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Year : 2015  |  Volume : 7  |  Issue : 2  |  Page : 27-34

Genetics and diabetic microangiopathy

1 Medical Student Research Committee, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Eye, Medical Faculty of Medicine, Bu Ali-Sina Hospital, Mazandaran University of Medical Sciences, Mazandaran, Iran

Date of Web Publication12-Nov-2015

Correspondence Address:
Ahmad Ahmadzadeh Amiri
Department of Eye, Bu Ali-Sina Hospital, Medical Faculty of Medicine, Mazandaran University of Medical Sciences, Mazandaran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1858-540X.169374

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Human vital organ systems may be affected by diabetic microvascular complications (DMC), lead to public health difficulty. Recent evidence shows genetic factors provide to the genetic and structural variants, and/or variability in disease severity play important roles in the development of DMC among the patients with similar risk factors. Several genetic loci have discovered that figure the risk of DMC as detected by genetic linkage studies. Genetic variants demonstrate for susceptibility to DMC as detected by genetic association studies. Copy number variation and interactions of gene Χ environment have been discovered by compelling analysis of structural variants. Mitochondrial DNA also acts a definite role in the development of DMC. Sequencing technologies have light important horizon on detecting rare and common genetic loci. This review focuses on the common science of the genetic context of DMC. Finally, recognition of genes or genetic loci and structural variants providing to risk of or guarding from DMC will help intuition the underlying mechanism of DMC, with conclusive suggestions for the evolvement of new medicine for diabetes mellitus complications.

Keywords: Diabetes mellitus, genetic, microangiopathy

How to cite this article:
Ahmadzadeh-Amiri A, Amiri AA. Genetics and diabetic microangiopathy. Sudanese J Ophthalmol 2015;7:27-34

How to cite this URL:
Ahmadzadeh-Amiri A, Amiri AA. Genetics and diabetic microangiopathy. Sudanese J Ophthalmol [serial online] 2015 [cited 2023 Jan 31];7:27-34. Available from: https://www.sjopthal.net/text.asp?2015/7/2/27/169374

  Introduction Top

Diabetes burdens the major cause of morbidity and mortality in the world. Diabetic patients have approximately a 7-year shorter life expectancy; as compared with nondiabetic population. [1] Microvascular complications of diabetes implicate multiple organ systems, causing diabetic retinopathy (DR), diabetic kidney disease (DKD), and/or diabetic neuropathy (DN). [2],[3],[4]

The most important sight-threatening complications are DR. The two most important factors in the development of retinopathy are the duration of diabetes and glycemic control. [5],[6] However; it may be nonexistent in some poor controlling patients even over a long time while others may evolve retinopathy in a relatively short period of time despite well-controlled blood sugar. Genetic susceptibility could discuss the occurrence of retinopathy. Several evidence encourage for a genetic role for retinopathy derives from twin and family studies. [7],[8],[9] Diabetes Control and Complications Study (DCCT) [10] and the United Kingdom Prospective Diabetes Study have been clearly discussed the importance of metabolic control in the prevention of diabetic complications. [11] However, in the analysis of both studies, retinopathy developed in groups of patients who were fairly good control and others preserved despite poor glycemic control. [8]

The classic descriptions of DKD show that it forms more than a decade after diabetes appearance. Microalbuminuria is the earliest sign of DKD (>30 mg/day), which with time progresses to macroalbuminuria (>300 mg/day) and diminish in glomerular filtration rate (GFR), ultimately resulting in end-stage renal failure (ESRD). [12] Diabetic nephropathy shows a strongly correlate with retinopathy in patients with type 1 diabetes mellitus (T1DM). DKD is a clinical diagnosis as detected by macroalbuminuria in a diabetic patient, with ruled out other causes of albuminuria. As recorded by recent reports; microalbuminuria can revert, and subsets of patients have ongoing DKD in the absence of proteinuria. [13],[14],[15] Some patients with diabetes will not progress DKD, even in the setting of poorly control glycemia, denoting an individual susceptibility. This role is well-founded by the familial aggregation study of kidney disease. [16] Genome-wide association studies (GWAS) emphasize genetic variants that display a strong association with the hazard of DKD. [17],[18],[19]

Neuropathy is one of a major complication with significant morbidity and mortality in both types of DM. [20] It can be categorized to focal mononeuropathies and generalized polyneuropathy. It should be noticed in adolescents with long duration of diabetes, even it is an infrequent finding during childhood, who may have both peripheral and autonomic DN. [4],[21] Patients with DN can be presented by apparent symptoms or it can be subclinically evident, with abnormalities acquirable only by careful experiment. DCCT reported, clinical neuropathy developed in 9.8% of patients after 5 years of diabetic onset. Based on the definition, clinical neuropathy was as an abnormal neurologic finding confirmed with peripheral sensorimotor polyneuropathy in addition either abnormal nerve conduction in at least two peripheral nerves or explicit abnormal autonomic neuropathy. [22],[23] The Rochester Diabetic Study offering the most beneficial community-based investigation of 380 diabetic subjects. In 278 patients with T2DM, 59% had some figure of neuropathy, and 45% had polyneuropathy; in 102 patients with T1DM, 66% had some figure of neuropathy, whereas 54% had polyneuropathy; polyneuropathy with peculiar involvement of the autonomic nervous system was detected in 5% of patients with T2DM and 7% of patients with T1DM. [24]

