Functional Variants in the Glutathione Peroxidase-1 (<i>GPx-1</i>) Gene Are Associated With Increased Intima-Media Thickness of Carotid Arteries and Risk of Macrovascular Diseases in Japanese Type 2 Diabetic Patients

Hamanishi, Tohru; Furuta, Hiroto; Kato, Hisako; Doi, Asako; Tamai, M; Shimomura, Hiroko; Sakagashira, Setsuya; Nishi, Masahiro; Sasaki, Hideyuki; Sanke, Tokio; Nanjo, Kishio

doi:10.2337/diabetes.53.9.2455

Cited by 211 publications

(182 citation statements)

References 26 publications

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“…Several studies have investigated genetic polymorphisms in candidate pathways implicated in the pathogenesis of atherosclerosis [43][44][45][46][47][48][49][50][51][52][53]. For instance, functional variants in the genes APO A-E [44,45,50], eNOS [47], PCK1 [48], PON1 [49], OPG [53], PPARG [52], and GPx-1 [51] are associated with carotid IMT or its risk factors. However, association studies of genetic polymorphisms with carotid IMT are inconsistent.…”

Section: Discussionmentioning

confidence: 99%

Heritability of carotid intima-media thickness: A twin study

Zhao¹,

Cheema²,

Bremner³

et al. 2008

Atherosclerosis

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Objective-To estimate the heritability of carotid intima-media thickness (IMT), a surrogate marker for atherosclerosis, independent of traditional coronary risk factors.Methods and Results-We performed a classical twin study of carotid IMT using 98 middleaged male twin pairs, 58 monozygotic (MZ) and 40 dizygotic (DZ) pairs, from the Vietnam Era Twin Registry. All twins were free of overt cardiovascular disease. Carotid IMT was measured by ultrasound. Bivariate and multivariate analyses were used to determine the association between traditional cardiovascular risk factors and carotid IMT. Intraclass correlation coefficients and genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in carotid IMT. In our sample, the mean of the maximum carotid IMT was 0.75 ± 0.11. Age, systolic blood pressure and HDL were significantly associated with carotid IMT. The intraclass correlation coefficient for carotid IMT was larger in MZ (0.66; 95% confidence interval [CI], 0.62-0.69) than in DZ twins (0.37; 95% CI, 0.29-0.44), and the unadjusted heritability was 0.69 (95% CI, 0.54-0.79). After adjusting for traditional coronary risk factors, the heritability of carotid IMT was slightly reduced but still of considerable magnitude (0.59; 95% CI, 0.39-0.73).Conclusion-Genetic factors have a substantial influence on the variation of carotid IMT. Most of this genetic effect occurs through pathways independent of traditional coronary risk factors.

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Section: Discussionmentioning

confidence: 99%

Heritability of carotid intima-media thickness: A twin study

Zhao¹,

Cheema²,

Bremner³

et al. 2008

Atherosclerosis

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“…The presence of a leucine at this position has been shown to reduce enzyme activity by 40%. 7 Scarce information is available on polymorphisms in the SOD2 and GPX1 genes in Caucasian patients and their relevance in DILI development susceptibility. To perform a more comprehensive approach to the study of mitochondrial antioxidant genetics in DILI, this study was undertaken to investigate potential associations between the SOD2 Val16Ala and GPX1 Pro200Leu polymorphisms and the risk of developing idiosyncratic hepatotoxicity.…”

Section: Because Environmentalmentioning

confidence: 99%

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

et al. 2010

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Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible associations between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (SOD2 Val16Ala) and glutathione peroxidase (GPX1 Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex-and age-matched controls were analyzed. The SOD2 and GPX1 genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quantitative polymerase chain reaction, respectively. The statistical power to detect the effect of variant alleles with the observed odds ratio (OR) was 98.2% and 99.7% for bilateral association of SOD2 and GPX1, respectively. The SOD2 Ala/Ala genotype was associated with cholestatic/mixed damage (OR 5 2.3; 95% confidence interval [CI] 5 1.4-3.8; corrected P [Pc] 5 0.0058), whereas the GPX1 Leu/Leu genotype was associated with cholestatic injury (OR 5 5.1; 95%CI 5 1.6-16.0; Pc 5 0.0112). The presence of two or more combined risk alleles (SOD2 Ala and GPX1 Leu) was more frequent in DILI patients (OR 5 2.1; 95%CI 5 1.4-3.0; Pc 5 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have the SOD2 Ala/Ala genotype (OR 5 3.6; 95%CI 5 1.4-9.3; Pc 5 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR 5 3.0; 95%CI 5 1.7-5.5; Pc 5 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR 5 16.0; 95%CI 5 1.8-146.1; Pc 5 0.009). Conclusion: Patients homozygous for the SOD2 Ala allele and the GPX1 Leu allele are at higher risk of developing cholestatic DILI. SOD2 Ala homozygotes may be more prone to suffer DILI from drugs that are mitochondria hazardous or produce reactive intermediates. (HEPATOLOGY 2010;52:303-312)

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“…One possible mechanism is impaired microcirculation in the peripheral nerve caused by vascular endothelial dysfunction elicited through accelerated oxidative stress in patients with a Pro/Leu genotype. We have previously reported that anti‐oxidative activity of GPx‐1 decreased in the Pro/Leu genotype 9 . Significant relationships between the GPx‐1 genotype and painful leg cramps might support this possibility, because painful leg cramps are considered to reflect a circulatory disturbance in the leg and are frequently experienced in cold ischemic conditions.…”

Section: Discussionmentioning

confidence: 93%

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

Matsuno

Sasaki

Yamasaki

et al. 2011

Journal of Diabetes Investigation

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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)

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Functional Variants in the Glutathione Peroxidase-1 (GPx-1) Gene Are Associated With Increased Intima-Media Thickness of Carotid Arteries and Risk of Macrovascular Diseases in Japanese Type 2 Diabetic Patients

Cited by 211 publications

References 26 publications

Heritability of carotid intima-media thickness: A twin study

Heritability of carotid intima-media thickness: A twin study

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

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

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