AJCN Tufts Nutrition Symposium, Boston & Online Sept 2009
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American Journal of Clinical Nutrition, Vol. 87, No. 6, 1939-1944, June 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Glutathione peroxidase 1 Pro198Leu variant contributes to the metabolic syndrome in men in a large Japanese cohort1,2,3

Masafumi Kuzuya, Fujiko Ando, Akihisa Iguchi and Hiroshi Shimokata

1 From the Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan (MK and AI), and the Department of Epidemiology, National Institute for Longevity Sciences, Obu, Aichi, Japan (FA and HS)

2 Supported by Research Grants for Longevity Sciences (H18-ko-02) from the Ministry of Health, Labor, and Welfare of Japan.

3 Address reprint requests to M Kuzuya, Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: kuzuya{at}med.nagoya-u.ac.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: There has been much interest in the role of free radicals and oxidative stress in the pathogenesis of metabolic syndrome (MetS). Cellular antioxidant enzymes such as glutathione peroxidase 1 (GPX1) play a central role in the control of reactive oxygen species.

Objective: We examined whether GPX1 polymorphism (Pro198Leu) is associated with MetS as well as with each component of MetS.

Design: The study was a cross-sectional analysis of randomly selected, community-dwelling Japanese persons aged 40–70 y (1128 M, 1105 F).

Results: The genotype frequencies for the GPX1 Pro198Leu polymorphism in this cohort were 0.846, 0.151, and 0.003 for CC, CT, and TT, respectively. The CT/TT genotypes had significantly higher waist-hip ratios, triacylglycerol concentrations, homeostasis model assessment for β-cell function, and systolic and diastolic blood pressures in men (P = 0.045, 0.012, 0.011, 0.004, and 0.003, respectively) than did the CC genotype; the CC/TT genotypes also had higher insulin in both sexes (P = 0.019 for men, P = 0.010 for women) and higher body fat mass (P = 0.027) and homeostasis model assessment for insulin resistance (P = 0.008) in women. The CT/TT genotypes showed significant association with higher prevalence of MetS as defined by 2 commonly used criteria in men [odds ratio (OR): 2.02; 95% CI: 1.30, 3.15 by the International Diabetes Federation criteria; OR: 1.49; 95% CI: 1.02, 2.18 by the modified National Cholesterol Education Program criteria) but not in women. The CT/TT genotypes showed a higher prevalence of central obesity (OR: 1.93; 95% CI: 1.31, 2.85) and hypertriglyceridemia (OR: 1.52; 95% CI: 1.08, 2.15) in men but not in women; there were no differences in other components of MetS between the CC and CT/TT genotypes in either sex.

Conclusion: GPX1 Pro198Leu variants are associated with the prevalence of MetS in Japanese men but not in women.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Accumulating evidences suggest that oxidative stress is involved in various hyperglycemia-induced diabetic complications as well as insulin resistance (1-3). Furthermore, in recent years, there has been much interest in the role of free radicals and oxidative stress in the pathogenesis of metabolic syndrome (MetS) (4, 5). It has been shown that obesity per se may induce systemic oxidative stress and that increased oxidative stress in accumulated fat is, at least in part, the underlying cause of the dysregulation of adipocytokines and the development of MetS (6, 7). In addition, the imbalance between reactive oxygen species and antioxidants improves insulin resistance in mice and humans (8, 9). It has been proposed that increased oxidative stress also underlies the pathophysiology of hypertension (10).

Oxidative stress may be defined as an imbalance between the production and degradation of reactive oxygen species. Enzymatic inactivation of reactive oxygen species is achieved mainly by antioxidative enzymes including glutathione peroxidase (GPX), superoxide dismutase, and catalase. In mammalian cells, glutathione and the GPX constitute the principal antioxidant defense system. There are at least 6 different GPX isoenzymes, all of which contain selenocysteine at their active sites (11).

