GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms.
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ABSTRACT:
SUBMITTER: Ward LD
PROVIDER: S-EPMC8316433 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. We localized the genetic defect by homozygosity mapping and then identified two different homozygous frameshift SLC30A10 mutations, segregating with disease. SLC30A10 is highly expressed in the liver and brain, including in the basal ganglia. Its encoded protein belongs to a large family of membrane transporters, mediating the efflux of divalent cations from the cytosol. We show the localization of SLC30A10 in normal human liver and nervous system, and its depletion in liver from one affected individual. Our in silico analyses suggest that SLC30A10 possesses substrate specificity different from its closest (zinc-transporting) homologs. We also show that the expression of SLC30A10 and the levels of the encoded protein are markedly induced by manganese in vitro. The phenotype associated with SLC30A10 mutations is broad, including neurologic, hepatic, and hematologic disturbances. Intrafamilial phenotypic variability is also present. Chelation therapy can normalize the manganesemia, leading to marked clinical improvements. In conclusion, we show that SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport. This work has broad implications for understanding of the manganese biology and pathophysiology in multiple human organs.
| S-EPMC3309204 | biostudies-literature
Project description:AimsThe ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is of great interest as a possible novel marker of metabolic syndrome. However, longitudinal studies emphasizing the incremental predictive value of the AST-to-ALT ratio in diagnosing individuals at higher risk of developing metabolic syndrome are very scarce. Therefore, our study aimed to evaluate the AST-to-ALT ratio as an incremental predictor of new onset metabolic syndrome in a population-based cohort study.Material and methodsThe population-based cohort study included 2276 adults (903 men and 1373 women) aged 40-70 years, who participated from 2005-2008 (baseline) without metabolic syndrome and were followed up from 2008-2011. Metabolic syndrome was defined according to the harmonized definition of metabolic syndrome. Serum concentrations of AST and ALT were determined by enzymatic methods.ResultsDuring an average follow-up period of 2.6-years, 395 individuals (17.4%) developed metabolic syndrome. In a multivariable adjusted model, the odds ratio (95% confidence interval) for new onset of metabolic syndrome, comparing the fourth quartile to the first quartile of the AST-to-ALT ratio, was 0.598 (0.422-0.853). The AST-to-ALT ratio also improved the area under the receiver operating characteristic curve (AUC) for predicting new cases of metabolic syndrome (0.715 vs. 0.732, P = 0.004). The net reclassification improvement of prediction models including the AST-to-ALT ratio was 0.23 (95% CI: 0.124-0.337, P<0.001), and the integrated discrimination improvement was 0.0094 (95% CI: 0.0046-0.0143, P<0.001).ConclusionsThe AST-to-ALT ratio independently predicted the future development of metabolic syndrome and had incremental predictive value for incident metabolic syndrome.
| S-EPMC4999188 | biostudies-literature
Project description:OBJECTIVE:The association between unbalanced iron indices and the conditions of schizophrenia are not well understood. Liver dysfunction which has been linked to iron metabolism might be a contributing factor. This case-control study evaluated serum iron indices and liver function in treatment-naïve schizophrenia patients and those already on treatment at the Psychiatric Department of the Komfo Anokye Teaching Hospital (KATH), Kumasi-Ghana. RESULTS:The mean age of the respondents was 39.6 ± 0.8 years. Increased levels of serum iron, TS, AST, ALT and AST:ALT ratio and lower levels of UIBC, TIBC, Transferrin, and log Ferritin:AST ratio levels were observed among the treatment-naïve group compared to the control. The treatment-naïve and treatment groups showed significantly higher serum AST:ALT ratio, and lower log10ferrtin:AST ratio than the healthy controls. There was a significant correlation between log10ferritin and AST, and log10ferritin and GGT in both treatments (r = 0.343; p = 0.003, and r = 0.502; p = 0.001 respectively) and treatment-naïve groups (r = 0.348; p = 0.002, and r = 0.614; p < 0.001 respectively). Percentage transferrin saturation correlated significantly with GGT only, in the treatment-naïve group (r = 0.667; p < 0.001), and ALT and GGT in the treatment group (r = 0.252; p = 0.030 and r = 0.646; p = 0.014 respectively).
