Highly Elevated Plasma γ-Glutamyltransferase Elevations: A Trait Caused by γ-Glutamyltransferase 1 Transmembrane Mutations.
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ABSTRACT:
SUBMITTER: De Grandi A
PROVIDER: S-EPMC7155009 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Observational epidemiological evidence supports a linear and independent association between serum gamma-glutamyltransferase (GGT) concentrations and the risk of Alzheimer's disease (AD). However, the causality of this association has not been previously investigated. We sought to assess the causal nature of this association using a Mendelian randomization (MR) approach. Using inverse-variance weighted MR analysis, we assessed the association between GGT and AD using summary statistics for single nucleotide polymorphism (SNP)-AD associations obtained from the International Genomics of Alzheimer's Project of 17,008 individuals with AD and 37,154 controls. We used 26 SNPs significantly associated with GGT in a previous genome-wide association study on liver enzymes as instruments. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR. The odds ratio of AD was 1.09 (95% confidence interval, 0.98 to 1.22; p = 0.10) per one standard deviation genetically elevated GGT based on all 26 SNPs. The results were similar in both MR-Egger and weighted median MR methods. Overall, our findings cannot confirm a strong causal effect of GGT on AD risk. Further MR investigations using individual-level data are warranted to confirm or rule out causality.
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Project description:Seminal plasma, because of its proximity to prostate, is a promising fluid for biomarker discovery and noninvasive diagnostics. In this study, we investigated if seminal plasma proteins could increase diagnostic specificity of detecting primary prostate cancer and discriminate between high- and low-grade cancers. To select 147 most promising biomarker candidates, we combined proteins identified through five independent experimental or data mining approaches: tissue transcriptomics, seminal plasma proteomics, cell line secretomics, tissue specificity, and androgen regulation. A rigorous biomarker development pipeline based on selected reaction monitoring assays was designed to evaluate the most promising candidates. As a result, we qualified 76, and verified 19 proteins in seminal plasma of 67 negative biopsy and 152 prostate cancer patients. Verification revealed a prostate-specific, secreted and androgen-regulated protein-glutamine gamma-glutamyltransferase 4 (TGM4), which predicted prostate cancer on biopsy and outperformed age and serum Prostate-Specific Antigen (PSA). A machine-learning approach for data analysis provided improved multi-marker combinations for diagnosis and prognosis. In the independent verification set measured by an in-house immunoassay, TGM4 protein was upregulated 3.7-fold (p = 0.006) and revealed AUC = 0.66 for detecting prostate cancer on biopsy for patients with serum PSA ?4 ng/ml and age ?50. Very low levels of TGM4 (120 pg/ml) were detected in blood serum. Collectively, our study demonstrated rigorous evaluation of one of the remaining and not well-explored prostate-specific proteins within the medium-abundance proteome of seminal plasma. Performance of TGM4 warrants its further investigation within the distinct genomic subtypes and evaluation for the inclusion into emerging multi-biomarker panels.
| S-EPMC6731075 | biostudies-literature
Project description:Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children with high gamma-glutamyltransferase (GGT) cholestasis. Here, we report whole-exome sequencing of germline DNA from 2 unrelated children, both offspring of consanguineous union, with neonatal cholestasis and high GGT of unclear etiology. Both children had a rare homozygous damaging mutation (p.Arg219* and p.Val204Met) in kinesin family member 12 (KIF12). Furthermore, an older sibling of the child homozygous for p.Val204Met missense mutation, who was also found to have cholestasis, had the same homozygous mutation, thus identifying the cause of the underlying liver disease. Conclusion: Our findings implicate rare homozygous mutations in KIF12 in the pathogenesis of cholestatic liver disease with high GGT in 3 previously undiagnosed children.
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Project description:We assessed GGT fractions correlates and their reference values in the Offspring Cohort of the Framingham Heart Study.Correlates of GGT fractions were assessed by multivariable regression analysis in 3203 individuals [47% men, mean age (SD): 59 (10) years]. GGT fractions reference values were established by empirical quantile analysis in a reference group of 432 healthy subjects [45% men, 57 (10) years].Fractional GGT levels were higher in men than in women (P<0.0001). In both sexes, fractions were associated with: triglycerides were associated with b-GGT, alcohol consumption with m-, s- and f-GGT. C-reactive protein with m- and s-GGT, while plasminogen activator inhibitor-1 with b- and f-GGT. Body mass index, blood pressure, glucose and triglycerides correlated with b- and f-GGT. In comparison with the reference group [b-GGT/s-GGT median (Q1-Q3): 0.51 (0.35-0.79)U/L], subjects affected by cardiovascular disease or diabetes showed no change of b/s ratio [0.52 (0.34-0.79)U/L, 0.57 (0.40-0.83)U/L, respectively]. The b/s ratio was higher in presence of metabolic syndrome [0.61 (0.42-0.87)U/L, P<0.0001], while lower in heavy alcohol consumers [0.41 (0.28-0.64)U/L, P<0.0001].Metabolic and cardiovascular risk markers are important correlates of GGT fractions, in particular of b-GGT.