The most abundant of these isoenzymes is GPX1, a ubiquitous intracellular form and key antioxidant enzyme within most cells, which uses glutathione to reduce hydrogen peroxide to water and lipid peroxides to their respective alcohols, and also acts as a peroxynitrite reductase (12, 13). GPX1 is polymorphic at codon 198 (at nucleotide 594, a cytosine-to-thymine (C->T) substitution (rs1050450), which results in either a proline or a leucine at that position, and the frequency of the leu allele is strongly associated with an increase in the risk of various kinds of cancer (14-18). The identity of the amino acid at codon 198 (proline or leucine) has functional consequences with regard to the level of enzyme activity in response to the provision of increasing amounts of selenium to cells in culture (15). In fact, it has been reported that human erythrocyte GPX activity was lowered according to the T allele dose (17). In addition, the 198Leu polymorphism in the coding region of the GPX1 gene had a 40% decrease in enzyme activity in vitro functional analyses (18). The overexpression of GPX1 in cultured endothelial cells rescued the endothelial dysfunction induced by homocysteine-mediated oxidative stress, which suggests that GPX1 constitutes the principal antioxidant defense system (19)

However, the contribution of the GPX1 Pro198Leu variant to the prevalence of MetS or the components of MetS remains unknown. In the present study, we used 2233 randomly selected, community-dwelling, middle-aged and older Japanese people to examine whether GPX1 Pro198Leu is associated with MetS as well as with each component of MetS among Asian populations.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The present study consisted of a cross-sectional analysis of 1105 women and 1128 men who participated in the first wave of examinations at the National Institute for Longevity Sciences–Longitudinal Study of Aging (NILS-LSA) from April 1998 to March 2000. The subjects of the NILS-LSA were local men and women ranging in age from 40 to 79 y. The populations of the city of Obu and the town of Higashiura in the Aichi prefecture in central Japan were stratified by both age and sex, and the subjects were randomly selected from resident registrations in cooperation with the local governments. The number of men and women was to be the same so that sex difference could be tested. Age at the baseline was to be 40–79 y, and the number of participants in each decade (40–49, 50–59, 60–69, and 70-79 y old) was to be the same. The examinations included various areas of gerontology and geriatrics, such as medical examination; anthropometric measurements; analysis of body composition, physical function, and physical activity; psychological assessment; nutritional analysis; and molecular epidemiology. The subjects will be followed up every 2 y. The details of the NILS-LSA were reported elsewhere (20-22). Randomly selected men and women were invited by mail to attend an explanatory meeting. At that meeting, the procedures for each examination and the follow-up schedule were fully explained.

Written informed consent to the entire procedure was obtained from each participant. The study was approved by the Ethics Committee of NILS.

Anthropometric variables
Body weight was measured to the nearest 0.01 kg by using a digital scale, height was measured to the nearest 0.1 cm by using a wall-mounted stadiometer, and body mass index (BMI; in kg/m2) was calculated. Waist circumference (WC) and waist-to-hip ratio (WHR) were used as the indexes of body fat distribution in this study. WHR was calculated as the ratio of waist circumference measured at the midpoint between the anterior superior iliac crest to the lowest rib-to-hip circumference. Whole-body fat mass, assessed by using dual-energy X-ray absorptiometry (DXA, QDR-4500; Hologic, Waltham, MA) was used as an index for determining body composition.

Biochemical assays of blood
An antecubital blood sample was drawn from each subject after an overnight fast. Serum total cholesterol, triacylglycerols, and LDL cholesterol were determined enzymatically, whereas serum HDL cholesterol was measured by using the heparin-manganese precipitation method. Fasting plasma glucose was assayed by using the glucose oxidase method (23). Plasma insulin, an immunoreactive insulin (IRI), was measured by radioimmunoassay (24). Homeostasis model assessments of insulin resistance (HOMA-IR) and β-cell function (HOMA-β) were calculated as described by Matthews et al (25).

Measurement of blood pressure
Blood pressure was measured with an automatic sphygmomanometer (BP-203RV-II; Colin, Tokyo, Japan) in subjects who had rested in a sitting position for ≥15 min. The blood pressure in each subject was confirmed by a mercury manometer recording made by a physician according to the guidelines of the American Heart Association (26).

Definition of the metabolic syndrome
We applied both the International Diabetes Federation (IDF) and the modified National Cholesterol Education Program (NCEP) definitions of MetS. MetS, according to the modified NCEP criteria (27), included any 3 of the following: 1) WC > 90 cm in men and > 80 cm in women; 2) triacylglycerol concentrations > 1.7 mmol/L or drug treatment for elevated triacylglycerol; 3) HDL-cholesterol concentrations < 1.0 mmol/L in men and < 1.3 mmol/L in women or drug treatment for reduced HDL cholesterol; 4) systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg or antihypertensive drug treatment; and 5) fasting plasma glucose concentrations ≥ 5.6mmol/L or drug treatment for elevated glucose. The IDF definition of MetS includes central obesity (WC > 90 cm in men and > 80 cm in women) plus any other 2 criteria in the modified NCEP criteria as proposed (28).

