Genome-wide association analysis of serum alanine and aspartate aminotransferase, and the modifying effects of BMI in 388k European individuals.
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ABSTRACT:
SUBMITTER: Gao C
PROVIDER: S-EPMC8457092 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundWe aimed to evaluate the association between the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and subsequent development of any type of cancer in an apparently healthy population.MethodsWe conducted a retrospective cohort study at St. Luke's International Hospital, Tokyo, Japan between 2005 and 2018. All participants who visited for voluntary health checkups were included. We divided the participants into different quintiles based on the baseline AST/ALT ratios and examined the outcomes.ResultsA total of 85,658 participants were included. The mean age was 44.7 years (standard deviation 12.0) at baseline, and 42,913 (50.1%) of them were men. During a median follow-up of 61.6 months, 4701 (5.5%) participants developed some type of cancer. Compared with the middle AST/ALT ratio group, no other groups had similar adjusted hazard ratios (HR) for the development of any type of cancer in both men and women. When stratified by alcohol consumption, very high (adjusted HR 1.36; 95% CI 1.13-1.63) and high (adjusted HR 1.26; 95% CI 1.05-1.50) AST/ALT ratio groups among men who were regular drinkers had increased adjusted HRs for any type of cancer development, but the very high AST/ALT ratio group among men who were abstainers (adjusted HR 0.64; 95% CI 0.42-0.97) and very low AST/ALT ratio group among men who were occasional drinkers (adjusted HR 0.69; 95% CI 0.48-0.98) had lower adjusted HRs compared with the middle AST/ALT ratio group. Among women, regardless of alcohol consumption, adjusted HR for any type of cancer development was similar across all AST/ALT ratio groups.ConclusionPeople with higher AST/ALT ratios tended to have a higher risk of developing any type of cancer among men who were regular drinkers, but this risk was lower among men who were abstainers. Among women, regardless of alcohol consumption, there was no association between the development of any type of cancer and AST/ALT ratio.
| S-EPMC8817090 | biostudies-literature
Project description:We carried out a genome-wide association study of serum aspartate aminotransferase (AST) activity in 866 Amish participants of the Heredity and Phenotype Intervention Heart Study and identified significant association of AST activity with a cluster of single nucleotide polymorphisms located on chromosome 10q24.1 (peak association was rs17109512; P=2.80E-14), in the vicinity of GOT1, the gene encoding cytosolic AST (cAST). Sequencing of GOT1 revealed an in-frame deletion of three nucleic acids encoding asparagine at position 389 c.1165_1167delAAC (p.Asn389del) in the gene. Deletion carriers had significantly lower AST activity levels compared with homozygotes for the common allele (mean±s.d.: 10.0±2.8 versus 18.8±5.2?U?l(-1); P=2.80E-14). Further genotyping of the deletion in other Amish samples (n=1932) identified an additional 20 carriers (minor allele frequency (MAF)=0.0052). The deletion was not detected in 647 outbred Caucasians. Asn at codon 389 is conserved among known mammalian cASTs. In vitro transient transfection of wild-type and mutant cAST indicated that mutant cAST protein was barely detectable in the cells. Furthermore, even after correction for cAST expression, mutant cAST had markedly diminished enzymatic activity. Remarkably, we did not find any association between the deletion and metabolic traits including serum fasting glucose or insulin, fasting and post-meal lipids, inflammatory markers, or sub-clinical markers of cardiovascular disease. In conclusion, we discovered a rare in-frame deletion in GOT1 gene, which inactivates cAST enzyme in the Old Order Amish. This finding will help us to understand structure and function of the enzyme and would be useful for predicting serum AST levels.
