36.
Liew G, Klein R, Wong TY. The role of genetics in susceptibility to diabetic retinopathy. Int Ophthalmol Clin [Internet]. 2009;49(2):35–52. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746819/
Lim LS, Wong TY. Lipids and diabetic retinopathy. Expert Opin Biol Ther. 2012;12(1):93–105.
Zhang W, Liu H, Rojas M, Caldwell RW, Caldwell RB. Anti-inflammatory therapy for diabetic retinopathy. Immunotherapy [Internet]. 2011;3(5):609–28. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671852/
Levene R, Horton G, Gorn R. Flat-mount studies of human retinal vessels. Am J Ophthalmol [Internet]. 2018;61(2):283–9. Available from: https://doi.org/10.1016/0002-9394(66)90285-6
Yanoff M. Ocular pathology of diabetes mellitus. Am J Ophthalmol [Internet]. 2018;67(1):21–38. Available from: https://doi.org/10.1016/0002-9394(69)90004-X
Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW. Neural apoptosis in the retina during experimental and human diabetes. J Clin Invest. 1998;102(4):783–91.
Abu El-Asrar AM, Dralands L, Missotten L, Al-Jadaan IA, Geboes K. Expression of apoptosis markers in the retinas of human subjects with diabetes. Investig Ophthalmol Vis Sci. 2004;45(8):2760–6.
Lutty GA, DS ML, Merges C, Diggs A, Plouét J. Localization of vascular endothelial growth factor in human retina and choroid. Arch Ophthalmol [Internet]. 1996;114(8):971–7. Available from: https://doi.org/10.1001/archopht.1996.01100140179011
Carrasco E, Hernández C, Miralles A, Huguet P, Farrés J, Simó R. Lower somatostatin expression is an early event in diabetic retinopathy and is. Diabetes Care [Internet]. 2007;30(11):2902–8. Available from: http://care.diabetesjournals.org/content/30/11/2902
Carrasco E, Hernández C, de Torres I, Farrés J, Simó R. Lowered cortistatin expression is an early event in the human diabetic retina and is associated with apoptosis and glial activation. Mol Vis [Internet]. 2008;14(July):1496–502. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2516506&tool=pmcentrez&rendertype=abstract
Kase S, Ishida S, Rao NA. Increased expression of αA-crystallin in human diabetic eye. Int J Mol Med. 2011;28(4):505–11.
Simó R, Hernández C. Advances in the medical treatment of diabetic retinopathy. Diabetes Care. 2009;32(8):1556–62.
Abu El-Asrar AM, Struyf S, Kangave D, Geboes K, Van Damme J. Chemokines in proliferative diabetic retinopathy and proliferative vitreoretinopathy. Eur Cytokine Netw. 2006;17(3):155–65.
Wakabayashi Y, Usui Y, Okunuki Y, Kezuka T, Takeuchi M, Goto H, et al. Correlation of vascular endothelial growth factor with chemokines in the vitreous in diabetic retinopathy. Retina. 2010;30(2):339–44.
Cheung CMG, Vania M, Ang M, Chee SP, Li J. Comparison of aqueous humor cytokine and chemokine levels in diabetic patients with and without retinopathy. Mol Vis [Internet]. 2012;18(November 2011):830–7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3327438&tool=pmcentrez&rendertype=abstract
Suzuki Y, Nakazawa M, Suzuki K, Yamazaki H, Miyagawa Y. Expression profiles of cytokines and chemokines in vitreous fluid in diabetic retinopathy and central retinal vein occlusion. Jpn J Ophthalmol. 2011;55(3):256–63.
Schwartzman ML, Iserovich P, Gotlinger K, Bellner L, Dunn MW, Sartore M, et al. Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy. Diabetes. 2010;59(7):1780–8.
Oh IK, Kim S-W, Oh J, Lee TS, Huh K. Inflammatory and angiogenic factors in the aqueous humor and the relationship to diabetic retinopathy. Curr Eye Res. 2010;35(12):1116–27.
Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480–7.
Kitada S, Otsuka Y, Kokubu N, Kasahara Y, Kataoka Y, Noguchi T, et al. Post-load hyperglycemia as an important predictor of long-term adverse cardiac events after acute myocardial infarction: a scientific study. Cardiovasc Diabetol [Internet]. 2010;9(1):75. Available from: http://www.cardiab.com/content/9/1/75
Santos JM, Mohammad G, Zhong Q, Kowluru RA. Diabetic retinopathy, superoxide damage and antioxidants. Curr Pharm Biotechnol [Internet]. 2011;12(3):352–61. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3214730&tool=pmcentrez&rendertype=abstract
Frank RN. Diabetic retinopathy. N Engl J Med. 2004;350(1):48–58.
