Publications by authors named "Jiao Lou"

48 Publications

Risk SNP-Mediated Enhancer-Promoter Interaction Drives Colorectal Cancer through Both and .

Cancer Res 2020 05 3;80(9):1804-1818. Epub 2020 Mar 3.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17-1.36; = 2.57 × 10). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer-promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth and by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology. SIGNIFICANCE: This study provides an oncogenic regulatory circuit among several oncogenes including , and underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer-promoter interaction loops. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1804/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2389DOI Listing
May 2020

Systematic Functional Interrogation of Genes in GWAS Loci Identified ATF1 as a Key Driver in Colorectal Cancer Modulated by a Promoter-Enhancer Interaction.

Am J Hum Genet 2019 07 13;105(1):29-47. Epub 2019 Jun 13.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China. Electronic address:

Genome-wide association studies (GWASs) have identified approximately 100 colorectal cancer (CRC) risk loci. However, the causal genes in these loci have not been systematically interrogated. We conducted a high-throughput RNA-interference functional screen to identify the genes essential for proliferation in the CRC risk loci of Asian populations. We found that ATF1, located in the 12q13.12 region, functions as an oncogene that facilitates cell proliferation; ATF1 has the most significant effect of the identified genes and promotes CRC xenograft growth by affecting cell apoptosis. Next, by integrating a fine-mapping analysis, a two-stage affected-control study consisting of 6,213 affected individuals and 10,388 controls, and multipronged experiments, we elucidated that two risk variants, dbSNP: rs61926301 and dbSNP: rs7959129, that located in the ATF1 promoter and first intron, respectively, facilitate a promoter-enhancer interaction, mediated by the synergy of SP1 and GATA3, to upregulate ATF1 expression, thus synergistically predisposing to CRC risk (OR = 1.77, 95% CI = 1.42-2.21, p = 3.16 × 10; P = 1.20 × 10; P = 6.50 × 10). Finally, we performed RNA-seq and ChIP-seq assays in CRC cells treated with ATF1 overexpression in order to dissect the target programs of ATF1. Results showed that ATF1 activates a subset of genes, including BRAF, NRAS, MYC, BIRC2, DAAM1, MAML2, STAT1, ID1, and NKD2, related to apoptosis, Wnt, TGF-β, and MAPK pathways, and these effects could cooperatively increase the risk of CRC. These findings reveal the clinical potential of ATF1 in CRC development and illuminate a promoter-enhancer interaction module between the ATF1 regulatory elements dbSNP: rs61926301 and dbSNP: rs7959129, and they bring us closer to understanding the molecular drivers of cancer.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612518PMC
July 2019

A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk.

Mol Carcinog 2019 05 17;58(5):760-766. Epub 2019 Jan 17.

Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

9p21.3 has been identified as an unexpected hot point in multiple diseases GWAS including cancers, and we performed a two-stage case-control studies integrating functional assay strategy to find the potential functional variants modified susceptibility to pancreatic cancer (PC). An expanded Illumina HumanExome Beadchip of PC including 943 cases and 3908 controls was used to examine 39 tagSNPs in 9p21.3 and the promising single nucleotide polymorphism (SNP) was validated in stage 2 comprising 624 cases and 1048 controls. The strongest signal was rs6475609 (Odds ratio, OR = 0.81, 95% confidence interval, CI = 0.72-0.91) maps to the long non-coding RNA ANRIL. Bioinformatics analysis revealed rs1537373 lies in the linkage disequilibrium (LD) block which the rs6475609 tagged might have potential function and was also associated with a decreased risk of PC in both stages (OR = 0.82, 95% CI = 0.75-0.90 in combined analysis). Dual luciferase reporter assay and the electrophoretic mobility shift assay (EMSA) verified rs1537373 as the best candidate causative variant for influencing the activity of enhancer through differential binding to certain transcription factor. The expression quantitative trait loci (e-QTL) analysis indicated the genotypes of rs1537373 were associated with expression of CDKN2B gene (P dominant = 6.00 × 10 ). In conclusion, our study provided evidence that rs1537373 in ANRIL may influence transcription factor binding and regulate CDKN2B expression, thus confer the susceptibility to PC.
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http://dx.doi.org/10.1002/mc.22968DOI Listing
May 2019

Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations.

Nat Commun 2018 09 11;9(1):3688. Epub 2018 Sep 11.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, 430030, Wuhan, China.

Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48-2.12, P = 5.35 × 10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50-2.27, P = 4.34 × 10), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72-3.16, P = 4.21 × 10). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and thus enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease.
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http://dx.doi.org/10.1038/s41467-018-06136-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134090PMC
September 2018

Integrative functional genomics identifies regulatory genetic variant modulating RAB31 expression and altering susceptibility to breast cancer.

Mol Carcinog 2018 12 19;57(12):1845-1854. Epub 2018 Sep 19.

Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Despite the successes of genome-wide association study (GWAS) in identifying breast cancer (BC) risk-associated variants, only a small fraction of the heritability can be explained. The greatest challenge in the post-GWAS is to identify causal variants and underlying mechanisms responsible for BC susceptibility. In this study, we integrated functional genomic data from ENCODE ChIP-seq, ANNOVAR, and the TRANSFAC matrix to identify potentially regulatory variants with modulating FOXA1-binding affinity across the whole genome, and then conducted a two-stage case-control study including 2164 cases and 2382 controls to investigate the associations between candidate SNPs and BC susceptibility. We identified a BC susceptibility SNP, rs6506689 G>T, with an odds ratio (OR) of 1.23 (95% confidence interval = 1.07-1.40, P = 0.003) under a dominant model in the combined study. Biological assays indicated that the germline G>T variation at rs6506689 creates a FOXA1-binding site and up-regulates the expression of RAB31, thus playing an important role in the development of BC. Our results highlight the importance of regulatory genetic variants in the development of BC by influencing TF-DNA interaction and provide critical insights to pinpoint causal genetic variants.
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http://dx.doi.org/10.1002/mc.22902DOI Listing
December 2018

A Rare Missense Variant in TCF7L2 Associates with Colorectal Cancer Risk by Interacting with a GWAS-Identified Regulatory Variant in the MYC Enhancer.