| S-EPMC3608855 | biostudies-literature
Project description:BackgroundThe prognostic significance of the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio in hepatocellular carcinoma remains uncertain. The aim of the current study was to evaluate the association between the AST/ALT ratio and prognosis in patients with hepatocellular carcinoma after hepatectomy, and to explore the role of underlying liver diseases as mediators.MethodsThis retrospective study included patients with hepatocellular carcinoma who underwent hepatectomy between January 2014 and January 2018 at two Chinese hospitals. The maximally selected rank statistic and g-computation approach were used to quantify and visualize the association between the AST/ALT ratio and overall survival or recurrence-free survival. The role of mediators (chronic hepatitis B, hepatic steatosis and liver cirrhosis) was analysed.ResultsAmong the 1519 patients (mean(s.d.) age at baseline, 50.5(11.3) years), 1309 (86.2%) were male. During a median follow-up of 46.0 months, 514 (33.8%) patients died and 358 (23.6%) patients experienced recurrence. The optimal cut-off value for the AST/ALT ratio was 1.4, and the AST/ALT ratio greater than or equal to 1.4 was independently associated with a 39.0% increased risk of death and a 30.0% increased risk of recurrence (overall survival: hazard ratio (HR), 1.39; 95% c.i. 1.15 to 1.68; recurrence-free survival: HR, 1.30; 95% c.i. 1.12 to 1.52) after adjusting for confounders. Chronic hepatitis B significantly mediated the association of the ratio of AST/ALT with both overall survival and recurrence-free survival (20.3% for overall survival; 20.1% for recurrence-free survival).ConclusionThe AST/ALT ratio greater than or equal to 1.4 was associated with shorter overall survival and recurrence-free survival in patients with hepatocellular carcinoma after hepatectomy, and chronic hepatitis B may play a role in their association.
| S-EPMC10798825 | biostudies-literature
Project description:BackgroundFew studies discussed the predictive ability of aspartate aminotransferase/alanine aminotransferase (AST/ALT, DeRitis) ratio for diabetes risk. The aim of this study was to characterize the role of AST/ALT ratio in the prediction of Chinese diabetes.MethodsThis retrospective cohort study analyzed a Chinese population comprising 87,883 participants without diabetes at baseline between 2010 and 2016. Cox proportional hazards regression was used to identify independent risk factors. Restricted cubic spline (RCS) was performed to investigate the non-linear correlation between AST/ALT ratio and diabetes risk.ResultsDuring a median follow-up period of 3.01 years, 1,877 participants developed diabetes. Comparing the baseline characteristics, diabetes group exhibited lower AST/ALT ratio. The Kaplan-Meier curve showed that participants with low AST/ALT ratio had higher cumulative incidence, and Cox regression also demonstrated that the lower AST/ALT ratio, the higher diabetes risk (HR: 0.56, 95% CI: 0.37-0.85, P = 0.006). The RCS model revealed a non-linear correlation between AST/ALT ratio and diabetes risk. In the condition of AST/ALT ratio ≤1.18, diabetes risk increased as it decreased (HR: 0.42, 95% CI: 0.19-0.91, P = 0.028). In contrast, AST/ALT ratio did not independently affect diabetes when beyond 1.18.ConclusionAST/ALT ratio is a valuable predictor of diabetes. Diabetes risk increases rapidly in the condition of AST/ALT ratio ≤1.18.
| S-EPMC9666731 | biostudies-literature
Project description:BackgroundThe aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio has been shown to be associated with poor clinical outcomes across various patient groups. However, little is unclear about the association between the two in critically ill older patients. Therefore, we aim to investigate the association of the AST/ALT ratio with hospital mortality in this special population.MethodsIn this retrospective cohort study, we extracted elderly patients (age ≥ 65 years) from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The primary outcome was in-hospital mortality. The association between the AST/ALT ratio and hospital mortality was studied using univariable and multivariable Cox regression analysis, as well as restricted cubic splines (RCS). Survival analysis was performed using the Kaplan-Meier (KM) method according to the AST/ALT ratio.ResultsAmong the 13,358 eligible patients, the mean age was 77.6 years, 7,077 patients (52.9%) were male, and 2,511 patients (18.8%) died in hospital. The AST/ALT ratio was found to be independently associated with in-hospital mortality (HR = 1.05, 95% CI: 1.01-1.09, P = 0.022) after adjusting for potential confounders. Furthermore, a non-linear relationship and saturation effect were observed between them, with the inflection point being 1.80. When the AST/ALT ratio was less than 1.80, we found that every 1 unit increase in the AST/ALT ratio resulted in a 39% increased risk of in-hospital mortality (HR = 1.39, 95% CI: 1.18-1.64, P < 0.001). However, when the AST/ALT ratio was greater than 1.80, the association became saturated (HR = 1.01, 95% CI: 0.96-1.07, P = 0.609). Sensitivity and subgroup analyses showed the results were robust.ConclusionIn critically ill older patients, the association between the AST/ALT ratio and in-hospital mortality was non-linear and showed a saturation effect. An elevated AST/ALT ratio was significantly associated with increased in-hospital mortality when the AST/ALT ratio was less than 1.80.
