Publications by authors named "Jiaoyuan Li"

51 Publications

Bisphenol A exposure, interaction with genetic variants and colorectal cancer via mediating oxidative stress biomarkers.

Environ Pollut 2021 Jun 23;287:117630. Epub 2021 Jun 23.

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, China.

Bisphenol A (BPA) may induce oxidative stress as well as the toxicity of colon cancer cells. We hypothesized that BPA exposure and interactions with genetic variants might be associated with colorectal cancer (CRC) risk, and the association might be partly mediated by oxidative stress. We measured urinary BPA and three oxidative stress markers [8-iso-prostaglandinF (8-isoPGF), 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] in 275 new CRC cases and 538 healthy controls. A set of 25 genetic variations in 12 candidate DNA repair genes and 5 metabolic enzyme genes were genotyped by Sequenom MassARRAY approach. In multivariable logistic regression, significant positive associations of CRC risk with BPA, 8-OHdG and HNE-MA were observed. Additionally, 8-OHdG, HNE-MA and 8-isoPGF were significantly positively associated with BPA (P < 0.05). The mediation analysis showed BPA-associated HNE-MA significantly mediated 11.81% of the effect of BPA on CRC risk. Moreover, BPA was found to interact with ERCC5 rs17655 and rs2296147 (both P < 0.05) to increase CRC risk. In brief, our results suggested BPA was associated with CRC risk and the positive association of BPA with CRC risk might be partly mediated by the oxidative stress HNE-MA. BPA might interact with ERCC5 rs17655 and rs2296147 to increase CRC risk.
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http://dx.doi.org/10.1016/j.envpol.2021.117630DOI Listing
June 2021

Temporal Profiles of Antibody Responses, Cytokines, and Survival of COVID-19 Patients: A Retrospective Cohort in Wuhan, China.

Engineering (Beijing) 2021 May 18. Epub 2021 May 18.

Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

The longitudinal immunologic status of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients and its association with the clinical outcome are barely known. Thus, we sought to analyze the temporal profiles of specific antibodies, as well as the correlations between the antibodies, proinflammatory cytokines, and survival of patients with coronavirus disease 2019 (COVID-19). A total of 1830 laboratory-confirmed COVID-19 cases were recruited. The temporal profiles of the virus, antibodies, and cytokines of the patients until 12 weeks since illness onset were fitted by the locally weighted scatter plot smoothing (LOWESS) method. The mediation effect of cytokines on the associations between antibody responses and survival were explored by mediation analysis. Of the 1830 patients, 1435 were detectable for SARS-CoV-2, while 395 were positive in specific antibodies only. Of the 1435 patients, 2.4% presented seroconversion for neither immunoglobulin G (IgG) nor immunoglobulin M (IgM) during hospitalization. The seropositive rates of IgG and IgM were 29.6% and 48.1%, respectively, in the first week, and plateaued within five weeks. For the patients discharged from the hospital, the IgM decreased slowly, while high levels of IgG were maintained at around 188 AU·mL for the 12 weeks since illness onset. In contrast, in the patients who subsequently died, IgM declined rapidly and IgG dropped to 87 AU·mL at the twelfth week. Elevated interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-1β (IL-1β), interleukin-2R (IL-2R), and tumor necrosis factor-α (TNF-α) levels were observed in the deceased patients in comparison with the discharged patients, and 12.5% of the association between low IgG level and mortality risk was mediated by these cytokines. Our study deciphers the temporal profiles of SARS-CoV-2-specific antibodies within the 12 weeks since illness onset and indicates the protective effect of antibody response on survival, which may help to guide prognosis estimation.
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http://dx.doi.org/10.1016/j.eng.2021.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129785PMC
May 2021

Exosome detection via the ultrafast-isolation system: EXODUS.

Nat Methods 2021 02 11;18(2):212-218. Epub 2021 Jan 11.

Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Exosomes have shown great potential in disease diagnostics and therapeutics. However, current isolation approaches are burdensome and suffer from low speed, yield and purity, limiting basic research and clinical applications. Here, we describe an efficient exosome detection method via the ultrafast-isolation system (EXODUS) that allows automated label-free purification of exosomes from varied biofluids. We obtained the ultra-efficient purification of exosomes by negative pressure oscillation and double coupled harmonic oscillator-enabled membrane vibration. Our two coupled oscillators generate dual-frequency transverse waves on the membranes, enabling EXODUS to outperform other isolation techniques in speed, purity and yield. We demonstrated EXODUS by purifying exosomes from urine samples of 113 patients and validated the practical relevance in exosomal RNA profiling with the high-resolution capability and high-throughput analysis.
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http://dx.doi.org/10.1038/s41592-020-01034-xDOI Listing
February 2021

An integrative microfluidic device for isolation and ultrasensitive detection of lung cancer-specific exosomes from patient urine.

Biosens Bioelectron 2020 Sep 18;163:112290. Epub 2020 May 18.

School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325001, China; The First Affiliated Hospital, Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address:

Exosomes, derived from various biofluids, may serve as potential biomarkers for cancer early detection. Nevertheless, exosome clinical translation remains challenging due to the lack of reliable isolation and detection methods. Herein, we present a novel integrated microfluidic device specifically designed for isolation and in-situ detection of lung cancer-specific exosomes collected from patient's urine. The new device has been fabricated using polymethyl methacrylate (PMMA) and a nanoporous gold (Au) nanocluster membrane modified with the capture antibody. The second antibody-conjugated Au nanorod probe was then loaded to identify and quantify lung cancer-specific exosomes using a dark field microscope. AuNC-Exosome-AuR complex produces a significant scattering wavelength shift and an improved scattering intensity due to resonance Rayleigh scattering, which enables the ultrasensitive detection of exosomes with a LOD below 1000 particles/mL. The proteomic analysis revealed that the high-purity exosomes has been isolated by the device. We then validated this method with 500 μL urine samples from lung cancer patients and controls, which showed great promise for differentiating early-stage lung cancer patients from healthy individuals. Taken together, the presented method is fast and ultrasensitive and can be easily adapted for the isolation and detection of cancer specific exosomes from other malignant tumors.
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http://dx.doi.org/10.1016/j.bios.2020.112290DOI Listing
September 2020

Urinary bisphenol A and its interaction with ESR1 genetic polymorphism associated with non-small cell lung cancer: findings from a case-control study in Chinese population.

Chemosphere 2020 Sep 19;254:126835. Epub 2020 Apr 19.

Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Bisphenol A (BPA), a well-known endocrine disruptor, was reported to promote migration and invasion of lung cancer cells, but findings in human study is absent. A case-control study in Chinese population was conducted to evaluate the association between BPA exposure and non-small cell lung cancer (NSCLC), and explore the interaction between BPA exposure and estrogen-related genetic polymorphism on NSCLC. BPA concentrations were measured in urine samples using an UHPLC-MS method and rs2046210 in estrogen receptor α (ESR1) gene was genotyped by TaqMan genotyping system. Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association analyses. As a result, 615 NSCLC cases and 615 healthy controls were enrolled from Wuhan, central China. The mean age was 58.0 (SD: 7.9) years old for controls and 59.2 (SD: 8.8) years old for cancer cases. The creatinine-adjusted BPA levels were significantly higher in NSCLC cases than that in healthy controls (median: 0.97 vs 0.73 μg/L, P < 0.001). Exposure to high levels of BPA was significantly associated with NSCLC (adjusted OR = 1.91, 95%CI: 1.39-2.62, P < 0.001 for the highest quartile). We also observed a shallow concave dose-response relationship about the overall association between BPA and NSCLC. Moreover, interaction analyses showed that BPA exposure interacted multiplicatively with rs2046210, with a marginal P value (P = 0.049), to contribute to NSCLC. In conclusion, exposure to high levels BPA may be associated with NSCLC and the relationship may be modified by genetic polymorphism in ESR1.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126835DOI Listing
September 2020

CpG-methylation-based risk score predicts progression in colorectal cancer.

Epigenomics 2020 04 17;12(7):605-615. Epub 2020 Mar 17.

