Background: Tacrolimus is widely used as a first-line immunosuppressant in transplant immunology; however, its clinical application is constrained by the narrow therapeutic index and considerable interindividual variability. In this study, we identified the potential regulatory role of a novel promoter polymorphism, rs4519508 C > T, in the tacrolimus pharmacodynamic pathway.
Methods: Dual-luciferase reporter assays and bioinformatic analysis were applied to assess the impact of allelic variation.
Schizophrenia (SCZ) is a severe mental disorder affecting around 1% of individuals worldwide. The variability in response to antipsychotic drugs (APDs) among SCZ patients presents a significant challenge for clinicians in determining the most effective medication. In this study, we investigated the biological markers and established a predictive model for APD response based on a large-scale genome-wide association study using 3269 Chinese schizophrenia patients.
View Article and Find Full Text PDFPancreatic ductal adenocarcinoma (PDA) has been found to have a high mortality rate. Despite continuous efforts, current histopathological classification is insufficient to guide individualized therapies of PDA. We first define the molecular subtypes of PDA (MSOP) based on a meta-cohort of 845 samples from 11 PDA datasets.
View Article and Find Full Text PDFBackground: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease affecting multiple organs and tissues with high cellular heterogeneity. CD8 T cell activity is involved in the SLE pathogenesis. However, the cellular heterogeneity and the underlying mechanisms of CD8 T cells in SLE remain to be identified.
View Article and Find Full Text PDFFront Pharmacol
December 2022
Accumulating evidence shows that DNA methylation plays a role in antipsychotic response. However, the mechanisms by which DNA methylation changes are associated with antipsychotic responses remain largely unknown. We performed a methylome-wide association study (MWAS) to evaluate the association between DNA methylation and the response to risperidone in schizophrenia.
View Article and Find Full Text PDFAntipsychotic-induced metabolic syndrome (APs-induced Mets) is the most common adverse drug reaction, which affects more than 60% of the psychiatric patients. Although the etiology of APs-induced Mets has been extensively investigated, there is a lack of integrated analysis of the genetic and epigenetic factors. In this study, we performed genome-wide, whole-exome sequencing (WES) and epigenome-wide association studies in schizophrenia (SCZ) patients with or without APs-induced Mets to find the underlying mechanisms, followed by in vitro and in vivo functional validations.
View Article and Find Full Text PDFBackground: Olanzapine is an effective antipsychotic medication for treatment-resistant schizophrenia (TRS); however, the therapeutic effectiveness of olanzapine has been found to vary in individual patients. It is imperative to unravel its resistance mechanisms and find reliable targets to develop novel precise therapeutic strategies.
Methods: Unbiased RNA sequencing analysis was performed using homogeneous populations of neural stem cells derived from induced pluripotent stem cells in 3 olanzapine responder (reduction of Positive and Negative Syndrome Scale score ≥25%) and 4 nonresponder (reduction of Positive and Negative Syndrome Scale score <25%) inpatients with TRS.
Risperidone is routinely used in the clinical management of schizophrenia, but the treatment response is highly variable among different patients. The genetic underpinnings of the treatment response are not well understood. We performed a pharmacogenomic study of the treatment response to risperidone in patients with schizophrenia by using a SNP microarray -based genome-wide association study (GWAS) and whole exome sequencing (WES)-based GWAS.
View Article and Find Full Text PDFHuman cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1-3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action.
View Article and Find Full Text PDFBackground: Schizophrenia (SCZ) is a severe psychiatric disorder that affects approximately 0.75% of the global population. Both genetic and environmental factors contribute to development of SCZ.
View Article and Find Full Text PDFDrug-induced liver injury (DILI) is a common and serious adverse drug reaction with insufficient clinical diagnostic strategies and treatment methods. The only clinically well-received method is the Roussel UCLAF Causality Assessment Method scale, which can be applied to both individuals and prospective or retrospective studies. However, in severe cases, patients with DILI still would develop acute liver failure or even death.
View Article and Find Full Text PDFHepatic fibrosis is a spontaneous wound-healing response triggered by chronic liver injury. Pien Tze Huang (PZH), a traditional Chinese herbal medicine, has been widely used to treat various hepatic diseases in Asia. We used a CCl-induced mouse model to establish a PZH group of hepatic fibrosis mice treated with PZH and a control group of hepatic fibrosis mice without any treatment.