Diabetic autonomic neuropathy (DAN) has also been documented among the children with T1DM. [25] Cardiovascular autonomic neuropathy (CAN) is the most serious feature of DAN. The multicenter study of Ziegler et al. revealed that 34.3% of patients with T2DM and 25.3% of patients with T1DM had abnormal results in more than two of six autonomic activity exams. [26]

Nerve growth factor (NGF) also has an important impression in the pathogenesis of DN. [27] NGF-related to a gene family encoding proteins entitled neurotrophins. Decline in NGF synthesis may provide to the development of neuropathy, particularly in function of small fibers, which involve in pain and thermal sensation. [28]

Currently, recognition of genetic loci or genes at risk for diabetic complications is take place with multiple genetic facilities. Genetic linkage analysis and genetic association analysis are classical genetic approaches, which have been used to identify genetic aptitude variants or genes. [29] Genetic linkage analysis has been targeted to acquire the location of disease genes on the chromosome, Which are closer and stay linked during meiosis. This include the following processes: Detecting linked loci, confirming linked loci, fine mapping of confirmed loci, and finally assay genes in the linked region. [30] Dense marker map also called genetic association analysis based on common variant hypothesis has recognize genetic flair. [29] This approach used the frequency of the allele in irrelevant patients with equivalent controls. [31] Among the most important genetic markers for genetic association analysis, are single nucleotide polymorphisms (SNPs). [32] The whole human genome is a powerful method for detecting gene associated with a special disease. HapMap of the human genome introduce GWAS as a reality. [33] Genetic association-based gene mapping include the following processes: Tag SNPs, emphasize SNP association, gene detection, and then functional evaluation.

Mitochondrial DNA (mtDNA) that is located in DNA located within mitochondria is nongenomic, which is responsible for ATP production. This genome is highly dense, comprised circular double-stranded DNA larger than 16 kb. Each cell contains several hundred mitochondria, with 2-10 copies of mtDNA in each mitochondria. Genetic analysis of mtDNA, consist of its genome association and copy number evaluation. [34] Mutation in mtDNA may lead to a change in the protein-coding order, which may modify metabolism, affect several complex diseases such as DM. [35],[36],[37] Mitochondrial haplogroups and single mutations are associated with DM and a mtDNA genome-wide association evaluation inquire into a role for diabetic complications, including the development of diabetic microvascular complications (DMC). [38] This study detect that H haplotype mtDNA increase the risk of retinopathy (P = 0.0007). This finding also showed that other subtype of mitochondrial haplogroups H3, U3, and V were increase incidence of DKD. Epigenetic alterations in chromatin persuade by environmental factor also implicated in gene transcription in the progression of DMC. [39]

Environmental stimuli with interactions of gene polymorphisms impress a disease development. [40] Gene × environment interactions are valuable research in GWAS. [41] This study reveal the effects of individual factor on a complex composition that can be important for risk prognosis and benefit of environmental modification on organ health. [42],[43],[44] Gene × environment interaction study showed that the T allele rs4673 polymorphism was more prevalent in smokers with ESRD or gross proteinuria than in nonalbuminuric patients (P = 0.045). [45]

The cornerstone of this review based on the common sciences of the genetic of DMC and outline data from prior genetic studies regarding aptitude genetic and structural variants changes that affect DMC.

  Genetics and diabetic retinopathy Top

Genetic susceptibility to DR has been suggested to locate on chromosome 3 locus. [46] Further, as in Pima Indians linkage study showed that chromosome 1 may hold on to genes allow susceptibility to DR. [47] Looker et al. conducted genome-wide linkage scans, reported DR linkage to chromosomes 3 and 12 in Mexican-Americans. [48] As mentioned in [Table 1] chromosome 3 locus has been noticed in two independent linkage analysis.
Table 1: Analysis of genetic linkage for diabetic microvascular complications

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Recent studies demonstrate that several genes, including advanced glycation end (AGE), vascular endothelial growth factor (VEGF) and ALR2, are responsible for DR. [49] It is certify that AGE and its receptor (RAGE), contribute to DMC through direct tissue damage. [50] Polymorphisms in the RAGE gene in the Caucasian population, suggest that associated DR is linked to glycosylated hemoglobin levels. [51],[52] These results have been firmly make over in other similar studies in Asian Indians. [53],[54],[55] Neovascularization of proliferative retinopathy is linked to VEGF. [56] Polymorphism in the promoter region of VEGF in Japanese and Indian populations have been associated with DR. [57],[58],[59] Further VEGF polymorphisms studies have been signify in the development of DR. [60],[61],[62],[63],[64],[65] ALR2 as a first and rate limiting enzyme of the polyol pathway is associated to DMC. [66] ALR2 gene polymorphisms have been constantly disclosed to associate with DR in various populations including Chinese, Japanese, Indians, Brazilians, and Iranians. [67],[68],[69],[70],[71],[72],[73],[74],[75],[76] Similar results have not been confirmed in other studies, such as Koreans. [77],[78] Other candidate genes, such as ACE, MTHFR, GLUT1, HP, and APOE have been implicated with DR, although limitations of sample sizes or method design, make not consistent [Table 2]. [79],[80],[81],[82],[83],[84],[85]
Table 2: Analysis of genetic association for diabetic microvascular complications