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

To identify patients with colorectal cancer (CRC) who are at a truly higher risk of progression, which is key for individualized approaches to precision therapy. We developed a predictor associated with progression-free interval (PFI) using The Cancer Genome Atlas CRC methylation data. The risk score was associated with PFI in the whole cohort (p < 0.001). A nomogram consisting of the risk score and other significant clinical features was generated to predict the 3- and 5-year PFI in the whole set (area under the curve: 0.79 and 0.71, respectively). The risk score based on 23 DNA-methylation sites may serve as the basis for improved prediction of progression in patients with CRC in future clinical practice.
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http://dx.doi.org/10.2217/epi-2019-0300DOI Listing
April 2020

Nut Consumption and Risk of Cancer: A Meta-analysis of Prospective Studies.

Cancer Epidemiol Biomarkers Prev 2020 03 10;29(3):565-573. Epub 2020 Feb 10.

Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Epidemiologic studies have investigated the association between nut intake and risk for multiple cancers. However, current findings are inconsistent and no definite conclusion has been drawn from prospective studies. We therefore conducted this meta-analysis to evaluate the relationship between nut consumption and risk of cancer.

Methods: Prospective studies reporting associations between nut intake and risk for all types of cancer were identified by searching Web of Science and PubMed databases up to June 2019. Risk ratios (RR) and 95% confidence intervals (CI) were extracted and then pooled across the studies using a random-effect model. A dose-response analysis was modeled by performing restricted cubic splines when data were available.

Results: Thirty-three studies that included more than 50,000 cancer cases were eligible for the analysis. When comparing the highest with the lowest category of nut intake, high consumption of nuts was significantly associated with decreased risk of overall cancer (RR = 0.90; 95% CI, 0.85-0.95). The protective effect of nut consumption was especially apparent against cancers from the digestive system (RR = 0.83; 95% CI, 0.77-0.89). Among different nut classes, significant association was only obtained for intake of tree nuts. We also observed a linear dose-response relationship between nut consumption and cancer: Per 20 g/day increase in nut consumption was related to a 10% (RR = 0.90; 95% CI, 0.82-0.99) decrease in cancer risk.

Conclusions: Our analysis demonstrated an inverse association of dietary nut consumption with cancer risk, especially for cancers from the digestive system.

Impact: This study highlights the protective effect of nuts against cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1167DOI Listing
March 2020

TERT-rs33963617 and CLPTM1L-rs77518573 reduce the risk of non-small cell lung cancer in Chinese population.

Gene 2020 Mar 11;731:144357. Epub 2020 Jan 11.

Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address:

Background: Genome-wide association studies (GWAS) have identified 5p15.33 as a susceptible locus for lung cancer. However, for non-small cell lung cancer (NSCLC), low-frequency risk variants in this region have not been systematically studied. We intended to explore the associations between low-frequency variants on 5p15.33 and NSCLC using a next-generation sequencing based approach in this study.

Methods: We have acquisited the variation spectrum of 400 NSCLC patients on 5p15.33 by sequencing the targeted region before. Candidate variants were primarily selected by restricting the minor allele frequency (MAF 1-5%) and then by comparing their frequency in 400 NSCLC patients with 1008 East Asians from The genome Aggregation Database (gnomAD). The associations between candidate variants and NSCLC were discovered and replicated in two case-control sets: discovery stage with 960 cases and 916 controls, and replication stage with 1596 cases and 1614 controls in total.

Results: Five low-frequency variants were selected as our candidates and subsequent association analyses showed that 2 polymorphisms were significantly associated with risk of NSCLC, including rs33963617 (OR = 0.63, 95% CI: 0.53-0.76, P = 3.80 × 10) in TERT and rs77518573 (OR = 0.73, 95% CI: 0.63-0.84, P = 2.00 × 10) in upstream of CLPTM1L. When stratified by histologic subtype, a significant association was only investigated in adenocarcinoma for rs77518573. We also observed an obvious cumulative effect of the two significant variants.

Conclusions: We newly identified two NSCLC related variants on chromosome 5p15.33. Both TERT-rs33963617 and CLPTM1L-rs77518573 conferred reduced risk for NSCLC in Chinese Han population.
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http://dx.doi.org/10.1016/j.gene.2020.144357DOI Listing
March 2020

LINC01149 variant modulates MICA expression that facilitates hepatitis B virus spontaneous recovery but increases hepatocellular carcinoma risk.