Ma JH, Wang JJ, Zhang SX. The unfolded protein response and diabetic retinopathy. J Diabetes Res [Internet]. 2014;2014:160140. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=25530974
Kowluru RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes. 2001;50(8):1938–42.
Neural. Mechanisms of retinal neuroprotection of calcium dobesilate: therapeutic implications. Neural Regen Res. 2017;12(10):2017–9.
Robinson R, Barathi VA, Chaurasia SS, Wong TY, Kern TS. Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals. Dis Model Mech [Internet]. 2012;5(4):444–56. Available from: http://dmm.biologists.org/cgi/doi/10.1242/dmm.009597
Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA. 2007;298(8):902–16.
Toussaint D, Cogan DG, Kuwabara T. Extravascular lesions of diabetic retinopathy. Arch Ophthalmol [Internet]. 1962;67(1):42–7. Available from: https://doi.org/10.1001/archopht.1962.00960020044007
Rezaee MRS, Amiri AA, Hashemi-Soteh MB, Daneshvar F, Emady-Jamaly R, Jafari R, et al. Aldose reductase C-106T gene polymorphism in type 2 diabetics with microangiopathy in Iranian individuals. Indian J Endocrinol Metab [Internet]. 2015;19(1):95–9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287789/
Marzouk SA, Zied AAA, Zakaria NH, Gharraf ES. Experimental and clinical research original article role of aldose reductase C-106T polymorphism among diabetic Egyptian patients with different microvascular complications. Am J Exp Clin Res. 2014;1(2):18–24.
Deng Y, Yang X-F, Gu H, Lim A, Ulziibat M, Snellingen T, et al. Association of C(−106)T polymorphism in aldose reductase gene with diabetic retinopathy in chinese patients with type 2 diabetes mellitus. Vol. 29, Chinese medical sciences journal = Chung-kuo i hsüeh k’o hsüeh tsa chih/Chinese Academy of Medical Sciences; 2014. 1–6 p.
Hampton BM, Schwartz SG, Brantley MA, Flynn HW. Update on genetics and diabetic retinopathy. Clin Ophthalmol. 2015;2015:2175–93.
Kaur N, Vanita V. Association of aldose reductase gene (AKR1B1) polymorphism with diabetic retinopathy. Diabetes Res Clin Pract [Internet]. 2016;121:41–8. Available from: https://doi.org/10.1016/j.diabres.2016.08.019
Kumaramanickavel G, Sripriya S, Ramprasad VL, Upadyay NK, Paul PG, Sharma T. Z-2 aldose reductase allele and diabetic retinopathy in India. Ophthalmic Genet. 2003;24(1):41–8.
Abhary S, Hewitt AW, Burdon KP, Craig JE. A systematic meta-analysis of genetic association studies for diabetic retinopathy. Diabetes. 2009;58(9):2137–47.
Ichikawa F, Yamada K, Ishiyama-Shigemoto S, Yuan X, Nonaka K. Association 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 mellitus. Diabet Med. 1999;16(9):744–8.
Ko BC, Lam KS, Wat NM, Chung SS. An (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 patients. Diabetes. 1995;44(7):727–32.
Petrovic MG, Peterlin B, Hawlina M, Petrovic D. Aldose reductase (AC)n gene polymorphism and susceptibility to diabetic retinopathy in type 2 diabetes in Caucasians. J Diabetes Complicat. 2005;19(2):70–3.
Li Q, Xie P, Huang J, Gu Y, Zeng W, Song H. Polymorphisms and functions of the aldose reductase gene 5′ regulatory region in Chinese patients with type 2 diabetes mellitus. Chin Med J. 2002;115:209–13.
Ikegishi Y, Tawata M, Aida K, Onaya T. Z-4 allele upstream of the aldose reductase gene is associated with proliferative retinopathy in Japanese patients with NIDDM, and elevated luciferase gene transcription in vitro. Life Sci [Internet]. 1999;65(20):2061–70. Available from: http://www.sciencedirect.com/science/article/pii/S002432059900329X
Uthra S, Raman R, Mukesh BN, Rajkumar SA, Kumari P, Lakshmipathy P, et al. Diabetic retinopathy: validation study of ALR2, RAGE, iNOS and TNFB gene variants in a south indian cohort. Ophthalmic Genet. 2010;31(4):244–51.
Taverna MJ, Elgrably F, Selmi H, Selam J-L, Slama G. The T-786C and C774T endothelial nitric oxide synthase gene polymorphisms independently affect the onset pattern of severe diabetic retinopathy. Nitric Oxide Biol Chem. 2005;13(1):88–92.
9_chapters_thesis [Internet]. Available from: shodhganga.inflibnet.ac.in/jspui/bitstream/10603/124402/4/9_chapters_thesis.doc.