Determination of GPX1 genotypes
Genotypes were determined by using a fluorescence-based, allele-specific DNA primer assay system (Toyobo Gene Analysis Co, Ltd, Osaka, Japan). The polymorphic regions of rs1050450 were amplified by polymerase chain reaction with allele-specific sense primers labeled at the 5'-end with either fluorescein isothiocyanate (5'-GCGCCCTAGGCACAGCTxAG-3') or Texas red (5'- GCGCCCTAGGCACAGCTxGG-3') as allele-specific hybridization probe and with an antisense primer labeled at the 5'-end with biotin (5'-GTGTGCCCCTACGCAGGTACA-3'). The reaction mixtures (25 µL) contained 20 ng DNA, 10 pmol fluorescein isothiocyanate–and biotin-labeled primer, 5 pmol Texas red–labeled primer, 2.5 mmol/L of each deoxynucleoside triphosphate, 2.5 mmol MgCl2/L, and 0.625 U rTaq DNA polymerase (Toyobo Gene Analysis Co, Ltd) in polymerase buffer. The amplification protocol consisted of initial denaturation at 95 °C for 5 min, followed by 35 cycles of denaturation at 95 °C for 30 s, annealing at 65 °C for 30 s, and extension at 72 °C for 30 s; a final extension was conducted at 72 °C for 2 min. Our genotyping error rate was {approx}0.1%.

Data analysis
Quantitative data were compared between the 2 groups by the unpaired Student's t test. In the analyses of the association between genotypes and glucose, lipid metabolisms, or blood pressure, participants who were being treated with oral hypoglycemic agents or insulin, hypolipidemic agents, or antihypertensive agents were excluded, respectively. Allele frequencies were estimated by the gene-counting method, and the chi-square test was used to identify any significant departure from Hardy-Weinberg equilibrium. Because the prevalence of TT homozygosity in this cohort was only 0.3%, we analyzed it in combination with CT and labeled this group CT/TT. Logistic regression was performed to calculate the odds ratio (OR) for the CT/TT genotypes compared with the CC allele homozygote, and MetS was defined according to the IDF and modified NCEP criteria as described above—ie, it included hypertension, hypertriglyceridemia, low HDL cholesterol, elevated fasting glucose, and central obesity—or by specifying a number of components of MetS with the use of age as a covariate. A general linear model was applied to control for age. P < 0.05 was considered significant. The data were analyzed by using SAS software (version 8.2; SAS Inc, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The genotype frequencies for GPX1 Pro198Leu polymorphism were 0.846, 0.151, and 0.003 for CC, CT, and TT, respectively, and the T allele frequency was 0.078 among this cohort (Table 1Go). These frequencies are consistent with those expected under Hardy-Weinberg equilibrium. There were no significant differences in the genotype distributions of GPX1 Pro198Leu polymorphism between men and women (Table 1Go).


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  		TABLE 1. Genotype frequency of GPX1 Pro198Leu1

 
The means (and SEs) of the anthropometric variables, lipid or glucose metabolic variables, or blood pressure tested in the CC and CT/TT genotypes are shown in Table 2Go. In men, there was a significant difference in WHR and a marginal difference in WC between genotypes (these variables were higher in the CT/TT genotypes), but no significant differences were observed in other anthropometric measurements. In women, higher body fat mass was detected in the CT/TT genotypes than in the CC genotype, but there were no significant differences in other anthropometric measurements. Although there were no significant differences in lipid metabolic variables between the genotypes in women, significant differences in triacylglycerol concentrations were detected in men, who had higher triacylglycerol concentrations in the CT/TT genotypes. No significant differences in fasting glucose and glycated hemoglobin concentrations were observed between the genotypes, and no difference was seen in the rate of participants of either sex who were previously diagnosed with diabetes mellitus (control group men: 86.1% and 13.9% in the CC and CC/TT genotypes, respectively; men with diabetes: 85.2% and 14.8% in the CC and CT/TT genotypes, respectively; P = 0.7966, chi-square test; control group women: 82.9% and 17.1% in the CC and CC/TT genotypes, respectively; women with diabetes: 88.3% and 11.8% in the CC and CC/TT genotypes, respectively; P = 0.2763). However, significantly higher IRI concentrations were observed in the CT/TT genotypes than in the CC genotype in both men and women. In addition, higher HOMA-IR and HOMA-β concentrations were observed in the CT/TT genotypes in both sexes, but the differences were significant only for HOMA-IR in women and for HOMA-β in men. There were significant differences in systolic and diastolic blood pressure between the genotypes only in men, with higher blood pressure in the CT/TT genotypes.