| S-EPMC4154585 | biostudies-literature
Project description:Prostate-specific antigen, a blood serum biomarker of prostate cancer, lacks specificity and prognostic significance, so considerable efforts are devoted to developing novel biomarkers. Seminal plasma, due to its proximity to prostate, is a promising fluid for biomarker discovery and non-invasive diagnostics. In this study, we investigated if seminal plasma proteins could increase specificity of detecting primary prostate cancer and discriminate between high- and low-grade cancers. To select 148 most promising biomarker candidates, we combined proteins identified through five independent data mining or experimental approaches: tissue transcriptomics, seminal plasma proteomics, cell secretomics, tissue specificity and androgen regulation. A rigorous biomarker development pipeline based on targeted proteomics assays was designed to evaluate the most promising candidates. We qualified 77 and verified 19 proteins in seminal plasma of 67 negative biopsy and 155 prostate cancer patients. Verification revealed a prostate-specific, secreted and androgen-regulated protein-glutamine gamma-glutamyltransferase 4 (TGM4), which could predict prostate cancer on biopsy and outperformed age and serum PSA. Machine-learning approaches also revealed improved multi-marker combinations for diagnosis and prognosis. In the independent verification set measured by an in-house ELISA, TGM4 was up-regulated 3.7-fold (P=0.006) and revealed AUC 0.66 for detecting prostate cancer on biopsy for patients serum PSA≥4 ng/mL and age≥50. Low levels of TGM4 (120 pg/mL) were detected in blood serum, but could not differentiate between negative biopsy, prostate cancer or prostate inflammation. To conclude, performance of TGM4 warrants its further investigation within the distinct genomic subtypes of prostate cancer and evaluation for the inclusion into emerging multi-biomarker panels.
2019-08-02 | PXD007657 | Pride
Project description:Emerging evidence that an elevated serum gamma-glutamyltransferase (GGT) level is associated with an increased risk of gastrointestinal cancer, but still controversial. The aim of this study to assess the relationship between GGT level and risk of gastrointestinal cancer, and the contribution of the interaction of hyperglycemia with elevated GGT level to the incidence of gastrointestinal cancer by the stratified analysis. A total of 8,120,665 Koreans who received medical checkups in 2009 were included. Subjects were classified according to the quartile of GGT level for women and men. The incidence rates of gastrointestinal cancer for each group were analyzed using Cox proportional hazards models. During follow-up, 129,853 cases of gastrointestinal cancer newly occurred (esophagus, 3,792; stomach, 57,932; and colorectal, 68,789 cases). The highest GGT quartile group showed an increased risk of gastrointestinal cancer (esophagus, hazard ratio = 2.408 [95% confidence interval, 2.184-2.654]; stomach, 1.121 [1.093-1.149]; and colorectal, 1.185 [1.158-1.211]). The risk increased significantly with the rise in GGT quartile level, regardless of the site of cancer. The stratified analysis according to glycemic status showed that the effect of elevated GGT was predominant in the risk of esophageal cancer. The effect of elevated GGT further increased the risk of stomach and colorectal cancers in diabetic patients. An elevated level of GGT was associated with an increased risk of gastrointestinal cancer, regardless of the site of cancer. The effect of the increase in GGT level on the risk of gastrointestinal cancer depended on the type of cancer and glycemic status.