Cancer Res 2018 09 19;78(17):5164-5172. Epub 2018 Jul 19.

Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

Genome-wide association studies (GWAS) of colorectal cancer have identified several common susceptible variants in gene regulatory regions. However, low-frequency or rare coding risk variants have not been systematically investigated in patients with colorectal cancer from Chinese populations. In this study, we performed an exome-wide association analysis with 1,062 patients with colorectal cancer and 2,184 controls from a Chinese population. Promising associations were further replicated in two replication sets: replication stage I with 2,478 cases and 3,880 controls, and replication stage II with 3,761 cases and 4,058 controls. We identified two variants significantly associated with colorectal cancer risk: a novel rare missense variant in [rs138649767, OR = 2.08, 95% confidence interval (CI): 1.69-2.57, = 5.66 × 10] and a previous European GWAS-identified 3'-UTR variant in (rs11169571, OR = 1.18, 95% CI: 1.13-1.24, = 1.65 × 10). We found a significant interaction between the missense variant rs138649767 and a previous GWAS-identified regulatory variant rs6983267 in the enhancer ( = 0.0002). Functional analysis of this variant revealed that TCF7L2 with rs138649767-A allele harbored the ability to activate the enhancer with rs6983267-G allele and enhance colorectal cancer cell proliferation. In addition, the rs11169571 variant significantly correlated with expression by affecting hsa-miR-1283 and hsa-miR-520d-5p binding. Further ChIP-seq and gene coexpression analyses showed that oncogenes and were activated by ATF1 in colorectal cancer. These results widen our understanding of the molecular basis of colorectal cancer risk and provide insight into pathways that might be targeted to prevent colorectal cancer. Exome-wide association analysis identifies a rare missense variant in and a common regulatory variant in as susceptibility factors of colorectal cancer. http://cancerres.aacrjournals.org/content/canres/78/17/5164/F1.large.jpg .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0910DOI Listing
September 2018

Educational and Behavioral Counseling in a Methadone Maintenance Treatment Program in China: A Randomized Controlled Trial.

Front Psychiatry 2018 4;9:113. Epub 2018 Apr 4.

Department of Epidemiology and Biostatistics, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Introduction: Methadone maintenance treatment (MMT) programs have been rapidly scaled up nationwide in China in recent years, and psychosocial intervention measures, including counseling, were recommended for improving the outcomes of MMT. However, the effectiveness of counseling in MMT programs remains controversial. This study investigated the efficacy of educational and behavioral counseling (EBC) mode in an MMT program in China.

Methods: A total of 125 eligible participants were randomized to EBC or a control group. Patients in the EBC group received weekly, manual-guided, group educational counseling for 8 weeks and individual behavioral counseling for the next 8 weeks. Patients in the control group received standard methadone maintenance treatment as usual (TAU).

Results: During the 16-week trial, the EBC group showed better treatment attendance ( = 0.022) and a greater increase in knowledge regarding heroin addiction ( = 0.001) and MMT ( = 0.005) than did the TAU group. Between the two groups, there were no significant differences regarding drug abstinence and reduction of risky behaviors.

Conclusion: EBC affiliated with MMT improved patients' cognition and adherence to treatment, facilitating their successful recovery.

Clinical Trial Registration: ChiCTR-IOR-15006673: http://www.chictr.org.cn.
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http://dx.doi.org/10.3389/fpsyt.2018.00113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893781PMC
April 2018

Integrative expression quantitative trait locus-based analysis of colorectal cancer identified a functional polymorphism regulating SLC22A5 expression.

Eur J Cancer 2018 04 9;93:1-9. Epub 2018 Feb 9.

State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Multiple single nucleotide polymorphisms (SNPs) have been found to be highly correlated with colorectal cancer (CRC) risk. However, the variants identified thus far only explain a small part of the cases, suggesting the existence of many uncharacterised genetic determinants. In this study, using the multilevel 'omics' data provided in The Cancer Genome Atlas, we systematically performed expression quantitative trait locus (eQTL) analysis for CRC and identified nine SNPs with significant effects on mRNA expression (correlation |r| > 0.3 and FDR < 0.01). Then we conducted a two-stage case-control study consisting of 1528 cases and 1528 controls to examine the associations between candidate SNPs and CRC risk. We found that rs27437 in SLC22A5 was significantly correlated with CRC risk in both stages and the combined study (additive model, OR = 1.31, 95%CI = 1.17-1.47, P = 1.97 × 10). eQTL analysis showed that rs27437 GG and GA genotypes were associated with lower expression of SLC22A5 compared with the AA genotype. Dual-luciferase reporter assays confirmed that the G risk allele could decrease the expression of luciferase. SLC22A5 was significantly decreased in CRC tumour tissues compared with adjacent normal tissues, indicating that SLC22A5 may play important roles in CRC, and rs27437 in SLC22A5 might serve as a novel biomarker for early detection and prevention of CRC.
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http://dx.doi.org/10.1016/j.ejca.2018.01.065DOI Listing
April 2018

Exome-wide analyses identify low-frequency variant in CYP26B1 and additional coding variants associated with esophageal squamous cell carcinoma.

Nat Genet 2018 03 29;50(3):338-343. Epub 2018 Jan 29.

Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Genome-wide association studies have identified common variants associated with risk of esophageal squamous cell carcinoma (ESCC). However, these common variants cannot explain all heritability of ESCC. Here we report an exome-wide interrogation of 3,714 individuals with ESCC and 3,880 controls for low-frequency susceptibility loci, with two independent replication samples comprising 7,002 cases and 8,757 controls. We found six new susceptibility loci in CCHCR1, TCN2, TNXB, LTA, CYP26B1 and FASN (P = 7.77 × 10 to P = 1.49 × 10), and three low-frequency variants had relatively high effect size (odds ratio > 1.5). Individuals with the rs138478634-GA genotype had significantly lower levels of serum all-trans retinoic acid, an anticancer nutrient, than those with the rs138478634-GG genotype (P = 0.0004), most likely due to an enhanced capacity of variant CYP26B1 to catabolize this agent. These findings emphasize the important role of rare coding variants in the development of ESCC.
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http://dx.doi.org/10.1038/s41588-018-0045-8DOI Listing
March 2018

A low-frequency variant in SMAD7 modulates TGF-β signaling and confers risk for colorectal cancer in Chinese population.

