Pro198Leu missense polymorphism of the glutathione peroxidase 1 gene might be a common genetic predisposition of distal symmetric polyneuropathy and macrovascular disease in Japanese type 2 diabetic patients

Abstract

Aims/Introduction: We have previously reported that the Pro198Leu missense polymorphism in the glutathione peroxidase 1 (GPx‐1) gene was associated with frequent macrovascular disease (MVD). Our goal was to examine whether the GPx‐1 genotype is associated with diabetic neuropathy.Materials and Methods: We determined the GPx‐1 genotype in 173 Japanese type 2 diabetic patients who received medical interviews, physical examinations, nerve conduction studies, quantitative vibratory perception (QVP), head‐up tilt and heart rate variability tests by polymerase chain reaction‐restriction fragment‐length polymorphism. Diabetic sensorimotor distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathy (DAN) were evaluated separately. DSPN and DAN were defined by two or more abnormalities of neuropathic leg symptoms, diminished Achilles tendon reflexes or impaired QVP in toes, and two autonomic dysfunctions, respectively. The association of the GPx‐1 genotype with DSPN, DAN, MVD and other clinical manifestations was analyzed.Results: The prevalence of DSPN, impaired QVP and painful leg cramps in patients having a genotype with Pro/Leu at the codon 198 (Pro/Leu type) was significantly higher than those with Pro/Pro type. As a result of multivariate analyses that contained the GPx‐1 genotype as an independent variable, the Pro/Leu type was extracted as a significant risk factor of DSPN, QVP impairment and MVD. The statistical significance did not disappear, even after proteinuria, retinopathy and a history of MVD were introduced as independent variables. In contrast, the GPx‐1 genotype was not associated with DAN.Conclusions: The Pro198Leu missense polymorphism of the GPx‐1 gene might have a common genetic predisposition to DSPN and MVD. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00127.x, 2011)

Pro198Leu Polymorphism in the Glutathione Peroxidase 1 Gene Contributes to Diabetic Peripheral Neuropathy in Type 2 Diabetes Patients

“…Oxidative stress is involved in the development of diabetes and its complications (Robertson et al 2004; Vincent et al 2004). Several studies have shown that the Gpx1 Pro198Leu polymorphism increases the incidence of oxidative stress-related diseases (Tang et al 2008; Matsuno et al 2011; Chen et al 2012; Ramprasath et al 2012; Cao et al 2014). …”

“…This association was independent of other risk factors. In a small Japanese study of 173 type 2 diabetes patients, the Pro198Leu polymorphism in Gpx1 gene was found to be a predisposing factor in distal symmetric polyneuropathy and macrovascular disease (Matsuno et al 2011). Our results are not consistent with a previous study performed in a Polish population that showed no association between the Gpx1 Pro198Leu polymorphism and distal symmetric polyneuropathy in patients with type 2 diabetes (Kasznicki et al 2016).…”

“…We also observed an association with the Pro198Leu T allele with diabetes itself when compared to healthy control subjects. In a Japanese study, the Pro198Leu polymorphism was associated with the development of diabetic polyneuropathy but not the onset of diabetes itself (Matsuno et al 2011). A similar result was observed in the study of Vats et al (2015).…”

Difference in normal limit values of nerve conduction parameters between Westerners and Japanese people might need to be considered when diagnosing diabetic polyneuropathy using a Point‐of‐Care Sural Nerve Conduction Device (NC‐stat®/DPNCheck™)

“…In order to verify the signs of symmetric decrease of distal sensation at lower limbs, quantitative vibration threshold (VT) at 125 Hz was assessed in both big toe tips using a vibratory sensation meter (AU‐02B™; RION Inc., Tokyo, Japan). The method of VT measurement was described previously.…”

Oxidative Stress Biomarkers for Diabetic Retinopathy and Medical Management Affecting Oxidative Stress

“…This missense polymorphism changes the amino acid from proline (Pro) to leucine (Leu) at position 197 (rs1050450) and was associated with a reduction in transcription and enzyme activity of GPx-1 [36].…”