CNDP1, NOS3, and MnSOD Polymorphisms as Risk Factors for Diabetic Nephropathy among Type 2 Diabetic Patients in Malaysia

Abstract

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of nephropathy. The aim of this study was to investigate the association of a genetic polymorphism of carnosinase (CNDP1-D18S880 and -rs2346061), endothelial nitric oxide synthase (NOS3-rs1799983), and manganese superoxide dismutase (MnSOD-rs4880) genes with the development of diabetic nephropathy among Malaysian type 2 diabetic patients. A case-control association study was performed using 652 T2DM patients comprising 227 Malays (without nephropathy = 96 and nephropathy = 131), 203 Chinese (without nephropathy = 95 and nephropathy = 108), and 222 Indians (without nephropathy = 136 and nephropathy = 86). DNA sequencing was performed for the D18S880 of CNDP1, while the rest were tested using DNA Sequenom MassARRAY to identify the polymorphisms. DNA was extracted from the secondary blood samples taken from the T2DM patients. The alleles and genotypes were tested using four genetic models, and the best mode of inheritance was chosen based on the least p value. The rs2346061 of CNDP1 was significantly associated with diabetic nephropathy among the Indians only with OR = 1.94 and 95% CI = (1.76–3.20) and fitted best the multiplicative model, while D18S880 was associated among all the three major races with the Malays having the strongest association with OR = 2.46 and 95% CI = (1.48–4.10), Chinese with OR = 2.26 and 95% CI = (1.34–3.83), and Indians with OR = 1.77 and 95% CI = (1.18–2.65) in the genotypic multiplicative model. The best mode of inheritance for both MnSOD and NOS3 was the additive model. For MnSOD-rs4880, the Chinese had OR = 2.8 and 95% CI = (0.53–14.94), Indians had OR = 2.4 and 95% CI = (0.69–2.84), and Malays had OR = 2.16 and 95% CI = (0.54–8.65), while for NOS3-rs1799983, the Indians had the highest risk with OR = 3.16 and 95% CI = (0.52–17.56), followed by the Chinese with OR = 3.55 and 95% CI = (0.36–35.03) and the Malays with OR = 2.89 and 95% CI = (0.29–28.32). The four oxidative stress-related polymorphisms have significant effects on the development of nephropathy in type 2 diabetes patients. The genes may, therefore, be considered as risk factors for Malaysian subjects who are predisposed to T2DM nephropathy.

The effects of the genetic polymorphisms of antioxidant enzymes on susceptibility to papillary thyroid carcinoma

“…Moreover, the rs4880 polymorphism which is located on the second exon of SOD2 gene (6, 6q25 region) and is a functional polymorphism at the 16th amino acid of SOD2 (Val16Ala) could alter the enzyme conformation . This substitution induces a 30–40% reduction in SOD2 antioxidant activity by the reduction of its transportation into the matrix of mitochondria . In addition, the rs7943316 polymorphism, in the promoter region of CAT gene (11p13 region), may lead to altered promoter activity, gene expression, and diminished catalytic activity of the CAT enzyme by altering the binding affinity of transcription factors …”

“…27 This substitution induces a 30-40% reduction in SOD2 antioxidant activity by the reduction of its transportation into the matrix of mitochondria. 12 In addition, the rs7943316 polymorphism, in the promoter region of CAT gene (11p13 region), may lead to altered promoter activity, gene expression, and diminished catalytic activity of the CAT enzyme by altering the binding affinity of transcription factors. 18 Krhin et al investigated whether common functional polymorphisms in antioxidant genes including SOD2, CAT, and GPX were associated with the development or clinical course of Hurthle cell thyroid carcinoma.…”

“…This enzyme inhibits the damages produced from free radicals. MnSOD or SOD2 is a mitochondrial enzyme with homotetramer structure, which catalyzes the production of H 2 O 2 and O 2 from superoxide byproducts …”

“…MnSOD or SOD2 is a mitochondrial enzyme with homotetramer structure, which catalyzes the production of H 2 O 2 and O 2 from superoxide byproducts. 12 GPX is another antioxidant metabolizing enzyme which detoxifies the hydrogen peroxide via converting it to water in presence of glutathione. There are eight isoforms for GPX (GPx1-8), of which GPx-1 is known as the main isoform.…”

Metabolic Nano-Machines: Extracellular Vesicles Containing Active Enzymes and Their Contribution to Liver Diseases

“…MnSOD protein is an antioxidant enzyme that participates in the mitochondrial respiration by detoxifying the free radical superoxides [92]. In relation with the critical role of MnSOD in the defense against reactive oxygen species, it has been implicated in different diseases, such as type 2 diabetes, cardiovascular diseases, and cancer [93][94][95]. For instance, MnSOD overexpression originated a reduction of EV-associated PYGB protein, being EVs containing PYGB, a sensitive biomarker of cardiac injury [96].…”