Mol Carcinog 2017 07 6;56(7):1798-1807. Epub 2017 Mar 6.

Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The TGF-β pathway plays an essential role in regulating cell proliferation and differentiation. GWASs and candidate approaches have identified a battery of genetic variants in the TGF-β pathway contributing to colorectal cancer (CRC). However, most of the significant variants are common variants and their functions remain ambiguous. To identify causal variants with low-frequency in the TGF-β pathway contributing to CRC susceptibility in Chinese population, we performed targeted sequencing of 12 key genes in TGF-β signaling in CRC patients followed by a two-stage case-control study with a total of 5109 cases and 5169 controls. Bioinformatic annotations and biochemical experiments were applied to reveal the potential functions of significant variants. Seven low-frequency genetic variants were captured through targeted sequencing. The two stage association studies showed that missense variant rs3764482 (c. 83C>T; p. S28F) in the gene SMAD7 was consistently and significantly associated with CRC risk. Compared with the wild type, the ORs for variant allele were 1.37 (95%CI: 1.10-1.70, P = 0.005), 1.55 (95%CI: 1.30-1.86, P = 1.15 × 10 ), and 1.48 (1.29-1.70, P = 2.44 × 10 ) in stage 1, stage 2, and the combined analyses, respectively. Functional annotations revealed that the minor allele T of rs3764482 was more effective than the major allele C in blocking the TGF-β signaling and inhibiting the phosphorylation of receptor-regulated SMADs (R-SMADs). In conclusion, low-frequency coding variant rs3764482 in SMAD7 is associated with CRC risk in Chinese population. The rs3764482 variant may block the TGF-β signaling via impeding the activation of downstream genes, leading to cancer cell proliferation, thus contributing to CRC pathogenesis.
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http://dx.doi.org/10.1002/mc.22637DOI Listing
July 2017

A functional polymorphism located at transcription factor binding sites, rs6695837 near LAMC1 gene, confers risk of colorectal cancer in Chinese populations.

Carcinogenesis 2017 02;38(2):177-183

Department of Epidemiology and Biostatistics and Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.

Genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) susceptibility. However, the elucidation of causal SNPs and the biological mechanisms behind are still limited. In this study, we initially performed systematic bioinformatics analyses on CRC GWAS-identified loci to seek for potential functional SNPs located at transcription factor binding sites (TFBSs), and then a two-stage case-control study comprised of 1353 cases and 1448 controls of Chinese populations and functional analyses were conducted. As a result, only one SNP rs6695837 out of the nine candidate SNPs survived after two-stage analyses by Bonferroni correction. In combined analyses, rs6695837 exhibited significant associations with CRC risk (TT: CC, odds ratio (OR) = 1.31, 95% confidence interval (CI) = 1.06-1.63; dominant model, OR = 1.21, 95% CI = 1.03-1.43; additive model, OR = 1.15, 95% CI = 1.03-1.28). Functional annotations by RegulomeDB and rSNPBase indicated its biological role and dual-luciferase reporter assays revealed a significant increase in luciferase expression for the reconstructed plasmid with rs6695837T allele, compared with the one with C allele (PSW480 = 0.0002, PLovo = 0.0003). Further gene expression analyses demonstrated significantly higher expression of LAMC1 gene in CRC tumor tissues than that in adjacent non-cancerous tissues (P = 0.0004). These findings strongly suggest that the functional SNP located at TFBSs, rs6695837 might contribute to CRC susceptibility, and the exact biological mechanism awaits further research.
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http://dx.doi.org/10.1093/carcin/bgw204DOI Listing
February 2017

A functional variant rs4442975 modulating FOXA1-binding affinity does not influence the risk or progression of breast cancer in Chinese Han population.

Oncotarget 2016 Dec;7(49):81691-81697

Department of Epidemiology and Biostatistics and State Key Laboratory of Environment Health (Incubation), Ministry of Education Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.

The DNA-binding protein FOXA1 has been shown to regulate nearly all estrogen receptor-chromatin interactions, thereby influencing target gene expression levels in breast cancer (BC) cells. Recently, the rs4442975 T-allele, which disrupts the recruitment of FOXA1 and interacts with the IGFBP5 promoter, was associated to BC susceptibility in a European population. We conducted a hospital-based case-control study that included 1227 cases and 1285 controls to explore the potential association between rs4442975 and BC risk in Chinese Han population, and the effect of this SNP on BC progression was also observed in cases. No significant associations between rs4442975 and BC risk were observed under any genetic models, with an odds ratio of 0.96 (95% confidence interval = 0.81-1.15) under the additive model. When stratified based on estrogen or progesterone receptor expression, smoking or drinking habits, or menopausal status, similar negative associations were observed for all subgroups. No significant associations were observed between rs4442975 and traditional progression factors such as tumor size, nodal status, distant metastasis, or TNM staging. These results reveal that rs4442975 may not confer a risk of BC occurrence or progression in the Chinese Han population, which indicates a distinct association related to genetic heterogeneity across ethnic populations.
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http://dx.doi.org/10.18632/oncotarget.13168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348423PMC
December 2016

A single nucleotide polymorphism in the 3'-UTR of STAT3 regulates its expression and reduces risk of pancreatic cancer in a Chinese population.

