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

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)