Dataset Information

Systematic functional study of cytochrome P450 2D6 promoter polymorphisms in the Chinese Han population.

ABSTRACT: The promoter polymorphisms of drug-metabolizing genes can lead to interindividual differences in gene expression, which may result in adverse drug effects and therapeutic failure. Based on the database of CYP2D6 gene polymorphisms in the Chinese Han population established by our group, we functionally characterized the single nucleotide polymorphisms (SNPs) of the promoter region and corresponding haplotypes in this population. Using site-directed mutagenesis, all the five SNPs identified and ten haplotypes with a frequency equal to or greater than 0.01 in the population were constructed on a luciferase reporter system. Dual luciferase reporter systems were used to analyze regulatory activity. The activity produced by Haplo3(-2183G>A, -1775A>G, -1589G>C, -1431C>T, -1000G>A, -678A>G), Haplo8(-2065G>A, -2058T>G, -1775A>G, -1589G>C, -1235G>A, -678A>G) and MU3(-498C>A) was 0.7-, 0.7-, 1.2- times respectively compared with the wild type in human hepatoma cell lines(p<0.05). These findings might be useful for optimizing pharmacotherapy and the design of personalized medicine.

SUBMITTER: Gong X

PROVIDER: S-EPMC3585152 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Systematic functional study of cytochrome P450 2D6 promoter polymorphisms in the Chinese Han population.

Gong Xueli X Liu Yichen Y Zhang Xiaoqing X Wei Zhiyun Z Huo Ran R Shen Lu L He Lin L Qin Shengying S

PloS one 20130228 2

The promoter polymorphisms of drug-metabolizing genes can lead to interindividual differences in gene expression, which may result in adverse drug effects and therapeutic failure. Based on the database of CYP2D6 gene polymorphisms in the Chinese Han population established by our group, we functionally characterized the single nucleotide polymorphisms (SNPs) of the promoter region and corresponding haplotypes in this population. Using site-directed mutagenesis, all the five SNPs identified and te ...[more]

PMID: 23469064

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Project description:Background:Severe mental health disorders in children and adolescents represent a major public health problem. Despite adequate drug treatment, some patients develop pharmacoresistant disease. As a consequence, physicians are confronted with prescribing challenges, prolonged hospitalization and increased risk of adverse events, thus aggravating short-, medium-, and long-term prognosis. The majority of psychotropic treatments, particularly antipsychotics and antidepressants, are metabolized at hepatic level by cytochrome P450 (CYP), particularly by CYP3A4 and CYP2D6. Several CYP2D6 genetic polymorphisms are described to be associated with ultrarapid (UM) or poor drug metabolism (PM), inducing clinical resistance and/or adverse events, and might therefore be related to pharmacoresistant severe mental health disease. Case presentation:A total of nine pharmacoresistant patients (four females, five males) aged 11-16 (mean 14.1) years have been genotyped for CYP2D6 between January, 2015 and April, 2016. Patients were diagnosed with schizophrenia (n?=?5), autism spectrum disorders (n?=?2), intellectual disability with challenging behavior (n?=?2), oppositional defiant disorder (n?=?1), and post-traumatic stress and borderline personality disorders (n?=?1). They had a treatment history with on average 6.1 (3-9) psychotropic, 5 (3-7) antipsychotic, and 3.4 (2-5) CYP2D6-metabolized antipsychotic and antidepressant molecules. Five patients (56%) presented functional anomalies of the CYP2D6 gene: three patients were UM metabolizers with gene duplication and two patients were PM with *4/*41 and *3/*4 polymorphisms. Conclusion:Functional anomalies of CYP2D6 concerned more than half of our pediatric inpatient sample with pharmacoresistant disease. However, our case reports are limited by the low sample size. Nevertheless, knowledge of individual metabolism and in particular CYP2D6 genotyping should be considered for clinical workup and therapy adjustment in resistant patients in child and adolescent psychiatry and might permit better treatment outcome, increased treatment adherence and diminished adverse events.

Project description:BackgroundTuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, is a major public health concern. Chemokines and their receptors, such as RANTES, CXCR3, and CCR5, have been reported to play important roles in cell activation and migration in immune responses against TB infection.MethodsTo understand the correlations involving CCR5 gene variations, M. tuberculosis infection, and TB disease progression, a case-control study comprising 450 patients with TB and 306 healthy controls from a Chinese Han population was conducted, along with the detection of polymorphisms in the CCR5 promoter using a sequencing method.ResultsAfter adjustment for age and gender, the results of logistic analysis indicated that the frequency of rs2734648-G was significantly higher in the TB patient group (P = 0.002, OR = 1.38, 95% CI: 1.123-1.696); meanwhile, rs2734648-GG showed notable susceptibility to TB (P = 6.32E-06, OR = 2.173, 95% CI: 1.546-3.056 in a recessive model). The genotypic frequency of rs1799987 also varied between the TB and control groups (P = 0.008). In stratified analysis, rs2734648-GG significantly increased susceptibility to pulmonary TB in a recessive model (P < 0.0001, OR = 2.382, 95% CI: 1.663-3.413), and the rs2734648-G allele significantly increased susceptibility to TB recurrence in a dominant model (P = 0.0032, OR = 1.936, 95% CI: 1.221-3.068), whereas rs1799987-AA was associated with susceptibility to pulmonary TB (P = 0.0078, OR = 1.678, 95% CI: 1.141-2.495 in a recessive model) but not with extra-pulmonary TB and TB recurrence. A haplotype constructed with the major alleles of the eight SNPs in the CCR5 promoter (rs2227010-rs2856758-rs2734648-rs1799987-rs1799988-rs41469351-rs1800023-rs1800024: A-A-G-G-T-C-G-C) exhibited extraordinarily increased risk of susceptibility to TB and pulmonary TB (P = 6.33E-11, OR = 24.887, 95% CI: 6.081-101.841).ConclusionIn conclusion, CCR5 promoter polymorphisms were found to be associated with pulmonary TB and TB progression in Chinese Han people.

Dataset Information

Systematic functional study of cytochrome P450 2D6 promoter polymorphisms in the Chinese Han population.

Publications

Systematic functional study of cytochrome P450 2D6 promoter polymorphisms in the Chinese Han population.

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