Oncotarget 2016 Sep;7(38):62305-62311

State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment and Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), and Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Pancreatic cancer (PC) is one of the deadliest solid malignancies carrying a gloomy 5-year survival rate less than 5%. The signal transducer and activator of transcription 3 (STAT3) is a common transcriptional regulator, whose aberrant expression has been widely found in human cancers, including PC. Our current study aimed to illustrate the roles of common variants, in the three prime untranslated region (3'UTR) of STAT3, in modifying the risk of PC through two-stage case-control studies integrating biological experiments. We first explored the associations between two common variants (rs1053004 and rs1053005) and PC risk in 774 PC cases and 777 controls. Only rs1053004 T > C showed a significant association with a reduced risk of PC with an odds ratio (OR) and 95% confidence interval (CI) of 0.85 (0.74-0.98). Then we attempted to validate the association in another 940 cases and 1398 controls, and the significant association persisted with OR (95%CI) of 0.86 (0.76-0.97). Dual luciferase reporter gene assays indicated that C allele conferred a higher expression of STAT3 in three PC cell lines including Panc-1 (P = 3.0 × 10-3), BxPC-3 (P = 6.7 × 10-5) and SW1990 (P = 4.0 × 10-3). In conclusion, the current study provided evidence that rs1053004 T > C in 3'UTR of STAT3 may decrease the risk of PC through up-regulating the gene expression.
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http://dx.doi.org/10.18632/oncotarget.11607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308728PMC
September 2016

Genetic variants in the regulatory region of SLC10A1 are not associated with the risk of hepatitis B virus infection and clearance.

Infect Genet Evol 2016 10 2;44:495-500. Epub 2016 Aug 2.

Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address:

The Na/taurocholate cotransporter NTCP (encoded by SLC10A1) was identified as a cellular entry receptor for the human hepatitis B virus (HBV), advancing our understanding of the molecular mechanism of HBV infection. An alternative hypothesis was put forward that regulatory variants in SLC10A1 might play an important role in HBV susceptibility by potentially influencing expression levels of NTCP. The three regulatory SNPs (rs8011311, rs7154439, rs111409076) were genotyped in 1023 HBV-persistent carriers, 735 subjects with HBV natural clearance and 732 HBV marker-negative subjects in a Han Chinese population. Real-time reverse transcription PCR analysis and luciferase assays have been performed to dissect the potential functionality. In logistic regression analysis, when subjects with HBV natural clearance were compared with HBV marker-negative subjects, no significant associations with the risk of HBV infection were observed for any of the three SNPs after adjusting for age, sex, smoking status and alcohol consumption (P>0.05). Similar negative results were also found for the three SNPs when HBV-persistent carriers were compared with HBV marker-negative subjects. Likewise, no significant associations with the risk of HBV clearance were observed when HBV-persistent carriers were compared with subjects with HBV natural clearance (P>0.05). Quantitative RT/PCR showed no significant difference in NTCP expression levels in normal liver tissue amongst individuals with different rs111409076 genotypes (P=0.317 for the general linear model). Moreover, no evident effect of the SLC10A1 rs111409076 AACA/- polymorphism on transcriptional activity was found by luciferase assay in either HepG2 (P=0.161) or Hep3b (P=0.129) cell lines. The present study indicated that the common variants in the regulatory region of SLC10A1 may not influence the expression of NTCP at the level of transcriptional regulation, and ultimately may not be associated with HBV susceptibility in this Chinese population.
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http://dx.doi.org/10.1016/j.meegid.2016.07.043DOI Listing
October 2016

Association between bilirubin and risk of Non-Alcoholic Fatty Liver Disease based on a prospective cohort study.

Sci Rep 2016 08 3;6:31006. Epub 2016 Aug 3.

Department of Epidemiology and Biostatistics and the Ministry of Education (MOE) Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, Hubei, China.

The study aimed to assess the association between total, direct, and indirect bilirubin and nonalcoholic fatty live disease (NAFLD) risk given its high prevalence and serious clinical prognosis. Among 27,009 subjects who participated in a healthy screening program from the Dongfeng-Tongji cohort study in 2008, 8189 eligible subjects (aged 35-86 years; males, 43.95%) were ultimately enrolled. The incidence rates of NAFLD in 2013 were compared with respect to baseline bilirubin levels among subjects free of NAFLD, and the effect sizes were estimated by logistic regression analysis. During 5 years follow-up, we observed 1956 cases of newly developed NAFLD with the overall incidence of 23.88%. Direct bilirubin was presented to inversely associate with NAFLD risk. Compared with quartile 1 of direct bilirubin, the multivariable-adjusted ORs (95% CIs) for NAFLD of quartile 2 to 4 were 1.104 (0.867-1.187), 0.843 (0.719-0.989), and 0.768 (0.652-0.905), respectively, P for trend 0.002). Similarly, inverse effects of direct bilirubin on NAFLD incidence were also observed when stratified by sex and BMI. However, no significant associations were found between total, and indirect bilirubin and NAFLD risk. Direct bilirubin reduced NAFLD risk independent of possible confounders among middle-aged and elderly Chinese population, probably based on the endogenous antioxidation of bilirubin.
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http://dx.doi.org/10.1038/srep31006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975069PMC
August 2016

The contribution of serum hepatitis B virus load in the carcinogenesis and prognosis of hepatocellular carcinoma: evidence from two meta-analyses.

Oncotarget 2016 Aug;7(31):49299-49309

Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Background And Aim: The meta-analysis aimed to quantify and summarize the contribution of serum hepatitis B virus (HBV) DNA load in the carcinogenesis and prognosis of hepatocellular carcinoma (HCC).

Results: Nine independent studies with a total of 1162 cases and 9365 participants on risk of HCC and seventeen studies with 1342 cases and 2891 participants on recurrence of HCC were finally included. The non-liner dose-response association between HBV DNA level and HCC risk was observed, with P value equal to 0.02 for linear test. Compared with 2 log10copies/ml HBV DNA level carriers, the summary relative risk of HCC were 1.65(95% CI: 0.94-2.92) for 4.5 log10copies/ml, 2.20(95% CI: 1.00-4.85) for 5.5 log10copies/ml, 3.06(95% CI: 1.11-8.44) for 6.5 log10copies/ml. Moreover, individuals with high viral load (HBV DNA levels > 105copies/ml) presented significant association with increased risk of HCC recurrence, with the pooled RR of 1.69 (95% CI: 1.49-1.92).

Materials And Methods: Pertinent studies were identified by searching PubMed, Embase and ISI Web of science databases up to January 2016 and by reviewing the references of retrieved articles. The dose-response meta-analysis was precisely performed to calculate the summary relative risks (RRs) by quantizing the association between HBV load and risk of HCC. Besides, the contribution of HBV load on recurrence of HCC was further clarified by general meta-analysis.