| S-EPMC6909526 | biostudies-literature
Project description:Substantial evidence suggests an important role of liver function in brain health. Liver function is clinically assessed by measuring the activity of hepatic enzymes in the peripheral blood. Brain-derived neurotrophic factor (BDNF) is an important regulator of brain function. Therefore, we hypothesized that blood BDNF levels are associated with liver function and fibrosis. To test this hypothesis, in this cross-sectional study, we investigated whether serum BDNF concentration is associated with liver enzyme activity, aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ratio, and fibrosis-4 (FIB-4) index in middle-aged and older women. We found that serum BDNF level showed a significant positive association with ALT and γ-glutamyltranspeptidase (GGT) activity and negative association with FIB-4 index, and a trend of negative association with the AST/ALT ratio after adjustment for age. Additionally, these associations remained statistically significant even after adjustment for body mass index (BMI) and fasting blood glucose level. These results demonstrate associations of serum BDNF levels with liver enzymes and hepatic fibrosis-related indices, which may underlie liver-brain interactions.
| S-EPMC9398011 | biostudies-literature
Project description:AbstractPrevious studies had shown that an increased aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT ratio) was associated with cardiovascular disease. This study aimed to assess the relationship between AST/ALT ratio and all-cause and cardiovascular mortality in patients with hypertension.By March 31, 2020, a cohort of 14,220 Chinese hypertensive patients was followed up. The end point was all-cause and cardiovascular death. Hazard ratios (HRs) and 95% CIs were calculated for mortality associated with AST/ALT ratio, using Cox proportional hazards models and competing risk model.In an average of 1.7 years of follow-up, 1.39% (n = 198) of patients died, 55.5% (n = 110) of whom from cardiovascular disease. AST/ALT ratio was associated with increased risk of all-cause death (HR:1.37, 95% CI:1.15-1.63) and cardiovascular death (HR:1.32, 95% CI:1.03-1.68) after adjustment for other potential confounders. Compared with low AST/ALT ratio (Tertile 1), high AST/ALT ratio was associated with high cause mortality (Tertile 2: HR:1.35, 95% CI:0.86-2.10; Tertile 3: HR:2.10, 95% CI:1.37-3.21; P for trend <.001). Compared with low AST/ALT ratio (Tertile 1), a statistically significant increased risk of cardiovascular mortality was also observed (Tertile 2: HR:1.27, 95% CI:0.70-2.29; Tertile 3: HR:1.92, 95% CI:1.09-3.37; P for trend <.001). High AST/ALT ratio was also associated with high cardiovascular mortality (Tertile 2: HR:1.27, 95% CI:0.70-2.29; Tertile 3: HR:1.92, 95% CI:1.09-3.37; P for trend <.001).Present study indicated that increased AST/ALT ratio levels were predictive of all-cause and cardiovascular mortality among Chinese hypertensive patients.Trial registration: CHICTR, CHiCTR1800017274. Registered 20 July 2018.
| S-EPMC8341222 | biostudies-literature
Project description:Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain ?pmr1. Expressing human wild-type SLC30A10 in the ?pmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs(?)17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes.
| S-EPMC3309187 | biostudies-literature
Project description:High levels of liver enzymes GGT, ALT and AST are predictive of disease and all-cause mortality and can reflect liver injury, fatty liver and/or oxidative stress. Variation in GGT, ALT and AST levels is heritable. Moderation of the heritability of these liver enzymes by age and sex has not often been explored, and it is not clear to what extent non-additive genetic and shared environmental factors may play a role. To examine the genetic architecture of GGT, ALT and AST, plasma levels were assessed in a large sample of twins, their siblings, parents and spouses (N = 8,371; age range 18-90). For GGT and ALT, but not for AST, genetic structural equation modeling showed evidence for quantitative sex differences in the genetic architecture. There was no evidence for qualitative sex differences, i.e. the same genes were expressed in males and females. Both additive and non-additive genetic factors were important for GGT in females (total heritability h(2) 60 %) and AST in both sexes (total h(2) 43 %). The heritability of GGT in males and ALT for both sexes was due to additive effects only (GGT males 30 %; ALT males 40 %, females 22 %). Evidence emerged for shared environmental factors influencing GGT in the male offspring generation (variance explained 28 %). Thus, the same genes influence liver enzyme levels across sex and age, but their relative contribution to the variation in GGT and ALT differs in males and females and for GGT across age. Given adequate sample sizes these results suggest that genome-wide association studies may result in the detection of new susceptibility loci for liver enzyme levels when pooling results over sex and age.