Lindholm E, Bakhtadze E, Sjogren M, Cilio CM, Agardh E, Groop L, et al. The −374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients. Diabetologia. 2006;49(11):2745–55.
Niu W, Qi Y, Wu Z, Liu Y, Zhu D, Jin W. A meta-analysis of receptor for advanced glycation end products gene: four wellevaluated polymorphisms with diabetes mellitus. Mol Cell Endocrinol. 2012;358(1):9–17.
Paine SK, Basu A, Mondal LK, Sen A, Choudhuri S, Chowdhury IH, et al. Association of vascular endothelial growth factor, transforming growth factor beta, and interferon gamma gene polymorphisms with proliferative diabetic retinopathy in patients with type 2 diabetes. Mol Vis. 2012;18:2749–57.
Simó-Servat O, Hernández C, Simó R. Genetics in diabetic retinopathy: current concepts and new insights. Curr Genomics. 2013;14:289–99.
Uthra S, Raman R, Mukesh BN, Rajkumar SA, Padmaja KR, Paul PG, et al. Association of VEGF gene polymorphisms with diabetic retinopathy in a south Indian cohort. Ophthalmic Genet. 2008;29(1):11–5.
Saleem S, Azam A, Maqsood SI, Muslim I, Bashir S, Fazal N, et al. Role of ACE and PAI-1 polymorphisms in the development and progression of diabetic retinopathy. PLoS One [Internet]. 2015;10(12):e0144557. Available from: https://doi.org/10.1371/journal.pone.0144557
Kankova K, Muzik J, Karaskova J, Beranek M, Hajek D, Znojil V, et al. Duration of non-insulin-dependent diabetes mellitus and the TNF-beta NcoI genotype as predictive factors in proliferative diabetic retinopathy. Ophthalmol J Int d’ophtalmologie Int J Ophthalmol Zeitschrift fur Augenheilkd. 2001;215(4):294–8.
Kumaramanickavel G, Sripriya S, Vellanki RN, Upadyay NK, Badrinath SS, Arokiasamy T, et al. Tumor necrosis factor allelic polymorphism with diabetic retinopathy in India. Diabetes Res Clin Pract. 2001;54(2):89–94.
Uthra S, Raman R, Mukesh BN, Rajkumar SA, Kumari RP, Lakshmipathy P, et al. Protein kinase C β (PRKCB1) and pigment epithelium derived factor (PEDF) gene polymorphisms and diabetic retinopathy in a south Indian cohort. Ophthalmic Genet [Internet]. 2010;31(1):18–23. Available from: https://doi.org/10.3109/13816810903426231
Uthra S, Raman R, Mukesh BN, Rajkumar SA, Kumari RP, Agarwal S, et al. Diabetic retinopathy and IGF-1 gene polymorphic cytosine-adenine repeats in a Southern Indian cohort. Ophthalmic Res. 2007;39(5):294–9.
Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, et al. A common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. 2002;51(5):1635–9.
Awata T, Kurihara S, Takata N, Neda T, Iizuka H, Ohkubo T, et al. Functional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macular retinal thickness in type 2 diabetes. Biochem Biophys Res Commun 2005;333(3):679–685.
Ray D, Mishra M, Ralph S, Read I, Davies R, Brenchley P. Association of the VEGF gene with proliferative diabetic retinopathy but not proteinuria in diabetes. Diabetes. 2004;53(3):861–4.
Suganthalakshmi B, Anand R, Kim R, Mahalakshmi R, Karthikprakash S, Namperumalsamy P, et al. Association of VEGF and eNOS gene polymorphisms in type 2 diabetic retinopathy. Mol Vis. 2006;12:336–41.
Yang X, Deng Y, Gu H, Lim A, Altankhuyag A, Jia W, et al. Polymorphisms in the vascular endothelial growth factor gene and the risk of diabetic retinopathy in Chinese patients with type 2 diabetes. Mol Vis [Internet]. 2011;17:3088–96. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233387/
Yuan Y, Wen Z, Guan Y, Sun Y, Yang J, Fan X, et al. The relationships between type 2 diabetic retinopathy and VEGF634G/C and VEGF-460C/T polymorphisms in Han Chinese subjects. J Diabetes Complicat. 2014;28(6):785–90.
Demaine A, Cross D, Millward A. Polymorphisms of the aldose reductase gene and susceptibility to retinopathy in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci. 2000;41(13):4064–8.