| S-EPMC10621830 | biostudies-literature
Project description:BackgroundAccumulating evidence has revealed that the aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio is a promising novel biomarker for insulin resistance (IR) and metabolic diseases. However, research on the association between the AST/ALT ratio and the incidence of diabetes progressing from prediabetes remains lacking. Herein, this study aimed to evaluate the relationship between the baseline AST/ALT ratio and risks of diabetes in patients with prediabetes.MethodsThis was a retrospective cohort study involving a total of 82,683 participants across 32 regions and 11 cities in China from 2010 to 2016. Data was obtained based on the DATADRYAD database from the health check screening program. Participants were stratified according to the interquartile range of the AST/ALT ratio (groups Q1 to Q4). The Cox proportional hazard model and smooth curve fitting were used to explore the relationship between the baseline AST/ALT ratio and the risk of diabetes in prediabetic patients. In addition, subgroup analysis was used to further validate the stability of the results.ResultsThe mean age of the selected participants was 49.9 ± 14.0 years, with 66.8% of them being male. During the follow-up period 1,273 participants (11.3%) developed diabetes progressing from prediabetes during the follow-up period. Participants who developed diabetes were older and were more likely to be male. The fully-adjusted Cox proportional hazard model revealed that the AST/ALT ratio was negatively associated with the risk of diabetes in prediabetic patients (HR = 0.40, 95% CI: 0.33 to 0.48, P < 0.001). Higher AST/ALT ratio groups (Q4) also presented with a lower risk of progressing into diabetes (HR = 0.35, 95% CI: 0.29 to 0.43, P < 0.001, respectively) compared with the lowest quintile group (Q1). Through subgroup analysis and interaction tests, it was found that the association stably existed in all subgroup variables, and there were a stronger interactive effects in people with age < 45 years, and TG ≤ 1.7 mmol/L in the association between AST/ALT ratio and diabetes incidences in patients with prediabetes (P for interaction < 0.05).ConclusionAccording to our study, a higher AST/ALT ratio is associated with a lower risk of progressing into diabetes from prediabetes. Regular monitoring of AST/ALT ratio dynamics and corresponding interventions can help prevent or slow prediabetes progression for diabetes.
| S-EPMC9846751 | biostudies-literature
Project description:The association between body-mass-index (BMI), alcohol consumption and their joint effect in increasing the risk of elevated serum alanine (ALT) and aspartate (AST) is unclear in older community-dwelling adults.To determine the association between alcohol, BMI, and their combined effect with serum ALT and AST in older community-dwelling adults in the United States.A cross-sectional, population-based study in participants (n = 2364) from the Rancho Bernardo Study (54% women; mean age: 70 years, BMI: 25 kg/m(2), alcohol users: 63%) who attended a research visit in 1984-87. BMI was recorded by a trained nurse and alcohol use ascertained by a validated questionnaire. Odds-ratio (OR) and 95% confidence intervals (CI) of elevated serum ALT and AST (defined as > or =30 U/L in men and > or =19 U/L in women) were calculated for alcohol and BMI separately and their joint exposure using logistic regression models.In multivariate logistic regression models adjusted for age, alcohol use, total cholesterol, serum triglycerides, fasting plasma glucose, systolic blood pressure, and diabetes mellitus, obesity independently increased the odds of elevated ALT in this cohort of older men and women by 3.0 (95% CI, 1.7-5.3) and 1.8 (95% CI, 1.1-2.7) respectively. Joint effects of consuming >3 alcoholic drinks/day and obesity raised the odds of elevated ALT by 8.9 (95% CI, 2.4-33.1) and AST by 21-fold (95% CI, 2.6-170.1), demonstrating synergism. Obese participants had higher odds of elevated ALT even at 0 < or = 1 drink/day.In older men and women, the combination of obesity with alcohol is synergistic in increasing the risk of liver injury.