| S-EPMC3918238 | biostudies-literature
Project description:BackgroundThe aspartate transaminase (AST)-to-alanine aminotransferase (ALT) ratio, which is used to measure liver injury, has been found to be associated with some chronic diseases and mortality. However, its relevance to cancer incidence resulting from population-based prospective studies has rarely been reported. In this study, we investigated the correlation of the AST/ALT ratio as a possible predictor of mortality and cancer incidence.MethodsA total of 9,946 participants fulfilled the inclusion criteria for a basic public health service project of the Health Checkup Program conducted by the BaiYun Community Health Service Center, Taizhou. Deceased participants and cancer incident cases were from The Taizhou Chronic Disease Information Management System. Odds ratios (ORs) and interval of quartile range (IQR) computed by logistic regression analysis and cumulative incidence rate were calculated by the Kaplan-Meier survival method and compared with log-rank test statistics.ResultsSerum ALT and AST levels were both increased in patients with chronic diseases, but the ratio of AST/ALT was generally decreased. The cancer incident cases (488 new cases) had a greater baseline ratio (median =1.23, IQR: 0.96-1.54) than noncancer cases (median =1.15, IQR: 0.91-1.44). Compared to the first quartile of the AST/ALT ratio, the population in the top quartile had a higher cumulative cancer incidence rate (7.54% vs. 4.44%) during follow-up period. Furthermore, an elevated AST/ALT ratio increased the risk of all-cause mortality.ConclusionsThe ratio of AST/ALT is a potential biomarker to assess healthy conditions and long-term mortality. Especially for cancer, the AST/ALT ratio not only increases at baseline but also predicts the future development of cancer. The clinical value and potential mechanism deserve further research.
| S-EPMC9102513 | biostudies-literature
Project description:The levels of liver function tests (LFTs) are often used to assess liver injury and non-liver disease-related mortality. In our study, the relationship between pretreatment serum LFTs and overall survival (OS) was evaluated in esophageal squamous cell carcinoma (ESCC) patients.Our purpose was to investigate the prognostic value of the preoperative alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in ESCC patients. A retrospective study was performed in 447 patients with ESCC, and follow-up period was at least 60 months until death. The prognostic significance of serum LFTs were determined by univariate and multivariate Cox hazard models.LFTs including ALT, AST, LSR, GGT, TBA and LDH were analyzed. Serum LSR (HR: 0.592, 95% CI = 0.457-0.768, p < 0.001 and GGT (HR: 1.507, 95% CI = 1.163-1.953, p = 0.002) levels were indicated as significant predictors of OS. The 5-year OS among patients with higher LSR levels was longer compared with those patients with decreased LSR levels, not only in the whole cohort but also in the subgroups stratified by pathological stage (T1-T2 subgroup, T3-T4 subgroup, N0 subgroup and M0 subgroup). We also found that patients with a higher GGT might predict worse OS than patients with a normal GGT, not only in the whole cohort but also in the subgroups stratified by pathological stage (T3-T4 subgroup and N1-N2 subgroup).Both increased levels of LSR and decreased levels of GGT might predict shorter overall survival in ESCC patients. Our findings suggest that serum LSR and GGT levels could be used as a key predictor of survival in patients with ESCC.
| S-EPMC5556356 | biostudies-other
Project description:This study investigates the prognostic value of the aspartate-to-alanine aminotransferase ratio (i.e., AST/ALT ratio) and bilirubin in patients with cardiogenic shock (CS). Despite ongoing improvements regarding the treatment of CS patients, invasive care unit (ICU) mortality in CS patients remains unacceptably high. Limited data regarding the prognostic value of the AST/ALT ratio and bilirubin in patients suffering from CS is available. The authors hypothesize the measurement of liver enzymes during the course of CS may be an easy and feasible method to assess right-heart dysfunction and prognosis in patients with CS. Consecutive patients with CS from 2019 to 2021 were included. Blood samples were retrieved from the day of disease onset (day 1), days 2, 3, 4 and 8. The prognostic value of the AST/ALT ratio and bilirubin was tested for 30-day all-cause mortality. Statistical analyses included univariable t-tests, Spearman's correlations, Kaplan-Meier analyses, as well as multivariable Cox proportional regression analyses. A total of 157 CS patients were included, with an overall rate of all-cause mortality at 30 days of 51%. The median AST/ALT ratio on day 1 was 1.4, and the median bilirubin was 0.63 mg/dL. No association of the baseline AST/ALT ratio (HR = 1.005; 95% CI 0.649-1.558; p = 0.981) and bilirubin (HR = 1.320; 95% CI 0.834-2.090; p = 0.236) with the risk of 30-day all-cause mortality was found. In contrast, the AST/ALT ratio on day 4 was associated with the risk of 30-day all-cause mortality (HR = 2.826; 95% CI 1.227-6.510; p = 0.015), which was still evident after the multivariable adjustment (HR = 2.830; 95% CI 1.054-7.690; p = 0.039). The AST/ALT ratio during the course of ICU hospitalization from day 4-but not the baseline AST/ALT ratio and bilirubin-was associated with an increased risk of 30-day all-cause mortality in CS patients.
| S-EPMC10455678 | biostudies-literature