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      Gamma-Glutamyltransferase Level and Risk of Hypertension: A Systematic Review and Meta-Analysis

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          Abstract

          Background

          Several prospective observational studies suggest that gamma-glutamyltransferase(GGT) level is positively associated with risk of hypertension. However, these studies draw inconsistent conclusions. Therefore, we conducted a systematic review and meta-analysis to evaluate the exact association between GGT level and subsequent development of hypertension.

          Methods

          We searched Pubmed, Embase, and Science Citation Index (ISI Web of Science) for prospective cohort studies examining the association between GGT level and hypertension. Then, pooled effect estimates (RRs) for the association between GGT level and hypertension were calculated.

          Results

          A total of 13 prospective cohort studies including 43314 participants and 5280 cases of hypertension were included. The pooled RR of hypertension was 1.94(95%CI: 1.55–2.43; P<0.001) when comparing the risk of hypertension between the highest versus lowest category of GGT levels. Moreover, the risk of hypertension increased by 23% (summary RR: 1.23; 95%CI: 1.13–1.32; P<0.001) per 1 SD logGGT increment. Subgroup analyses showed significant positive associations in each subgroup except in ≧160/95 subgroup (RR: 2.56, 95%CI: 0.87–7.54; P = 0.088) and nondrinkers subgroup (RR: 1.76, 95%CI: 0.88–3.53; P = 0.113). Sensitivity analyses showed no single study significantly affects the pooled RRs. No publication bias was found in our meta-analysis.

          Conclusions

          GGT level is positively associated with the development of hypertension. Further studies are needed to confirm our findings and elucidate the exact mechanisms between GGT level and the incidence of hypertension.

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          Most cited references20

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          Gamma glutamyl transferase.

          Serum gamma-glutamyl transferase (GGT) has been widely used as an index of liver dysfunction and marker of alcohol intake. The last few years have seen improvements in these areas and advances in understanding of its physiological role in counteracting oxidative stress by breaking down extracellular glutathione and making its component amino acids available to the cells. Conditions that increase serum GGT, such as obstructive liver disease, high alcohol consumption, and use of enzyme-inducing drugs, lead to increased free radical production and the threat of glutathione depletion. However, the products of the GGT reaction may themselves lead to increased free radical production, particularly in the presence of iron. There have also been important advances in the definition of the associations between serum GGT and risk of coronary heart disease, Type 2 diabetes, and stroke. People with high serum GGT have higher mortality, partly because of the association between GGT and other risk factors and partly because GGT is an independent predictor of risk. This review aims to summarize the knowledge about GGT's clinical applications, to present information on its physiological roles, consider the results of epidemiological studies, and assess how far these separate areas can be combined into an integrated view.
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            Is serum gamma glutamyltransferase a marker of oxidative stress?

            The primary role of cellular gamma glutamyltransferase (GGT) is to metabolize extracellular reduced glutathione (GSH), allowing for precursor amino acids to be assimilated and reutilized for intracellular GSH synthesis. Paradoxically, recent experimental studies indicate that cellular GGT may also be involved in the generation of reactive oxygen species in the presence of iron or other transition metals. Although the relationship between cellular GGT and serum GGT is not known and serum GGT activity has been commonly used as a marker for excessive alcohol consumption or liver diseases, our series of epidemiological studies consistently suggest that serum GGT within its normal range might be an early and sensitive enzyme related to oxidative stress. For example, serum and dietary antioxidant vitamins had inverse, dose-response relations to serum GGT level within its normal range, whereas dietary heme iron was positively related to serum GGT level. More importantly, serum GGT level within its normal range positively predicted F2-isoprostanes, an oxidative damage product of arachidonic acid, and fibrinogen and C-reactive protein, markers of inflammation, which were measured 5 or 15 years later, in dose-response manners. These findings suggest that strong associations of serum GGT with many cardiovascular risk factors and/or events might be explained by a mechanism related to oxidative stress. Even though studies on serum and/or cellular GGT is at a beginning stage, our epidemiological findings suggest that serum GGT might be useful in studying oxidative stress-related issues in both epidemiological and clinical settings.
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              Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study.

              To determine whether serum gamma-glutamyl transferase (GGT) predicts cardiovascular disease (CVD) morbidity and mortality, accounting for temporal changes in known CVD risk factors and C-reactive protein (CRP). In 3451 Framingham Study participants (mean age 44 years, 52% women) we examined the relations of GGT with CVD risk factors, and prospectively determined the risk of new-onset metabolic syndrome, incident CVD, and death. GGT was positively associated with body mass index, blood pressure, LDL cholesterol, triglycerides, and blood glucose in cross-sectional analysis (P<0.005). On follow-up (mean 19 years), 968 participants developed metabolic syndrome, 535 developed incident CVD, and 362 died. The risk of metabolic syndrome increased with higher GGT (multivariable-adjusted hazard ratio [HR] per SD increment log-GGT, 1.26 [95%CI; 1.18 to 1.35]). Adjusting for established CVD risk factors (as time-dependent covariates updated quadriennially) and baseline CRP, a 1-SD increase in log-GGT conferred a 13% increase in CVD risk (P=0.007) and 26% increased risk of death (P<0.001). Individuals in the highest GGT quartile experienced a 67% increase in CVD incidence (multivariable-adjusted HR 1.67, 95%CI; 1.25 to 2.22). An increase in serum GGT predicts onset of metabolic syndrome, incident CVD, and death suggesting that GGT is a marker of metabolic and cardiovascular risk.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                7 November 2012
                : 7
                : 11
                : e48878
                Affiliations
                [1]Department of Geriatrics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
                Cardiff University, United Kingdom
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: C-FL Y-TG N-YF. Analyzed the data: C-FL Y-TG H-YW. Contributed reagents/materials/analysis tools: C-FL Y-TG H-YW N-YF. Wrote the paper: C-FL N-YF.

                Article
                PONE-D-12-23824
                10.1371/journal.pone.0048878
                3492247
                23145005
                6bb475f9-e952-4633-9645-33a1599f1c22
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 August 2012
                : 1 October 2012
                Page count
                Pages: 7
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Medicine
                Cardiovascular
                Hypertension
                Clinical Research Design
                Cohort Studies
                Meta-Analyses
                Prospective Studies
                Systematic Reviews
                Epidemiology
                Biomarker Epidemiology

                Uncategorized
                Uncategorized

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