Evaluation of Glutathione Peroxidase and KCNJ11 Gene Polymorphisms in Patients with New Onset Diabetes Mellitus After Renal Transplantation

Abstract

Genetic mutations such as C599T polymorphism in glutathione peroxidase [GPX1] gene and polymorphisms in potassium channel (KCNJ11) genes have recently been proposed in the etiopathogenesis of new onset diabetes mellitus after renal transplantation (NODAT). We aimed to examine the association of GPX1 and KCNJ11 polymorphisms in NODAT. This is a monocenter case-control study with a total of 118 renal transplant recipients who were divided into 2 groups; NODAT and normal glucose tolerance. Relation of GPX1 and KCNJ11 polymorphisms were investigated between these groups. PCR-RFLP method was used for genotyping of polymorphisms in the GPX1 (rs1050450) and KCNJ11 (rs1805127) genes. Two alleles were visualized for each gene (C/T for GPX1 and A/G for KCNJ11). NODAT was correlated with age at transplantation (p<0.001, r=0.380), post-transplant systolic blood pressure (BP) (p=0.02, r=0.211), post-transplant non-HDL cholesterol levels (p=0.01, r=0.803), degree of weight change at the end of the first year (p=0.01, r=0.471), presence of pre-transplant hypertension (HT) (p=0.02, r=0.201), family history of diabetes (p=0.01, r=0.29) and dyslipidemia (p=0.012, r=0.362). GPX1 polymorphism of TT (mutant) allele was significantly more frequent in patients with NODAT (p<0.001, r=0.396) independent from other diabetogenic risk factors. KCNJ11 polymorphisms were similar in both groups and did not show any significant association with NODAT (p=0.10). In addition to several diabetogenic risk factors, C599T polymorphisms in GPX1 gene might also contribute to the development of NODAT. Further studies on larger patient series are necessary in order to reach definitive suggestions.

Current Understanding of Human Polymorphism in Selenoprotein Genes: A Review of Its Significance as a Risk Biomarker

“…In a cohort with 1244 type 2 Polish patients, the T allele and T/T genotype increased the risk of developing diabetic peripheral neuropathy [68]. Similar results were found in the Turkish population, in which the T allele was significantly more frequent in patients with new onset diabetes mellitus after renal transplantation [180]. When the evaluation of macrovascular diseases in type 2 diabetic Japanese patients was performed, the prevalence of peripheral vascular and cardiovascular diseases and the mean intima-media thickness of the common carotid arteries was higher in the Pro/Leu group when compared to the Pro/Pro group [181].…”

Association between Genetic Polymorphisms and Risk of Kidney Posttransplant Diabetes Mellitus: A Systematic Review and Meta-Analysis

“…ATP-sensitive potassium channel KCNJ11 plays an important role in the regulation of insulin secretion by pancreatic β cells, as well as glucose metabolism. KCNJ11 rs5219 glutamic acid to lysine amino acid substitution reduces potassium channels' sensitivity to ATP molecules, resulting in overactivity of the channel and subsequent inhibition of insulin secretion [ 12 , 24 , 25 ]. The meta-analysis of the Asian Indian population showed no significant association of KCNJ11 rs5219 polymorphism with risk of T2DM [ 52 ].…”

“…Transcription factor encoding gene HNF4A [ 12 ], genes encoding renin-angiotensin system (RAS) including ACE and AGT [ 35 , 44 ]; insulin-resistance genes of VDR ( Fox1 ) [ 33 ], adiponectin [ 34 , 40 ], and PAI-1 [ 46 ]; insulin-sensitive gene IRS [ 12 , 31 ]; glucose homeostasis genes CAPN10 [ 47 ], PPARα , and POR [ 32 , 36 ]; and inflammatory factor genes such as CCL5 [ 34 , 48 ], IL-6 [ 37 ], IL-1B , IL-2 , IL-4 , IL-17 , IL-7R, and IL-17R [ 18 , 29 , 39 ] have been shown to contribute to the pathogenesis of PTDM. Lower GPX1 enzyme activity, caused by GPX1 599C to T mutation, increases the exposure of pancreatic β cells to oxidative stress and development of PTDM [ 24 , 49 ]. Additionally, ATF6 , GST ( SOD and CAT ), INFγ and ( TGFβ1 , TNFα , and STAT4 ) polymorphisms, which play important roles in endoplasmic reticulum stress, oxidative stress, and inflammation respectively, were not found to be associated with PTDM [ 16 , 28 , 41 , 42 , 45 , 49 ].…”

Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies

“…36,37 A recent case control study evaluating variants in kidney transplant recipients identified variants in the voltage-gated K+ channel (KCNQ1) gene, matrix metalloproteinase-2 (MMP2) gene and the glutathione peroxidans (GPX1) gene along with clinical factors have been reported to be associated with NODAT risk. [38][39][40][41] A recent Swiss study identified rs2114592 in the SP110 nuclear body protein (SP110) as conveying a 9.9 times higher risk for NODAT. 42 This variant was not significant in their analysis of a nontransplant white population with type 2 diabetes and the investigators hypothesized a geneenvironment interaction may be present where immunosuppressants may unmask the gene effect.…”