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  Genetics and diabetic kidney disease Top

Functional polymorphisms that affect the activity of metabolic pathways may link to candidate genes for DKD, including lipid production, insulin resistance (IR), nitric oxide, renin-angiotensin, and bradykinin systems. However, genetic loci or polymorphism for DKD risk or protection has been no consistent due to phenotypic heterogeneity. [Table 1] shows list of disclosed chromosome regions for DKD.

Imperatore et al. discussed the powerful evidence of linkage to chromosome 7q and further to chromosomes 3, 9, and 20 for DKD in Pima Indians. [46] Angiotensin II type 1 receptor gene, is one of these regions which also has been found in a similar study. [116] Another genome-wide scan for DKD observed for nephropathy loci on chromosomes 3, 7p, and 18q in African-American families. [89]

Several important genes associated with DKD studies have recognized, including ACE, ENPP1, FABP2, and GLUT1. Polymorphism with I/D was reported in ACE and the development of DKD in T2DM Brazilian patients. [115] Remarkably, D allele (DD/ID) was at a greater risk for obvious DKD. [117] However, ethnic differences cause incompatible results regarding ACE I/D polymorphism with DKD in several studies. [118] IR gene can also be noted as DKD candidates. [95],[99] A feasible association between progressive DKD and the ENPP1 rs1805101 polymorphism was observed with IR. [100],[104] GLUT1 polymorphisms have also been considered as candidate risk factor for DKD due to they being associated with early kidney alterations, and also because GLUT1 functions as a glucose transporter in kidneys. As in genetic study, GLUT1 rs4673 polymorphism was more noted with smoking as an environmental factor, with persistent proteinuria than in normal populations. The CT and TT genotypes have been confirmed with a greater risk of obvious DKD among smokers. [101],[102] The DKD may also affected by 11 SNPs that located in four distinct chromosomal regions. The powerful of these association was a SNP located on chromosome 9p near FRMD3, and other three loci of SNPs were located near CHN2 and CPVL on chromosome7p, CARS on 11p, and in an intergenic region at 13q [Table 2]. This association of DKD with the 9q and 11p loci was reported in the EDIC/DCCT cohort and a recently four studies from Japan. [103],[119]

  Genetics and diabetic neuropathy Top

In the pathogenesis of DN, oxidative, and nitrosative stress play an important, as evidence display poly (ADP-ribose) polymerase (PARP) activation, is a compelling step in diabetic nerve function and metabolic pathways. Wild-type (PARP [sup+/+]) was the manifest diabetic motor and sensory nerve conduction slowing and nerve energy failure that were clearly protected in the PARP-deficient (PARP [sup−/−]) diabetes. Both endothelial and Schwann cells are the target cells of poly (ADP-ribose) accumulation. PARP inhibitors provide the potential therapeutic value of this devastating complication of diabetes. [120]

Different distribution of a VEGF gene polymorphism at promoter region (-7*C/T) between diabetic subjects with versus without neuropathy and the allele (C) allow susceptibility to DN (P = 0.02). Polymorphism of the VEGF gene at position -7*C/T may harbor functional/regulatory in gene expression. [121]

DN may associate with methylenetetrahydrofolate reductase (MTHFR) gene variants that also have been linked with vasculopathy. Yigit et al. shown a high association between the MTHFR gene C677T mutation and DPN. [122]

Diabetic microangiopathy may involve in the aldose reductase gene, with the most plausible data recognizing a (CA)n repeat microsatellite allele (Z−2) in a functional role in gene expression. The Z−2/Z−2 genotype is significantly associated with the development of DAN as a pupillary abnormality, in adolescent Australian patients with type 1 diabetes. [123]

  Conclusions Top

Extensive development of research on the genetic determinants of DMC has been observed in past two decades. Although a single candidate gene has been favorite, but several, possibly interlinked, genes are likely to be implicated. Genetic variants with linkage studies and candidate gene approaches points out many potential genetic susceptibility to disease. However, procreation of these results has often been conflicting due to different factors, e.g., research design or ethnicity. However, a few compatible associations implicating variants in the ALR2, VEGF, and RAGE genes have been described in genetic association analyses. The effective recognition of the disease at an early stage, result to changes in dietary behavior and lifestyle, is important for disease prevention and progression. It is anticipated that specifications of the genetic factors implicated in the DMC will lead to the perception of the molecular pathogenesis and the advancement of novel therapeutic options. Although mtDNA and nuclear DNA are differing, there is proportionate interaction and expression between the gene outputs of the mitochondria and nuclear genomes.

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  [Table 1], [Table 2]


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