Polymorphisms in the Mn-SOD and EC-SOD Genes and Their Relationship to Diabetic Neuropathy in Type 1 Diabetes Mellitus

Abstract

BackgroundOxidative stress, resulting in a marked increase in the level of oxygen free radicals (OFR), has been implicated in the etiology of diabetic neuropathy (DN). Antioxidant enzymes may protect against the rapid onset and progression of DN, by reducing the excess of OFR and peroxide. Mutations and polymorphisms in the genes encoding such enzymes may therefore result in predisposition to DN. We investigated the role of genes encoding two antioxidant enzymes, mitochondrial (Mn-SOD) and extracellular (EC-SOD) superoxide dismutase, in DN pathogenesis in a Russian population. We studied Ala(-9)Val and Ile58Thr polymorphisms of the Mn-SOD gene and Arg213Gly dimorphism of the EC-SOD gene in type 1 diabetic patients with (n = 82) and without DN (n = 84).ResultsWe developed and used a new polymerase chain reaction (PCR) assays for rapid detection of polymorphisms. These assays involved the use of mismatch PCR primers to create restriction sites in the amplified product only in presence of the polymorphic base. The PCR product was than digested with BshTI, Eco32I or Eco52I to detect Ala(-9)Val, Ile58Thr or Arg213Gly polymorphic site respectively. The frequencies of the Ala allele (50.6% vs. 68.5%, p < 0.002) and the Ala/Ala genotype (17.1% vs. 39.3%, p < 0.005) of the Mn-SOD gene were significantly lower in DN patients than in diabetic subjects without DN. In contrast, the Val allele (49.4% vs. 31.5%, p < 0.002) and the Val/Val genotype (15.9% vs. 2.4%, p < 0.01) were significantly more frequent in the DN patients than in the control group.ConclusionsAla(-9)Val substitution in the Mn-SOD gene was associated with DN in a Russian population

Association of the C47T polymorphism in SOD2 with diabetes mellitus and diabetic microvascular complications: a meta-analysis

“…Because of the above-mentioned inconsistent results from relatively small studies underpowered to detect the effect, a meta-analysis is the appropriate approach to obtain a more definitive conclusion regarding the role of SOD2 gene C47T polymorphism on risk of diabetes mellitus and DMI including diabetic nephropathy, diabetic retinopathy and DPN. Our meta-analysis, of 17 published articles [6,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] with 31 outcomes from different ethnic origins, allowed a much greater possibility of reaching reasonably strong conclusions.…”

“…Chistyakov et al [6] first showed the significant protective effect of C47T polymorphism in SOD2 gene on DPN risk in 82 DPN cases and 84 non-DPN controls in type 1 diabetes mellitus patients, but no association with risk of type 1 diabetes mellitus was found in 166 type 1 diabetes mellitus cases and 88 normal controls in a Russian population. Nevertheless, results of subsequent studies about the effect of this polymorphism on risk of diabetes mellitus, including type 1 and type 2 diabetes, and of DMI including diabetic nephropathy, diabetic retinopathy and DPN were conflicting.…”

“…Characteristics of studies We found 17 published articles [6,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] with 31 outcomes eligible for this meta-analysis on the relation of C47T polymorphism in SOD2 gene to diabetes mellitus and DMI including diabetic nephropathy, diabetic retinopathy and DPN. All 17 eligible studies were case-control designs.…”

“…The T to C nucleotide polymorphism (rs4880) (previously called C47T) [4], which is located in exon 2 of SOD2 gene and results in the amino acid substitution of valine with alanine at position 16 of the protein (Val16Ala), is considered the most interesting of several polymorphisms in SOD2 gene, because C allele instead of T allele results in more efficient transport of SOD2 into the mitochondrial matrix [5], which can increase the ability to neutralise superoxide radicals. Since Chistyakov et al first showed the significant association between C47T polymorphism in SOD2 gene and risk of diabetic polyneuropathy (DPN), and no significant association with type 1 diabetes risk [6], the associations of this polymorphism with diabetes mellitus, including type 1 and type 2 diabetes, and DMI including diabetic nephropathy, diabetic retinopathy and DPN have been investigated. However, the published results are controversial.…”

Manganese-Superoxide Dismutase (MnSOD) Polymorphisms

“…The frequency distributions of C and T alleles were found to be respec- has the similar CC genotype frequency as seen in AfricanAmerican [35], Finn [36], and Italian populations [37]. We detected considerably lower CC genotype frequency than those found in Korean [38], Japan [39], Chinese [40] and Taiwan [41] populations and higher frequencies than those found in American [23], Polish [42], Danish [43], German [44] and Russian [45] populations. Eventually, CC genotype frequency in populations of the eastern countries, were lower (between 0-17%) found than the western countries (between 42-67%) ( Table 4).…”