Single Nucleotide Polymorphisms of the RAC1 Gene as Novel Susceptibility Markers for Neuropathy and Microvascular Complications in Type 2 Diabetes

Abstract

Single nucleotide polymorphisms (SNP) in the RAC1 (Rac family small GTPase 1) gene have recently been linked to type 2 diabetes (T2D) and hyperglycemia due to their contribution to impaired redox homeostasis. The present study was designed to determine whether the common SNPs of the RAC1 gene are associated with diabetic complications such as neuropathy (DN), retinopathy (DR), nephropathy, angiopathy of the lower extremities (DA), and diabetic foot syndrome. A total of 1470 DNA samples from T2D patients were genotyped for six common SNPs by the MassArray Analyzer-4 system. The genotype rs7784465-T/C of RAC1 was associated with an increased risk of DR (p = 0.016) and DA (p = 0.03) in males, as well as with DR in females (p = 0.01). Furthermore, the SNP rs836478 showed an association with DR (p = 0.005) and DN (p = 0.025) in males, whereas the SNP rs10238136 was associated with DA in females (p = 0.002). In total, three RAC1 haplotypes showed significant associations (FDR < 0.05) with T2D complications in a sex-specific manner. The study’s findings demonstrate, for the first time, that the RAC1 gene’s polymorphisms represent novel and sex-specific markers of neuropathy and microvascular complications in type 2 diabetes, and that the gene could be a new target for the pharmacological inhibition of oxidative stress as a means of preventing diabetic complications.

NADPH oxidase 5 is a novel gene for type 2 diabetes susceptibility determined by gene-body mass index and gene-environment interactions

“…From November 2016 to October 2019, T2D patients were admitted to the endocrinology department of the Kursk Emergency Hospital. In our most recent work [20], we reported on the study groups' demographic, clinical, and laboratory features. WHO criteria [26][27] were used for the diagnosis of T2D: fasting blood glucose (FBG) level 7.0 mmol/L, random blood glucose level 11.1 mmol/L, and/or glycated hemoglobin (HbA1c) level 6.5%.…”

“…All of these enzymes work by transferring an electron to oxygen across cellular membranes to create reactive oxygen species, which play crucial physiological and pathological roles [9,16]. The involvement of NOX subunits and isoforms in the etiology of T2D and its complications is supported by increasing data [17][18][19][20], but NOX5 is likely the least understood of these NOX isoforms, in part because the gene is absent in mice and rats [21]. Numerous investigations [22][23][24][25] con rmed that NOX5 causes diabetic nephropathy in people with diabetes.…”