Conclusions: These findings indicated a non-linear dose-response relationship between serum HBV DNA level and risk of HCC, and confirmed the significant contribution of serum HBV DNA level in the prognosis of HCC.
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http://dx.doi.org/10.18632/oncotarget.10335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226509PMC
August 2016

Common genetic variants of GPC1 gene reduce risk of biliary atresia in a Chinese population.

J Pediatr Surg 2016 Oct 31;51(10):1661-4. Epub 2016 May 31.

Department of General Surgery, Shenzhen Children Hospital, Shenzhen, China. Electronic address:

Background: Biliary atresia (BA) is a major neonatal cholestatic disease and main indication for pediatric liver transplantation in the world. Recently, GPC1 has been implicated as a risk gene for BA by genetic studies and follow-up functional experiments on zebrafish.

Methods: Two common genetic variants of GPC1, rs2292832 and rs3828336, were selected systematically through 'SNPinfo', and were examined using TaqMan Genotyping Assays for association studies in a Chinese population containing 134 cases and 618 controls.

Results: Of the two single nucleotide polymorphisms (SNPs), we found a significantly decreased BA risk associated with rs2292832 (additive model: OR=0.638, 95% CI: 0.467-0.873, P=0.005), and a marginal effect for rs3828336 (heterozygous model: OR=0.564, 95% CI: 0.312-1.020, P=0.058). The haplotype analysis indicated that either Crs2292832-Crs3828336&Trs3828336 or Trs2292832-Trs3828336 conferred a protective effect from BA (OR=0.569, 95% CI=0.414-0.783, P<0.001; OR=0.528, 95% CI: 0.301-0.926, P=0.026). Moreover, bioinformatics analysis suggested that rs2292832 altered GPC1 expression via effect on transcription-factor-binding sites (TFBS) of upstream binding transcription factor (UBTF), as a regulatory DNA variation in Deoxyribonuclease I (DNase I) hypersensitive sites (DHSs).

Conclusion: Common variants of GPC1 gene were genetically involved in BA risk.
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http://dx.doi.org/10.1016/j.jpedsurg.2016.05.009DOI Listing
October 2016

Nighttime sleep duration and risk of nonalcoholic fatty liver disease: the Dongfeng-Tongji prospective study.

Ann Med 2016 09 21;48(6):468-476. Epub 2016 Jun 21.

a Department of Epidemiology and Statistics, and the Ministry of Education (MOE) Key Lab of Environment and Health, School of Public Health, Tongji Medical College , Huazhong University of Science and Technology , Wuhan , China.

Background: To examine the association between self-reported nighttime sleep duration and nonalcoholic fatty liver disease (NAFLD) risk by comparing the incidence rates of NAFLD among healthy subjects with different sleep duration during the 5 years follow-up.

Methods: 8965 eligible NAFLD-free subjects with a mean age of 61.6 years (males, 43.4%) from Dongfeng-Tongji cohort study at baseline were enrolled in the study. Logistic regression analysis was used to estimate the association between sleep duration and incident NAFLD with potential confounders adjusted. Sleep duration was categorized into five groups: <6 h, 6-7 h, 7-8 h, 8-9 h, ≥9 h.

Result: During the 5-years of follow-up, a total of 2,197 participants were newly diagnosed as NAFLD. Compared with those reported 7-8 h per day of nighttime sleep, the multivariable-adjusted odds ratio (95% confidence intervals) were 1.21 (1.07-1.38) for those who sleep 8-9 h/day, and 1.31 (1.13-1.52) for those who sleep over 9 h/day. However, no significant association was found with short nightly sleep duration (<7 h/day).

Conclusion: Long nighttime sleep duration was associated with a modestly increased risk of NAFLD in a middle-aged and elderly Chinese population. Key messages Long nighttime sleep duration was associated with a modestly increased risk of NAFLD in a middle-aged and elderly Chinese population. The effect of long nighttime sleep on the risk of incident NAFLD was attenuated greatly by body mass index (BMI) in men.
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http://dx.doi.org/10.1080/07853890.2016.1193787DOI Listing
September 2016

Identification of a functional variant for colorectal cancer risk mapping to chromosome 5q31.1.

Oncotarget 2016 Jun;7(23):35199-207

Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Genome-wide association studies (GWASs) have established chromosome 5q31.1 as a risk locus for colorectal cancer (CRC). We previously identified a potentially regulatory single nucleotide polymorphism (SNP) rs17716310 within 5q31.1. Now, we extended our study with another independent Chinese population, functional assays and analyses of TCGA (The Cancer Genome Atlas) data. Significant associations between rs17716310 and CRC risk were found in Present Study including 1075 CRC cases and 1999 controls (additive model: OR = 1.149, 95% CI = 1.027-1.286, P = 0.016), and in Combined Study including 1766 cases and 2708 controls (additive model: OR = 1.145, 95% CI = 1.045-1.254, P = 0.004). Dual luciferase reporter gene assays indicated that the variant C allele obviously increased transcriptional activity. Using TCGA datasets, we indicated rs17716310 as a cis expression quantitative trait locus (eQTL) for the gene SMAD5, whose expression was significantly higher in CRC tissues. These findings suggested that the functional polymorphism rs17716310 A > C might be a genetic modifier for CRC, promoting the expression of SMAD5 that belonged to the transforming growth factor beta (TGF-β) signaling pathway.
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http://dx.doi.org/10.18632/oncotarget.9298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085221PMC
June 2016

Identification of a Potential Regulatory Variant for Colorectal Cancer Risk Mapping to 3p21.31 in Chinese Population.

Sci Rep 2016 04 28;6:25194. Epub 2016 Apr 28.

