Shanghai Genome Pilot Institutes for Genomics and Human Health

Shanghai, China

Shanghai Genome Pilot Institutes for Genomics and Human Health

Shanghai, China
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Chung W.-H.,Chang Gung Memorial Hospital | Chung W.-H.,Chang Gung University | Chang W.-C.,National Yang Ming University | Lee Y.-S.,Ming Chuan University | And 51 more authors.
JAMA - Journal of the American Medical Association | Year: 2014

IMPORTANCE: The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown. OBJECTIVE: To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia. MAIN OUTCOMES AND MEASURES: Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. RESULTS: The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95%CI, 6.6-20; P=1.1 × 10-17). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. Ameta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95%CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease. CONCLUSIONS AND RELEVANCE: This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions. Copyright 2014 American Medical Association. All rights reserved.

Shi Y.,Huazhong University of Science and Technology | Shi Y.,Shanghai Genome Pilot Institutes for Genomics and Human Health | Shi Y.,Changning Mental Health Center | Li L.,Guangxi Province Tumor Hospital | And 86 more authors.
Nature Genetics | Year: 2013

To identify new genetic risk factors for cervical cancer, we conducted a genome-wide association study in the Han Chinese population. The initial discovery set included 1,364 individuals with cervical cancer (cases) and 3,028 female controls, and we selected a 'stringently matched samples' subset (829 cases and 990 controls) from the discovery set on the basis of principal component analysis; the follow-up stages included two independent sample sets (1,824 cases and 3,808 controls for follow-up 1 and 2,343 cases and 3,388 controls for follow-up 2). We identified strong evidence of associations between cervical cancer and two new loci: 4q12 (rs13117307, Pcombined, stringently matched = 9.69 × 10-9, per-allele odds ratio (OR)stringently matched = 1.26) and 17q12 (rs8067378, Pcombined, stringently matched = 2.00 × 10-8, per-allele ORstringently matched = 1.18). We additionally replicated an association between HLA-DPB1 and HLA-DPB2 (HLA-DPB1/2) at 6p21.32 and cervical cancer (rs4282438, Pcombined, stringently matched = 4.52 × 10-27, per-allele ORstringently matched = 0.75). Our findings provide new insights into the genetic etiology of cervical cancer. © 2013 Nature America, Inc. All rights reserved.

Du H.,Shanghai JiaoTong University | Du H.,Shanghai Genome Pilot Institutes for Genomics and Human Health | Wei Z.,Shanghai JiaoTong University | Wei Z.,Shanghai Genome Pilot Institutes for Genomics and Human Health | And 18 more authors.
Frontiers in Pharmacology | Year: 2016

Variability in activity of CYP2C9, which is involved in the metabolism of approximately 15% of current therapeutic drugs, is an important contributor to interindividual differences in drug response. To evaluate the functional alternations of CYP2C9*2, CYP2C9*3, CYP2C9*8, CYP2C9*11 and CYP2C9*31, identified in our previous study in Chinese Han population, allelic variants as well as the wild-type CYP2C9 were transiently expressed in COS-7 cells. Kinetic parameters (Km, Vmax, and Clint) for S-warfarin 7-hydroxylation by these recombinant CYP2C9s were determined. Relative to CYP2C9.1, recombinant CYP2C9.3 and CYP2C9.11 exhibited significantly higher Km values, and all allelic variants showed significantly decreased Vmax and Clint values. Among all allelic variants, catalytic activity of CYP2C9.3 and CYP2C9.11 reduced the most (8.2% and 9.8% of Clint ratio, respectively; P < 0.001). These findings should be useful for predicting the phenotype profiles of CYP2C9 in Chinese Han population, comparing the functional results of these alleles accurately, and finally optimizing pharmacotherapy of drug treatment. © 2016 Du, Wei, Yan, Xiong, Zhang, Shen, Ruan, Wu, Xu, He and Qin.

Wu H.,Shanghai JiaoTong University | Wang Y.,Shanghai JiaoTong University | Cao X.,Shanghai JiaoTong University | Wu Y.,Shanghai JiaoTong University | And 12 more authors.
ACS Synthetic Biology | Year: 2014

The ability to regulate endogenous gene expression is critical in biological research. Existing technologies, such as RNA interference, zinc-finger regulators, transcription-activator-like effectors, and CRISPR-mediated regulation, though proved to be competent in significantly altering expression levels, do not provide a quantitative adjustment of regulation effect. As a solution to this problem, we place CRISPR-mediated interference under the control of blue light: while dCas9 protein is constitutively expressed, guide RNA transcription is regulated by YF1-FixJ-PFixK2, a blue light responding system. With a computer-controlled luminous device, the quantitative relationship between target gene expression and light intensity has been determined. As the light intensifies, the expression level of target gene gradually ascends. This remarkable property enables sensor-CRISPRi to accurately interrogate cellular activities. © 2014 American Chemical Society.

Xu Q.,Shanghai JiaoTong University | Xu Q.,Shanghai Genome Pilot Institutes for Genomics and Human Health | Wu X.,Shanghai JiaoTong University | Wu X.,Shanghai Genome Pilot Institutes for Genomics and Human Health | And 8 more authors.
Frontiers of Medicine | Year: 2013

Schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population, and heritability of up to 80%. Drug therapy is an important approach to treating the disease. However, the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects. Many studies have indicated that about 30% of the patients exhibit little or no improvements associated with antipsychotics. The response of individual patients who are given the same dose of the same drug varies considerably. In addition, antipsychotic drugs are often accompanied by adverse drug reactions (ADRs), which can cause considerable financial loss in addition to the obvious societal harm. So, it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity. There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians. Individual differences in drug response is due to a combination of many complex factors including ADEM (absorption, distribution, metabolism, excretion) process, transporting, binding with receptor and intracellular signal transduction. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response. In addition, epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients. In this review, we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes (CYP2D6, CYP1A2, CYP3A4, etc.), drug transporters (mainly ABCB1) and neurotransmitter receptors (dopamine receptors and serotonin receptors, etc.). We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications. © 2013, Higher Education Press and Springer-Verlag Berlin Heidelberg.