Katakami N, Kaneto H, Takahara M, Matsuoka TA, Imamura K, Ishibashi F, et al. Aldose reductase C-106T gene polymorphism is associated with diabetic retinopathy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract [Internet]. 2011;92(3):e57–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21420193, [cited 2018 Feb 27]
Cao M, Tian Z, Zhang L, Liu R, Guan Q, Jiang J. Genetic association of AKR1B1 gene polymorphism rs759853 with diabetic retinopathy risk: a meta-analysis. Gene [Internet]. 2018;676:73–8. Available from: http://www.sciencedirect.com/science/article/pii/S0378111
Albrecht EWJA, Stegeman CA, Heeringa P, Henning RH, van Goor H. Protective role of endothelial nitric oxide synthase. J Pathol [Internet]. 2002;199(1):8–17. Available from: https://doi.org/10.1002/path.1250
Li C, Dong Y, Lü W. The association between polymorphism of endothelial nitric oxide synthase gene and diabetic nephropathy. Zhonghua nei ke za zhi [Internet]. 2001;40(11):729–32. Available from: http://europepmc.org/abstract/MED/11930675
Taverna MJ, Sola A, Guyot-Argenton C, Pacher N, Bruzzo F, Chevalier A, et al. eNOS4 polymorphism of the endothelial nitric oxide synthase predicts risk for severe diabetic retinopathy. Diabet Med. 2002;19(3):240–5.
Kumaramanickavel G, Ramprasad VL, Sripriya S, Upadyay NK, Paul PG, Sharma T. Association of Gly82Ser polymorphism in the RAGE gene with diabetic retinopathy in type II diabetic Asian Indian patients. J Diabetes Complications [Internet]. 2002;16(6):391–4. Available from: https://www.sciencedirect.com/science/article/pii/S1056872702001873, [cited 2018 Feb 27]
Vanita V. Association of RAGE (p.Gly82Ser) and MnSOD (p.Val16Ala) polymorphisms with diabetic retinopathy in T2DM patients from North India. Diabetes Res Clin Pract. 2014;104(1):155–62.
Matsumoto A, Iwashima Y, Abiko A, Morikawa A, Sekiguchi M, Eto M, et al. Detection of the association between a deletion polymorphism in the gene encoding angiotensin I-converting enzyme and advanced diabetic retinopathy. Diabetes Res Clin Pract. 2000;50(3):195–202.
Imperatore G, Hanson RL, Pettitt DJ, Kobes S, Bennett PH, Knowler WC. Sib-pair linkage analysis for susceptibility genes for microvascular complications among pima Indians with type 2 diabetes. Pima Diabetes Genes Group Diabetes [Internet]. 1998;47(5):821–30. Available from: http://diabetes.diabetesjournals.org/content/47/5/821.abstract
Looker HC, Nelson RG, Chew E, Klein R, Klein BEK, Knowler WC, et al. Genome-wide linkage analyses to identify Loci for diabetic retinopathy. Diabetes. 2007;56(4):1160–6.
Hallman DM, Boerwinkle E, Gonzalez VH, Klein BEK, Klein R, Hanis CL. A genome-wide linkage scan for diabetic retinopathy susceptibility genes in Mexican Americans with type 2 diabetes from Starr County. Texas Diabetes. 2007;56(4):1167–73.
Grassi MA, Tikhomirov A, Ramalingam S, Below JE, Cox NJ, Nicolae DL. Genome-wide meta-analysis for severe diabetic retinopathy. Hum Mol Genet [Internet]. 2011;20(12):2472–81. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098732/
Huang Y-C, Lin J-M, Lin H-J, Chen C-C, Chen S-Y, Tsai C-H, et al. Genome-wide association study of diabetic retinopathy in a Taiwanese population. Ophthalmology. 2011;118(4):642–8.
Awata T, Yamashita H, Kurihara S, Morita-Ohkubo T, Miyashita Y, Katayama S, et al. A genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA. PLoS One. 2014;9(11):e111715.
Simo R, Sundstrom JM, Antonetti DA. Ocular anti-VEGF therapy for diabetic retinopathy: the role of VEGF in the pathogenesis of diabetic retinopathy. Diabetes Care. 2014;37(4):893–9.
Zhang L, Xia H, Han Q, Chen B. Effects of antioxidant gene therapy on the development of diabetic retinopathy and the metabolic memory phenomenon. Graefes Arch Clin Exp Ophthalmol. 2015;253(2):249–59.
Conflict of Interest
None of the authors have any proprietary interests or conflicts of interest related to this submission.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Nare, S., Mohan, S., Satagopan, U., Natarajan, S., Kumaramanickavel, G. (2019). Diabetic Retinopathy: Clinical, Genetic, and Health Economics (An Asian Perspective). In: Prakash, G., Iwata, T. (eds) Advances in Vision Research, Volume II. Essentials in Ophthalmology. Springer, Singapore. https://doi.org/10.1007/978-981-13-0884-0_28
Download citation
DOI: https://doi.org/10.1007/978-981-13-0884-0_28
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-13-0883-3
Online ISBN: 978-981-13-0884-0
eBook Packages: MedicineMedicine (R0)