View Article and Find Full Text PDFSchizophrenia (SCZ) is a severe neuropsychiatric disorder that affects 1% of the global population. Copy number variations (CNVs) have been shown to play a critical role in its pathophysiology; however, only case-control studies on SCZ susceptibility CNVs have been conducted in Han Chinese. Here, we performed an array comparative genomic hybridization-based genome-wide CNV analysis in 100 Chinese family trios with SCZ.
View Article and Find Full Text PDFThe genetic factors of tuberculosis (TB) susceptibility have been widely recognized. Here we performed a two-stage study in 616 TB patients and 709 healthy controls to systematically identify the genetic markers of TB susceptibility. In the discovery stage, we identified 93 single nucleotide polymorphisms (SNPs) and 3 human leucocyte antigen (HLA) class II alleles that had potential associations with TB susceptibility.
View Article and Find Full Text PDFLiver function tests (LFTs) measure a series of complex traits that are affected by genetic and environmental factors. Previous studies demonstrated that there exist significant differences in LFTs across individuals, which may be the results of the unique genetic profile of each individual. Therefore, we performed a genome-wide association study (GWAS) to evaluate the influence of single nucleotide polymorphisms (SNPs) in LFTs and identify the significant association between genotypes and phenotypes using 1653 Chinese subjects from the UK Biobank database.
View Article and Find Full Text PDFAim: The aim of the present study was to investigate the potential effects of genetic variations in the FKBP-CaN-NFAT pathway on clinical events associated with tacrolimus efficacy in Chinese renal transplant patients.
Methods: One hundred and forty Chinese renal transplant patients of Han ethnicity with over five years of follow-up were enrolled in our study. A pool of single nucleotide polymorphisms (SNPs) (1284 SNPs) was extracted from the Ensembl database according to chromosomal regions of the candidate genes.
Background: Catechol-O-methyltransferase (COMT) contributes to the control of synaptic dopamine (DA) transmission by catalyzing DA degradation in the presynaptic space. The COMT Val158Met polymorphism (rs4680) substantially alters enzymatic activity and consequently synaptic DA concentration in the prefrontal cortex and hippocampus. The COMT genotype could, therefore, exert a major influence on antipsychotic treatment response as many of these agents also target dopaminergic transmission.
View Article and Find Full Text PDFThe A(H7N9) virus strain that emerged in 2013 was associated with a high fatality rate and may become a long-term threat to public health. A(H7N9) disease incidence is disproportionate to viral exposure, suggesting that host genetic factors may significantly influence susceptibility to A(H7N9) infection. Human genome variation in conferring risk for A(H7N9) infection in Chinese populations was identified by a two-stage investigation involving 121 A(H7N9) patients and 187 healthy controls using next generation sequencing followed by functional analysis.
View Article and Find Full Text PDFTo systematically study the susceptible genetic markers for liver injury induced by anti-tuberculosis drugs in the Chinese population, 109 genes related to drug metabolism, transport and immunity were captured by Haloplex capture technique from DNA samples of 41 patients with liver injury induced by anti-tuberculosis drugs and 39 healthy controls, and sequenced completely. Association study was conducted using Plink software. To verify the significant candidate SNPs, the study was expanded to the control group from the 1000-person Genome Project of the East Asian population.
View Article and Find Full Text PDFSchizophrenia (SCZ) is a highly heritable psychiatric disorder that affects approximately 1% of population around the world. However, early relevant studies did not reach clear conclusions of the genetic mechanisms of SCZ, suggesting that additional susceptibility loci that exert significant influence on SCZ are yet to be revealed. So, in order to identify novel susceptibility genes that account for the genetic risk of SCZ, we performed a systematic family-based study using whole exome sequencing (WES) in 65 Han Chinese families.
View Article and Find Full Text PDFDrug-induced liver injury (DILI) is a life-threatening, adverse reaction to certain drugs. The onset and extent of DILI can vary drastically in different patients using identical drugs. Association studies suggested that subtle differences in DNA methylation may help explain the individual differences in DILI.
View Article and Find Full Text PDFWhat Is Known And Objective: Myelosuppression, an adverse drug reaction (ADR), often causes medical treatment termination in cancer patients. It has been known that genetic components, such as single-nucleotide polymorphisms (SNPs), influence the risk of myelosuppression at the individual-patient level. However, due to ethnic variation in frequency of genetic polymorphisms, results reported in Caucasian patients may not be generalizable to the Chinese Han population.
View Article and Find Full Text PDFTuberculosis (TB) is one of the most prevalent infections. However, anti-TB drugs induce adverse liver injury in up to 40% of patients. Studies on candidate genes have suggested that single-nucleotide polymorphisms account for only a small contribution to the occurrence of anti-TB drug-induced liver injury (ATLI).
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