Li M.,CAS Kunming Institute of Zoology | Li M.,University of Chinese Academy of Sciences | Shi C.-J.,Peking Union Medical College | Shi Y.-Y.,Shanghai JiaoTong University | And 16 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2012

ZNF804A, a recently identified risk gene for schizophrenia, has been extensively investigated and the principle finding for this locus has been the association with SNP rs1344706 in populations of European ancestries. However, in Asian populations, only a few studies have been conducted for rs1344706 and the results were inconsistent. Here, we studied rs1344706 and schizophrenia susceptibility in multiple Asian case-control samples (10 Chinese and 2 Japanese samples; N=21,062), and the meta-analyses indicated non-significant association of rs1344706 with schizophrenia (P=0.26), suggesting the same SNP identified in European samples is not predisposing risk in Asians. Further genotyping and association analyses of a set of SNPs spanning the entire genomic region of ZNF804A (520kb) identified no association except for SNP rs359895 (P=7.8×10-5, N=5,172), a newly reported risk SNP located in the ZNF804A promoter region with functional implications. This suggests that ZNF804A may also contribute to schizophrenia susceptibility in Asians although the risk SNP is different from that in Europeans, and it was supported by the detected up-regulation of ZNF804A mRNA expression in the blood cells of Chinese schizophrenia patients compared with normal controls (P=0.004). Additionally, the linkage disequilibrium (LD) structure analyses using data from HapMap indicated distinct LD blocks across ZNF804A between Chinese and Europeans, which may explain the different association patterns between them, and also highlight the compounding difficulty of genetic studies of complex diseases like schizophrenia when studying multiple ethnic populations. © 2012 Wiley Periodicals, Inc.

Shi Y.,Shanghai JiaoTong University | Shi Y.,Shanghai Genome Pilot Institutes for Genomics and Human Health | Liu Y.,Shanghai JiaoTong University | Liu Y.,Shanghai Genome Pilot Institutes for Genomics and Human Health | And 16 more authors.
Pharmacogenomics | Year: 2015

Aim: The huge interindividual difference of CYP3A4 expression may contribute to the variability of drug response. Post-transcriptional regulation of CYP3A4 remains elusive although transcriptional regulation has been studied much more clearly. microRNAs (miRNAs) were reported to be one of factors to regulate the expression of CYP3A4 previously. Materials & methods: Based on the in silico prediction of 3′-UTR-bindind site of microRNA-27a (miR-27a), the transcriptional and post-transcriptional regulation of miR-27a were investigated through luciferase reporter assay, real-time PCR and immunoblot. Results: The significantly decrease of CYP3A4 3′-UTR-luciferase activity in human embryonic kidney 293 and Hep3B cells was detected after transfected with plasmid that expressed miRNA-27a in luciferase reporter assay. Correlation study was conducted in human livers (n = 26) and significant correlation has been discovered between miRNA-27a and CYP3A4 mRNA and protein level. Conclusion: Together, these findings suggest that miR-27a might be involved in the regulation of CYP3A4 gene expression. © 2015 Future Medicine Ltd.

Gong X.,Shanghai JiaoTong University | Gong X.,Shanghai Genome Pilot Institutes for Genomics and Human Health | Liu Y.,Shanghai JiaoTong University | Liu Y.,Shanghai Genome Pilot Institutes for Genomics and Human Health | And 12 more authors.
PLoS ONE | Year: 2013

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. © 2013 Gong et al.

Jiang J.,Shanghai JiaoTong University | Jiang J.,Shanghai Genome Pilot Institutes for Genomics and Human Health | Zhang X.,Tongji University | Huo R.,Shanghai JiaoTong University | And 20 more authors.
Pharmacogenomics Journal | Year: 2015

Drug-induced liver injury (Dili) is caused by unpredictable adverse drug reaction due mainly to the accumulation of hepatotoxic compounds in the liver resulting in significant damage. Drug-metabolizing enzymes have been prime targets for molecular studies relevant to Dili. The gene UGT1A9 mainly expresses in the liver and has an important role in drug metabolism. The Han Chinese has a very long and complex demographic history, and the population stratification arising from the interplay of different geographic areas may influence the polymorphism pattern. We selected 260 healthy subjects in three different geographic areas (including Xian, Shanghai and Liuzhou) for systemic screening and analysis of single-nucleotide polymorphisms (SNPs) in the promoter region of UGT1A9. Eight SNPs were identified and no regional disparity exists among the three populations. Based on these results, 213 Dili patients from all over the Chinese mainland were further recruited to investigate possible association between UGT1A9 and Dili. We observed statistically significant associations between SNP rs2741045 and Dili at both allele and genotype levels (allele: P=0.032; genotype: P=0.029; after Bonferroni correction). Also, multivariate interaction analysis discovered the interaction between rs2741045 and age associated with Dili significantly. This is the first such screening study to investigate the association between UGT1A9 promoter polymorphisms and Dili in the Chinese population and it could provide the basis for further study of Dili mechanisms. © 2015 Macmillan Publishers Limited.

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