| S-EPMC3220929 | biostudies-literature
Project description:Cobalt nanoparticles (Co-NPs) have been extensively used in clinical practices and medical diagnosis. In this study, the potential toxicity effects of Co-NPs with special emphasis over the biochemical enzyme activities, such as aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) in serum, liver, and kidney of Wistar rats were investigated. This toxicity measurement of nanomaterials can support the toxicological data. The biochemical enzymatic variations are powerful tools for the assessment of toxicity. ASAT and ALAT enzymes have been widely used to predict tissue-specific toxicities associated with xenobiotic. The biochemical changes induced by Co-NPs have significance in their toxicological studies because the alterations in biochemical parameters before clinical symptoms indicate either their toxicant safety or detrimental effect. Herein, Co-NPs with particle size <50 nm significantly activated ASAT and ALAT enzymes in the serum, liver, and kidney of rats at concentration-dependent order.
| S-EPMC7184135 | biostudies-literature
Project description:BACKGROUND/AIMS:Enzymatic analysis of aspartate/alanine aminotransferase (AST/ALT) does not exactly represent the progression of liver fibrosis or inflammation. Immunoassay for AST (cytoplasmic [c] AST/mitochondrial [m] AST) and ALT (ALT1/ALT2) has been suggested as one alternatives for enzymatic analysis. The objective of this study was to evaluate the efficacy of immunoassay in predicting liver fibrosis and inflammation. METHODS:A total of 219 patients with chronic hepatitis B (CHB) who underwent hepatic venous pressure gradient (HVPG) and liver biopsy before antiviral therapy were recruited. Serum samples were prepared from blood during HVPG. Results of biochemical parameters including enzymatic AST/ALT and immunological assays of cAST, mAST, ALT1, and ALT2 through sandwich enzyme-linked immunosorbent assay (ELISA) immunoassay with fluorescence labeled monoclonal antibodies were compared with the results of METAVIR stage of live fibrosis and the Knodell grade of inflammation. RESULTS:METAVIR fibrosis stages were as follows: F0, six (3%); F1, 52 (24%); F2, 88 (40%); F3, 45 (20%); and F4, 28 patients (13%). Mean levels of AST and ALT were 121 ± 157 and 210 ± 279 IU/L, respectively. Mean HVPG score of all patients was 4.7 ± 2.5 mmHg. According to the stage of liver fibrosis, HVPG score (p < 0.001, r = 0.439) and ALT1 level (p < 0.001, r = 0.283) were significantly increased in all samples from patients with CHB. ALT (p < 0.001, r = 0.310), ALT1 (p < 0.001, r = 0.369), and AST (p < 0.001, r = 0.374) levels were positively correlated with Knodell grade of inflammation. CONCLUSION:ALT1 measurement by utilizing sandwich ELISA immunoassay can be useful method for predicting inf lammation grade and fibrosis stage in patients with CHB.
| S-EPMC7060995 | biostudies-literature
Project description:Elevated alanine aminotransferase (ALT) activity, an important marker of liver injury, has been associated inconsistently with higher mortality. We evaluated whether persons with nonelevated ALT levels are the most appropriate comparison group by examining the relationships of low ALT with mortality and body composition in the US National Health and Nutrition Examination Survey (NHANES). In NHANES 1988-1994, the mortality risk of persons in ALT deciles 1, 2, 3, and 10 was compared with that of persons in deciles 4-9 (mortality was relatively flat across these deciles) over an 18-year period (through 2006) among 14,950 viral-hepatitis-negative adults. In NHANES 1999-2006, low ALT was evaluated in association with dual-energy x-ray absorptiometry body composition measures among 15,028 adults. Multivariate-adjusted mortality was higher for decile 1 (hazard ratio (HR) = 1.42, 95% confidence interval (CI): 1.24, 1.63), decile 2 (HR = 1.27, 95% CI: 1.06, 1.53), and decile 3 (HR = 1.25, 95% CI: 1.04, 1.50) and nonsignificantly higher for decile 10 (HR = 1.21, 95% CI: 0.91, 1.61) than for deciles 4-9. Adjusted appendicular lean mass was decreased among the lowest ALT deciles. In the US population, low ALT was associated with higher mortality risk, possibly attributable to decreased appendicular lean mass. For mortality studies of elevated ALT levels, the most appropriate comparison group is persons in the middle range of ALT rather than all persons with nonelevated ALT.
| S-EPMC3858105 | biostudies-literature