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  		TABLE 2. Anthropometric and metabolic variables according to GPX1 Pro 198Leu genotypes1

 
The prevalence of MetS and each of the MetS components in the study population is shown in Table 3Go. Compared with the wild type (CC), the variant GPX1 (CT/TT) was associated with a higher frequency of MetS according to both the IDF and modified NCEP definitions in men but not in women. These variants were also associated with central obesity and hypertriglyceridemia in men but not in women. There were no associations between the genotypes and low HDL-cholesterol concentration, elevated blood pressure or hypertension, or elevated fasting glucose concentrations or diabetes mellitus.


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  		TABLE 3. The odds ratio (OR) for the metabolic syndrome (MetS) and each of the MetS components1

 
When logistic regression was performed to calculate the OR for the CT/TT genotypes as compared with the CC homozygote, with the prevalence of MetS defined according to the 2 different criteria of the IDF definition and the modified NCEP definition that uses age as a covariate, the CT/TT genotypes showed a significant association with a higher prevalence of MetS as defined by both criteria in men (OR: 2.02; 95% CI: 1.30, 3.15 for IDF; OR:1.49; 95% CI: 1.02, 2.18 for modified NCEP) but not in women (Table 3Go). When we examined whether this variant was associated with the prevalence of each component of MetS, no association between the CT/TT genotypes and the prevalence of low HDL cholesterol, elevated glucose concentrations or diabetes mellitus, or elevated blood pressure or hypertension was found in either sex. However, when the CT/TT genotypes were compared with the CC genotype, the OR for the prevalence of central obesity (WC > 90 cm and > 80 cm in men and women, respectively) was 1.93 (95% CI: 1.31, 2.85) for men. The OR for hypertriglyceridemia was 1.52 (95% CI: 1.08, 2.15) for men. However, no association was observed between the CT/TT genotypes and the prevalence of central obesity and hypertriglyceridemia among women.

The OR for the risk of showing different numbers of features of MetS for the CT/TT genotypes is shown in Figure 1Go. Significantly higher ORs for clusters of 2 to 4 risks of MetS (OR: 1.88; 95% CI: 1.07, 3.31 for 2 risks; OR: 1.97; 95% CI: 1.04, 3.74 for 3 risks; and OR: 2.66; 95% CI: 1.27, 5.56 for 4 risks) were observed in men with the CT/TT genotypes. In contrast, in women the only significant OR for this variant was observed at the 3-risk accumulation (OR: 2.05; 95% CI: 1.16, 3.64). In this cohort, only 60 participants (2.7%) showed a 5-risk accumulation.


Figure 1
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  		FIGURE 1.. Odds ratio (and 95% CIs) of the GPX1 Pro198Leu polymorphism for the cluster of risks of the metabolic syndrome (MetS). The y-axis represents the odds ratio on a log scale for the risks associated with the various numbers of features of MetS for CT/TT genotypes (reference group: CC genotype). {blacksquare}, Point estimates from a logistic regression model adjusted for age; error bars represent 95% CIs. Men: 1 risk (n = 353), 2 risks (n = 283), 3 risks (n = 161), and 4 risks (n = 76); women: 1 risk (n = 261), 2 risks (n = 203), 3 risks (n = 154), and 4 risks (n = 84).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we observed that GPX1 Pro198Leu variant is associated with higher WHRs, triacylglycerol concentrations, IRI, HOMA-IR and HOMA-β, and blood pressure levels than is the CC genotype in men. In women, however, those with the CT/TT genotypes had higher IRI, HOMA-IR, and body fat mass, but no differences were seen in triacylglycerol concentrations, WHRs, and blood pressure levels between genotypes. These results suggest that there is a sex difference in the association between the variant and these variables. In addition, higher body fat mass was observed in women in the CT/TT genotypes but not in men. The higher WHR and WC without any difference in body fat mass or BMI in men with the GPX1 Pro198Leu variant suggest that the CT/TT genotypes are associated with central obesity in men. On the basis of the role of GPX1 in the antioxidant defense system, it seems that subjects with the T allele have lower GPX1 activity, and thus those subjects have a weaker antioxidant defense system than do subjects with the C allele. The association between GPX1 198Leu variants and central obesity in men may suggest that a weaker antioxidant defense system or greater oxidative stress might be a causative factor for obesity. Further research will be required to elucidate the interactions between GPX1 and central obesity. It should be noted that the allelic distribution observed among Japanese persons in this study is different from those reported for other ethnicities. In fact, a greater frequency of the T allele was reported among other ethnicities—a T allele frequency of 0.326, 0.363, and 0.340 in African Americans (15), Finns (14), and Danes (29), respectively—than among Japanese, which indicates that there are ethnicity-specific variations at this position of GPX1.