State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment &Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Genome-wide association studies (GWAS) have established chromosome 3p21.31 as a susceptibility locus for colorectal cancer (CRC) that lacks replication and exploration in the Chinese population. We searched potentially functional single nucleotide polymorphisms (SNPs) in the linkage disequilibrium (LD) block of 3p21.31 with chromatin immunoprecipitation-sequencing (ChIP-seq) data of histone modification, and tested their association with CRC via a case-control study involving 767 cases and 1397 controls in stage 1 and 528 cases and 678 controls in stage 2. In addition to the tag SNP rs8180040 (odds ratio (OR) = 0.875, 95% confidence interval (95% CI) = 0.793-0.966, P = 0.008, P-FDR (false discovery rate) = 0.040), rs1076394 presented consistently significant associations with CRC risk at both stages with OR = 0.850 (95% CI = 0.771-0.938, P = 0.001, P-FDR = 0.005) under the additive model in combined analyses. Supported by the analyses of data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), it was suggested that rs1076394 served as an expression Quantitative Trait Loci (eQTL) for gene CCDC12 and NME6, while NME6's expression was obviously higher in CRC tissues. Using biofeature information such as ChIP-seq and RNA sequencing (RNA-seq) data might help researchers to interpret GWAS results and locate functional variants for diseases in the post-GWAS era.
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http://dx.doi.org/10.1038/srep25194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848543PMC
April 2016

A functional polymorphism in lnc-LAMC2-1:1 confers risk of colorectal cancer by affecting miRNA binding.

Carcinogenesis 2016 05 19;37(5):443-51. Epub 2016 Feb 19.

Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.

Genome-wide association studies (GWASs) have identified multiple susceptibility loci of colorectal cancer (CRC), however, causative polymorphisms have not been fully elucidated. Long non-coding RNAs (lncRNAs) are a recently discovered class of non-protein coding RNAs that involved in a wide variety of biological processes. We hypothesized that single nucleotide polymorphisms (SNPs) in lncRNA may associate with the CRC risk by influencing lncRNA functions. To evaluate the effects of SNPs on CRC susceptibility in Chinese populations, we first screened out all potentially functional SNPs in exons of lncRNAs located in CRC susceptibility loci identified by GWAS. Eight SNPs were selected and genotyped in 875 CRC cases and 855 controls and replicated in an independent case-control study consisting of 768 CRC cases and 768 controls. Analyses showed that CG and GG genotypes of the rs2147578 were significantly associated with increased risk for CRC occurrence in both case-control studies [combined analysis OR = 1.29; 95% confidence interval (CI) = 1.11-1.51, P = 0.001] compared to the rs2147578 CC genotype. Bioinformatics analyses showed that rs2147578 is located in the transcript of lnc-LAMC2-1:1 and could influence the binding of lnc-LAMC2-1:1/miR-128-3p. Further luciferase reporter assays demonstrated that the construct with the risk rs2147578G allele had relatively high expression activity compared with that of the rs2147578C allele. Expression quantitative trait loci analyses also showed that rs2147578 is correlated with the expression of a well established oncogene LAMC2 (laminin subunit gamma 2). These findings indicated that rs2147578 in lnc-LAMC2-1:1 might be a genetic modifier for the development of CRC.
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http://dx.doi.org/10.1093/carcin/bgw024DOI Listing
May 2016

[Risk prediction of colorectal cancer with common genetic variants and conventional non-genetic factors in a Chinese Han population].

Zhonghua Liu Xing Bing Xue Za Zhi 2015 Oct;36(10):1053-7

Department of Epidemiology and Biostatistics, School of Public Health; Email:

Objective: To understand the association between multiple genetic loci identified by genome-wide association studies (GWASs) and colorectal cancer (CRC) risk, and whether these genetic factors, along with traditional risk factors, could contribute to the colorectal cancer risk prediction in a Chinese Han population.

Methods: A case-control study (1 066 CRC cases and 3 880 controls) was initially conducted to assess the association between 21 recently discovered single-nucleotide polymorphisms (SNPs) and CRC risk. Genetic risk score (GRS) and weighted genetic risk score (wGRS) were calculated to evaluate the joint effects of selected loci. Multiple models combining genetic and non-genetic factors were established and receiver operating characteristic curve analysis was used to compare the discriminatory power of different predictive models.

Results: There were 7 SNPs significantly associated with CRC susceptibility. As the GRS or wGRS increased, the risk of CRC also increased (trend P=0.002 6 for GRS, trend P<0.000 1 for wGRS). The ORs for highest versus lowest quartile of GRS and wGRS were 1.33 (95% CI: 1.12-1.58, P=0.001 0) and 1.76 (95% CI: 1.45-2.14, P<0.000 1) , respectively. The model incorporating wGRS and traditional risk factors, including sex, age, smoking and drinking, was the best one to predict CRC risk in this population, with an area under curve of 0.593 (95% CI: 0.573-0.613).

Conclusion: Multiple genetic loci identified by GWASs jointly influenced the CRC risk. The combination of genetic factors and conventional non-genetic factors improved the performance of risk predictive model for colorectal cancer.
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October 2015

Genetic variant in DIP2A gene is associated with developmental dyslexia in Chinese population.

Am J Med Genet B Neuropsychiatr Genet 2016 Mar 9;171B(2):203-8. Epub 2015 Oct 9.

Department of Maternal and Child Health and MOE (Ministry of Education) Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Increasing evidence suggests that there is a substantial heritable component including several risk loci and candidate genes for developmental dyslexia (DD). DIP2A has been identified to be partially deleted on chromosome region 21q22.3, which cosegregates with DD. And it fits into a theoretical molecular network of DD implicated in the development of DD. Compared with some DD candidate genes that have been extensively studied (e.g., DYX1C1, DCDC2, KIAA0319, and ROBO1), very little is known about the association between candidate gene DIP2A and DD susceptibility. And given the linguistic and genetic differences between Chinese and other Western populations, it is worthwhile validating the association of DIP2A in Chinese dyslexic children. Here, we investigated two genetic variants, selected by bioinformatics analysis, in DIP2A in a Chinese population with 409 dyslexic cases and 410 healthy controls. We observed a significantly increased DD risk associated with rs2255526 G allele (OR = 1.297, 95% CI = 1.036-1.623, Padjusted  = 0.023) and GG genotypes (OR = 1.833, 95% CI = 1.043-3.223, Padjusted  = 0.035), compared with their wild-type counterparts. In addition, it was marginally significantly associated with DD under the recessive model (OR = 1.677, 95% CI = 0.967-2.908, Padjusted  = 0.066) and the dominant model (OR = 1.314, 95% CI = 0.992-1.741, Padjusted  = 0.057). However, we found no evidence of an association of SNP rs16979358 with DD. In conclusion, this study showed that a genetic variant in the DIP2A gene was associated with increased DD risk in China.
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http://dx.doi.org/10.1002/ajmg.b.32392DOI Listing
March 2016

Identification of a Potential Regulatory Variant for Colorectal Cancer Risk Mapping to Chromosome 5q31.1: A Post-GWAS Study.

