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Chen D.,Shanghai JiaoTong University | Fan J.,Shanghai JiaoTong University | Guo F.,Shanghai JiaoTong University | Qin S.,Shanghai JiaoTong University | And 3 more authors.
PLoS ONE | Year: 2013

Background:Tacrolimus is the first-line immunosuppressant after organ transplantation. It is mainly metabolized by cytochrome P450, family 3, subfamily A (CYP3A) enzymes, but there are large individual differences in metabolism. Interleukin 6 (IL6) has been shown to cause a pan-suppression of mRNA levels of ten major CYP enzymes in human hepatocyte cultures. IL6 has been shown to provide hepatoprotection in various models of liver injury. Rs1800796 is a locus in the IL6 gene promoter region which regulates cytokine production. We speculated that IL6 rs1800796 polymorphisms may lead to individual differences in tacrolimus metabolism by affecting CYP3A enzymes levels and liver function after liver transplantation.Methodology/Principal Findings:Ninety-six liver transplant patients receiving tacrolimus were enrolled in the study. Two single nucleotide polymorphisms (SNP), CYP3A5 rs776746 and IL6 rs1800796, were genotyped in both donors and recipients. The effects of SNPs on tacrolimus concentration/dose (C/D ratio) at four weeks after transplantation were studied, as well as the effects of donor IL6 rs1800796 polymorphisms on liver function. Both donor and recipient CYP3A5 rs776746 allele A showed association with lower C/D ratios, while donor IL6 rs1800796 allele G showed an association with higher C/D ratios. Donor CYP3A5 rs776746 allele A, IL6 rs1800796 allele C, and recipient CYP3A5 rs776746 allele A were associated with fast tacrolimus metabolism. With increasing numbers of these alleles, patients were found to have increasingly lower tacrolimus C/D ratios at time points after transplantation. Donor IL6 rs1800796 allele G carriers showed an association with higher glutamic-pyruvic transaminase (GPT) levels.Conclusions:Combined analysis of donor CYP3A5 rs776746, IL6 rs1800796, and recipient CYP3A5 rs776746 polymorphisms may distinguish tacrolimus metabolism better than CYP3A5 rs776746 alone. IL6 may lead to individual differences in tacrolimus metabolism mainly by affecting liver function. © 2013 Chen et al. Source


Huang X.,Shanghai JiaoTong University | Huang X.,Shanghai GenomePilot Institutes for Genomics and Human Health | Huang X.,CAS Shanghai Institutes for Biological Sciences | Wang Y.,Shanghai JiaoTong University | And 28 more authors.
Clinical Biochemistry | Year: 2012

Objectives: Colorectal cancer (CRC) is a common malignancy with worldwide prevalence. Familial adenomatous polyposis (FAP), a predisposition syndrome of CRC, is caused by germ line mutations in the APC gene. Mutations in APC are thought to be an early event in colorectal tumorigenesis. We hypothesized that common variants in APC might be associated with CRC. Design and methods: A case-control study genotyping ten SNPs was conducted in 312 CRC patients and 270 normal controls in the Chinese Han population. Results: The genotype frequency of rs2019720 showed a significant difference between cases and controls (p = 0.046, after Bonferroni correction). For the three pairs of SNPs in strong LD, we carried out haplotype analyses but no significant association was detected. Conclusion: Our results suggest that APC polymorphisms might be associated with CRC in the Chinese Han population. © 2012 The Canadian Society of Clinical Chemists. Source


Huang X.,Shanghai JiaoTong University | Huang X.,Shanghai GenomePilot Institutes for Genomics and Human Health | Chen L.,Shanghai JiaoTong University | Chen L.,Shanghai GenomePilot Institutes for Genomics and Human Health | And 11 more authors.
PLoS ONE | Year: 2012

CYP2E1 promoter polymorphisms can lead to significant interindividual differences in expression of CYP2E1. Using a database of CYP2E1 gene polymorphisms established in 2010, our study aimed to functionally characterize the single nucleotide polymorphisms (SNPs) of the promoter region and corresponding haplotypes in the Chinese Han population. Six novel SNPs and seven haplotypes with a frequency equal to or greater than 0.01 were constructed on a luciferase reporter system on the basis of site-directed mutagenesis. Dual luciferase reporter systems were used to analyze regulatory activity. The constructs including single novel SNP mutations exhibited insignificant change in luciferase activity, whereas, the activity produced by Haplo1(GTTGCTATAT), Haplo2 (CTTGCTATAT) and Haplo7 (GAGCTCACAT), containing a -333T>A polymorphism was significantly greater than for the wild type in Hep G2 cells (p<0.05), being 1.5-, 2.0- and 1.4- times greater respectively. These findings suggest the possibility of significant clinical prediction of adverse drug reaction and the facilitation of personalized medicine. © 2012 Huang et al. Source


Shi Y.,Shanghai JiaoTong University | Shi Y.,Shanghai GenomePilot Institutes for Genomics and Human Health | Shi Y.,Changning Mental Health Center | Li Z.,Shanghai JiaoTong University | And 51 more authors.
Nature Genetics | Year: 2011

Schizophrenia is a severe mental disorder affecting ∼1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10 -10) and 1q24.2 (rs10489202, P = 9.50 × 10 -9). Our findings provide new insights into the pathogenesis of schizophrenia. © 2011 Nature America, Inc. All rights reserved. Source


Shi Y.,Shanghai JiaoTong University | Shi Y.,Shanghai GenomePilot Institutes for Genomics and Human Health | Shi Y.,Changning Mental Health Center | Zhao H.,Shandong University | And 90 more authors.
Nature Genetics | Year: 2012

Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 × 10-8: 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS. © 2012 Nature America, Inc. All rights reserved. Source

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