We also showed that CT/TT genotypes were associated with the higher prevalence of MetS as defined by both the IDF and modified NCEP criteria in men but not in women. It should be noted that higher ORs were observed in MetS according to the IDF definition than in MetS according to the modified NCEP definition in men. It is obvious that this difference is attributable to the inclusion of central obesity (large waist) as an essential component of MetS in the IDF criteria. In fact, there is an association between CT/TT genotypes and central obesity in men. In addition, these variants are more likely to be associated with a higher prevalence of hypertriglyceridemia in men but not in women. In contrast, there was no association between the CT/TT genotypes and a higher prevalence of low HDL cholesterol, elevated blood pressure or hypertension, or elevated fasting glucose concentrations or diabetes mellitus in either sex. The possible explanation for the lack of the association with other components of MetS except for central obesity and hypertriglyceridemia may be a lack of statistical power or the low frequency of the T allele in this population. The men with CT/TT genotypes were associated with a greater number of MetS components, but no apparent association was observed in women. These results indicate that the GPX1 Pro198Leu variant is associated with the prevalence of MetS and the cluster of risks of MetS in men but not in women, which suggests that GPX1 genetic susceptibility to MetS is dependent on sex.

As described above, we showed that the CT/TT genotypes had higher HOMA-IR, as well as higher IRI and HOMA-β, although there was no significant difference in HOMA- IR in men and HOMA-β in women between the CC and CT/TT genotypes. We also observed no difference in the prevalence of diabetes mellitus between the CC and CT/TT genotypes and no association between the CT/TT genotypes and a greater prevalence of elevated fasting glucose concentrations or diabetes mellitus in either sex. The insulin resistance observed in the CT/TT genotypes may be compensated for by the elevated β-cell function (insulin secretion). Therefore, there appear to be no apparent differences in the prevalence of diabetes mellitus or of elevated glucose in this cohort.

The reasons for these sex differences are not known. However, the result is consistence with a number of prior reports (30-33). Among coronary heart disease patients, the polymorphism in the LDL receptor–related protein gene, LRPAP1, is associated with MetS in women but not in men (30). Regulator of G-protein signaling-2 polymorphism is associated with MetS in men but not in women in European populations (31). The beta2-adrenergic receptor gene (Arg16Gly, Gln27Glu) is associated with MetS only in men in the World Health Organization–Monitoring Trends in Cardiovascular Disease population survey (33). These observations and those of the present study indicate that genetic risk factors for MetS may differ between men and women. Although the biological basis of gene-sex interactions in the etiology of MetS remains to be elucidated, the clustering of the traits making up MetS may be due to pleiotropy, when the same gene or genes influence several traits, or to common environmental determinants. It has been shown that erythrocyte GPX activity was significantly higher in premenopausal than in postmenopausal women and higher in premenopausal women than in age-matched men (34). Estrogen seems to be responsible for the sex-related differences in GPX activity. This sexual dimorphism potentially may be conditioned by the activity of sex hormones, differences in lifestyle, or exposure to various environmental factors. Another possibility is that there may be sex differences in free radical homeostasis (35).

The present study has various strengths and limitations. It was conducted in a representative sample of the population, and therefore a possible bias due to the selection of participants was avoided. These findings may not be generalizable to other populations, given that differences in racial and ethnic attitudes toward lifestyle may influence these results. Limitations include the lack of the lifestyle and dietary data for the participants in the analysis, which may affect the prevalence of MetS.

In the present study, we observed that GPX1 Pro198Leu variants are associated with the prevalence of MetS in Japanese men but not in Japanese women. This result may support the hypothesis that oxidative stress is involved in the pathogenesis of MetS. However, further research is needed to establish whether the GPX1 Pro198Leu polymorphism is also associated with MetS in other populations and ethnicities and whether the functional variants of the potential antioxidative enzymes besides GPX1 may be associated with the prevalence of MetS.


   ACKNOWLEDGMENTS
 
The authors’ responsibilities were as follows—MK: contributed to the study concept and design and manuscript writing and editing; AF: contributed to data collection and statistical analysis; AI: contributed to the study concept and design; and HS: helped obtain funding and contributed to the study concept and design, data analysis, and statistical support. None of the authors had a personal or financial conflict of interest.


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 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication November 9, 2007. Accepted for publication March 3, 2008.





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