PLoS One 2015 18;10(9):e0138478. Epub 2015 Sep 18.

State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), and Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Large-scale genome-wide association studies (GWAS) have established chromosome 5q31.1 as a susceptibility locus for colorectal cancer (CRC), which was still lack of causal genetic variants. We searched potentially regulatory single nucleotide polymorphisms (SNPs) in the overlap region between linkage disequilibrium (LD) block of 5q31.1 and regulatory elements predicted by histone modifications, then tested their association with CRC via a case-control study. Among three candidate common variants, we found rs17716310 conferred significantly (heterozygous model: OR = 1.273, 95% confidence interval (95%CI) = 1.016-1.595, P = 0.036) and marginally (dominant model: OR = 1.238, 95%CI = 1.000-1.532, P = 0.050) increase risk for CRC in a Chinese population including 695 cases and 709 controls. This variation was suggested to be regulatory altering the activity of enhancer that control PITX1 expression. Using epigenetic information such as chromatin immunoprecipitation-sequencing (ChIP-seq) data might help researchers to interpret the results of GWAS and locate causal variants for diseases in post-GWAS era.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138478PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575091PMC
May 2016

The Roles of Genes in the Neuronal Migration and Neurite Outgrowth Network in Developmental Dyslexia: Single- and Multiple-Risk Genetic Variants.

Mol Neurobiol 2016 08 17;53(6):3967-3975. Epub 2015 Jul 17.

Department of Maternal and Child Health and MOE (Ministry of Education) Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Abnormal regulation of neural migration and neurite growth is thought to be an important feature of developmental dyslexia (DD). We investigated 16 genetic variants, selected by bioinformatics analyses, in six key genes in the neuronal migration and neurite outgrowth network in a Chinese population. We first observed that KIAA0319L rs28366021, KIAA0319 rs4504469, and DOCK4 rs2074130 were significantly associated with DD risk after false discovery rate (FDR) adjustment for multiple comparisons (odds ratio (OR) = 0.672, 95 % confidence interval (CI) = 0.505-0.894, P = 0.006; OR = 1.608, 95 % CI = 1.174-2.203, P = 0.003; OR = 1.681, 95 % CI = 1.203-2.348, P = 0.002). The following classification and regression tree (CART) analysis revealed a prediction value of gene-gene interactions among DOCK4 rs2074130, KIAA0319 rs4504469, DCDC2 rs2274305, and KIAA0319L rs28366021 variants. Compared with the lowest risk carriers of the combination of rs2074130 CC, rs4504469 CC, and rs2274305 GG genotype, individuals carrying the combined genotypes of rs2074130 CC, rs4504469 CT or TT, and rs28366021 GG had a significantly increased risk for DD (OR = 2.492, 95 % CI = 1.447-4.290, P = 0.001); individuals with the combination of rs2074130 CT or TT and rs28366021 GG genotype exhibited the highest risk for DD (OR = 2.770, 95 % CI = 2.265-6.276, P = 0.000). A significant dose effect was observed among these four variants (P for trend = 0.000). In summary, this study supports the importance of single- and multiple-risk variants in this network in DD susceptibility in China.
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http://dx.doi.org/10.1007/s12035-015-9334-8DOI Listing
August 2016

MAD1L1 Arg558His and MAD2L1 Leu84Met interaction with smoking increase the risk of colorectal cancer.

Sci Rep 2015 Jul 17;5:12202. Epub 2015 Jul 17.

Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.

The spindle assembly checkpoint (SAC) has been established as an important mechanism of driving aneuploidy, which occurs at a high frequency in the colorectal tumorigenesis. Two important components of SAC are MAD1L1 and MAD2L1, which function together in an interactive manner to initiate the checkpoint signal. We hypothesize that genetic variants in the binding domains of MAD1L1 and MAD2L1 may modulate protein structures and eventually contribute to CRC susceptibility. A case-control study including 710 CRC cases and 735 controls was performed to examine MAD1L1 Arg558His and MAD2L1 Leu84Met's conferring susceptibility to CRC. Cytokinesis-block micronucleus cytome assays were applied to assess the effect of two functional variants on chromosomal instability (CIN). Significant associations with CRC risk were observed for MAD1L1 Arg558His (OR = 1.38,95% CI: 1.09-1.75) and MAD2L1 Leu84Met in a dominant model (OR = 1.48,95% CI: 1.09-2.01). Moreover, significant multiplicative gene-smoking interactions were found in MAD1L1 Arg558His (P = 0.019) and MAD2L184 Leu/Met (P = 0.016) to enhance CRC risk. Additionally, the frequencies of lymphocytic micro-nucleated binucleated cells for MAD1L1 Arg558His polymorphism were significantly different in the exposed group (P = 0.013), but not in the control group. The study emphasized that MAD1L1 Arg558His and MAD2L1 Leu84Met can significantly interact with smoking to enhance CRC risk, and the genetic effects of MAD1L1Arg558His on CIN need to be further clarified in follow-up studies.
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http://dx.doi.org/10.1038/srep12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505328PMC
July 2015

Systematic confirmation study of GWAS-identified genetic variants for Kawasaki disease in a Chinese population.

Sci Rep 2015 Feb 3;5:8194. Epub 2015 Feb 3.

Department of Epidemiology and Biostatistics and Key Laboratory of Environment and Health, Ministry of Education &Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.

Genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) associated with Kawasaki disease (KD). In this study, we replicated the associations of 10 GWAS-identified SNPs with KD in a Han Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression, and cumulative effect of non-risk genotypes were also performed. Although none of the SNPs reached the corrected significance level, 4 SNPs showed nominal associations with KD risk. Compared with their respective wild type counterparts, rs1801274 AG+GG genotypes and rs3818298 TC+CC genotypes were nominally associated with the reduced risk of KD (OR = 0.77, 95% CI = 0.59-0.99, P = 0.045; OR = 0.74, 95% CI = 0.56-0.98, P = 0.038). Meanwhile, rs1801274 GG genotype, rs2736340 CC genotype or rs4813003 TT genotype showed a reduced risk trend (OR = 0.57, 95% CI = 0.35-0.93, P = 0.024; OR = 0.46, 95% CI = 0.26-0.83, P = 0.010; OR = 0.64, 95% CI = 0.43-0.94, P = 0.022), compared with rs1801274 AG+AA genotypes, rs2736340 CT+TT genotypes or rs4813003 TC+CC genotypes, respectively. Furthermore, a cumulative effect was observed with the ORs being gradually decreased with the increasing accumulative number of non-risk genotypes (Ptrend<0.001). In conclusion, our study suggests that 4 GWAS-identified SNPs, rs2736340, rs4813003, rs3818298 and rs1801274, were nominally associated with KD risk in a Han Chinese population individually and jointly.
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http://dx.doi.org/10.1038/srep08194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314627PMC
February 2015

A genetic variant rs1801274 in FCGR2A as a potential risk marker for Kawasaki disease: a case-control study and meta-analysis.

PLoS One 2014 5;9(8):e103329. Epub 2014 Aug 5.

Department of Epidemiology and Biostatistics and State Key Laboratory of Environment Health, Ministry of Education Key Laboratory of Environment and Health, Ministry of Environmental Protection Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Objectives: Recent genome-wide association study found rs1801274, a functional single nucleotide polymorphism (SNP) in IgG receptor gene FCGR2A, was associated with increased risk of Kawasaki disease (KD). However, subsequent studies on the role of this SNP were limited and controversial.

Methods: A case-control study was conducted in a Chinese Han population including 428 KD patients and 493 controls to examine the association between rs1801274 and KD susceptibility. A meta-analysis was performed in combination with the relevant published studies to further clarify such an association.

Results: Our case-control study found that rs1801274 was significantly associated with increased risk of KD in the Chinese Han population, with an odds ratio (OR) of 1.58 (95% CI = 0.96-2.62) for the GA genotype and 1.93 (95% CI = 1.16-3.19) for the AA genotype compared with the GG genotype. The result of meta-analysis further demonstrated that the A allele of rs1801274 was significantly correlated with KD risk under the allelic model (OR = 1.35, 95% CI = 1.27-1.44) without heterogeneity by fixed-effects model analysis (Q = 17.30, p = 0.139). Moreover, sensitivity analysis supported the robustness of this meta-analysis.

Conclusion: These results further confirm that rs1801274 in the FCGR2A gene is significantly associated with increased risk of KD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103329PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122468PMC
April 2015

The roles of Ca2+/NFAT signaling genes in Kawasaki disease: single- and multiple-risk genetic variants.

Sci Rep 2014 Jun 6;4:5208. Epub 2014 Jun 6.

Children's Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.

Ca(2+)/nuclear factor of activated T-cells (Ca(2+)/NFAT) signaling pathway may play a crucial role in Kawasaki disease (KD). We investigated 16 genetic variants, selected by bioinformatics analyses or previous studies, in 7 key genes involved in this pathway in a Chinese population. We observed a significantly or marginally increased KD risk associated with rs2720378 GC + CC genotypes (OR = 1.39, 95% CI = 1.07-1.80, P = 0.014) or rs2069762 AC + CC genotypes (OR = 1.28, 95% CI = 0.98-1.67, P = 0.066), compared with their wild type counterparts. In classification and regression tree analysis, individuals carrying the combined genotypes of rs2720378 GC or CC genotype, rs2069762 CA or CC genotype and rs1561876 AA genotype exhibited the highest KD risk (OR = 2.12, 95% CI = 1.46-3.07, P < 0.001), compared with the lowest risk carriers of rs2720378 GG genotype. Moreover, a significant dose effect was observed among these three variants (Ptrend < 0.001). In conclusion, this study implicates that single- and multiple-risk genetic variants in this pathway might contribute to KD susceptibility. Further studies on more comprehensive single nucleotide polymorphisms, different ethnicities and larger sample sizes are warranted, and the exact biological mechanisms need to be further clarified.
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http://dx.doi.org/10.1038/srep05208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047536PMC
June 2014

Dietary mushroom intake may reduce the risk of breast cancer: evidence from a meta-analysis of observational studies.

PLoS One 2014 1;9(4):e93437. Epub 2014 Apr 1.

State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), and Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Epidemiological studies have investigated the potential anticancer effects of mushroom intake. This review aims to clarify the evidence on the association of dietary mushroom intake with breast cancer risk and to quantify its dose-response relationship. Relevant studies were identified by a search of PubMed, Web of Science and Google Scholar up to December 31, 2013. Observational studies with relative risks (RRs) or hazard ratios (HRs) or odd ratios (ORs) and 95% confidence intervals (CIs) of breast cancer for three or more categories of mushroom intake were eligible. The quality of included studies was assessed by using Newcastle-Ottawa Scale. A dose-response meta-analysis was performed by utilizing generalized least squares trend estimation. Eight case-control studies and two cohort studies with a total of 6890 cases were ultimately included. For dose-response analysis, there was no evidence of non-linear association between mushroom consumption and breast cancer risk (P = 0.337) and a 1 g/d increment in mushroom intake conferred an RR of 0.97 (95% CI: 0.96-0.98) for breast cancer risk, with moderate heterogeneity (I(2) = 56.3%, P = 0.015). Besides, available menopause data extracted from included studies were used to evaluate the influence of menopausal statues. The summary RRs of mushroom consumption on breast cancer were 0.96 (95% CI: 0.91-1.00) for premenopausal women and 0.94 (95% CI: 0.91-0.97) for postmenopausal women, respectively. Our findings demonstrated that mushroom intake may be inversely associated with risk of breast cancer, which need to be confirmed with large-scale prospective studies further.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093437PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972098PMC
December 2015