| S-EPMC7864398 | biostudies-literature
Project description:BackgroundThe incidence of breast cancer has been gradually increasing in Korea. Recently, the elevated level of serum gamma-glutamyltransferase (GGT) has emerged to be associated with the development and progression of some malignancies. This study aimed to determine the effect of serum GGT levels on the risk of developing breast cancer in Korean women.MethodsWe used National Health Insurance Service Health Checkup data to examine the association between serum GGT levels and breast cancer development in Korean women. Women aged 40 years or older who participated in the Korean National Health Screening Examination between January 2009 and December 2009 and who did not develop any cancer within 1-year post examination were included in this analysis (n = 3,109,506). Cox proportional hazard regression analysis was conducted to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).ResultsOverall, an elevated serum GGT level was associated with the increased risk of developing breast cancer; compared to the Q1 group, the Q4 group showed a significantly increased breast cancer risk (HR: 1.120,95% CI: 1.08-1.162). Such a relationship was stronger in post-menopausal women than pre-menopausal women (HR: 1.173, 95% CI: 1.107-1.243; HR: 1.070, 95% CI:1.019-1.124). Women with a high GGT level (Q4) were also at an increased risk of developing carcinoma in situ (CIS) (HR: 1.114, 95% CI: 1.04-1.192). In post-menopausal women, the Q4 group also exhibited higher CIS risk (HR: 1.266, 95% CI: 1.132-1.416). However, no significant difference in the risk of developing CIS was observed between the Q1 and Q4 groups in pre-menopausal women. Further analysis revealed that obese, post-menopausal women with a high GGT level (Q4) were associated with an increased risk of developing breast cancer (HR: 1.214, 95% CI: 1.125-1.31) and CIS (HR: 1.348, 95% CI: 1.159-1.569).ConclusionsOur study results demonstrate that increased serum GGT level is a risk factor for developing breast cancer. The post-menopausal women group with obesity and elevated serum GGT level showed the highest incidence of breast cancer. Thus, serum GGT concentration could be a novel and potential risk factor for breast cancer. Further validation in different ethnic groups would be warranted.
| S-EPMC8191736 | biostudies-literature
Project description:Gamma-glutamyltransferase (GGT) is a marker for hepatic injury and alcohol consumption. However, the association of GGT with the risk of oesophageal carcinoma (OC) has not been fully recognized to date. Therefore, this study aimed to determine the association between elevated GGT and OC, by also considering the body mass index (BMI) of the subjects. Clinical data from 8,388,256 Korean individuals, who were aged 40 years and over and who received healthcare check-ups arranged by the national insurance program in 2007 and 2008, were analysed. Newly diagnosed OC was identified using claims data during a median follow-up duration of 8.72 years. During the study period, 6,863 individuals (0.08%) developed OC. We found that there was an increased risk of OC in subjects with serum GGT values >18 IU/L. Furthermore, a BMI <18.5 kg/m2 (underweight) was associated with increased OC risk, while a BMI ≥23.0 kg/m2 was associated with a reduced OC risk. Individuals who were both underweight and in the highest GGT quartile (≥40 IU/L) had a far greater risk of OC compared to other individuals (hazard ratio: 3.65, 95% confidence interval: 3.10-4.30). In conclusion, increased serum GGT was associated with an increased risk of developing OC in the general Korean population, regardless of age, sex, smoker status, or alcohol consumption.
| S-EPMC5419599 | biostudies-literature
Project description:BackgroundAlthough elevated serum gamma-glutamyltransferase (GGT) is a known indicator of increased risk of several cancers, the clinical value of repeated measurements of GGT has not been determined. Therefore, we aimed to investigate whether repeatedly elevated serum GGT levels are associated with the risk of respiratory cancer incidence.MethodsWe included participants who had undergone the Korean Health screening four times during 2009-2012 and had previously undergone four consecutive examinations. Those who were diagnosed with respiratory cancer before the date of examination were excluded. The participants obtained one GGT point if their GGT levels were in the highest quartile (the quartile 4 group). We analyzed the association between GGT points and respiratory cancer incidence by Cox proportional hazard models.ResultsDuring mean follow-up of 6.39 ± 1.2 years, 3,559,109 participants were enrolled. Of them, 8,944 (0.34%) men and 1,484 (0.14%) women were newly diagnosed with respiratory cancer. In multivariate analysis adjusted for confounding factors, male participants with 4 GGT points had a significantly higher hazards of developing respiratory cancer than those with 0 GGT points (hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.31-1.48). Among female, participants with the highest points of GGT also had sixfold increased risk of developing laryngeal cancer. However, no significant association was observed between GGT points and lung cancer incidence among women (HR: 0.95; 95% CI: 0.81-1.11).ConclusionRepeatedly elevated serum levels of GGT were associated with a higher risk of respiratory cancer incidence, especially in men. This finding suggests that physicians can identify a person with a higher risk of respiratory cancer through a simple repeated measurement of GGT.
| S-EPMC7925999 | biostudies-literature
Project description: Not available
| S-EPMC7702107 | biostudies-literature