Oncogene 2020 02 21;39(9):1944-1956. Epub 2019 Nov 21.

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, China.

Interpreting disease-causing variants, especially in noncoding regions by genome-wide association studies (GWAS), has become one of the most challenging and demanding tasks. We hypothesized that functional lncRNAs variants in GWAS-identified loci might alter expression level of genes associated with persistent HBV infection and hepatocellular carcinoma (HCC). Integrated bioinformatics approaches were used to prioritize potentially functional variants and a two-stage case-control study (2473 HBV positive HCC patients, 2248 persistent HBV carriers and 2294 spontaneously recovered subjects) was performed to assess the roles of these variants. The rs2844512 G > C variant in LINC01149 was identified to facilitate HBV spontaneous recovery (OR = 0.84, 95% CI = 0.77-0.92) but increase the risk of HCC (OR = 1.21, 95% CI = 1.11-1.32) in combined samples. Subsequent biological assays indicated this variant created a binding site for miR-128-3p and upregulated MICA expression by serving as a miRNA sponge, which might recruit NK-cells to lyse infected cells, but release highly soluble MICA by shedding to induce NK-cells exhaustion and tumor immune evasion. These findings highlight a regulatory circuit between LINC01149 and MICA, mediating by miR-128-3p, and the important role of upregulated MICA in conferring susceptibility to persistent HBV infection and HCC.
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http://dx.doi.org/10.1038/s41388-019-1117-7DOI Listing
February 2020

Three functional variants were identified to affect RPS24 expression and significantly associated with risk of colorectal cancer.

Arch Toxicol 2020 01 23;94(1):295-303. Epub 2019 Oct 23.

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

GWAS-identified 10q22.3 loci with lead SNP rs704017 are significantly associated with CRC risk in both Asian and European populations. However, the functional mechanism of this region is unclear. In this study, we performed a fine-mapping analysis to identify the causal SNPs. To identify potential functional SNPs in linkage disequilibrium with the lead SNP, we searched for the potential target genes using a Hi-C database and an RNA interfering-based on-chip approach. The results indicated that rs12263636 (r = 0.41) showed the highest potential to be functional. It resided in a region with enhancer markers and a topologically associating domain. We found that RPS24 was the only gene that significantly promoted the proliferation rate of CRC cells and might have promoter-enhancer interaction with rs12263636. Dual-luciferase reporter assays confirmed that the risk alleles of two variants (rs3740253 and rs7071351) in RPS24 promoter could increase the expression of luciferase. Case control study consisting of 1134 cases and 2039 health controls confirmed that both the two variants were associated with risk of CRC (rs3740253: P = 0.0079, OR = 1.15, 95% CI 1.04-1.28; rs7071351: P = 0.0085, OR = 1.15, 95% CI 1.04-1.28). And plasmid containing mutant haplotypes containing all the three mutations (rs12263636 or rs3740253 and rs7071351) could most significantly increase luciferase expression, compared with any haplotype of the three mutations. The study explained the functional mechanism for the 10q22.3 loci and provided new insights into the prevention and treatment of CRC.
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http://dx.doi.org/10.1007/s00204-019-02600-9DOI Listing
January 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

SLC10A1 S267F variant influences susceptibility to HBV infection and reduces cholesterol level by impairing bile acid uptake.

J Viral Hepat 2019 10 2;26(10):1178-1185. Epub 2019 Jul 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, China.

The SLC10A1 Ser267Phe (S267F) variant has been reported to severely inhibit hepatitis B virus (HBV) infection and taurocholate transport activity. This study aimed to clarify the effects of this variant on HBV infection and bile acid metabolism. SLC10A1 S267F was genotyped in 2907 HBV-exposed subjects (including HBV persistent carriers and spontaneously recovered subjects) and 1364 unexposed subjects (HBV marker-negative subjects), followed by replication I, comprising 914 exposed subjects and 1123 unexposed subjects, and replication II, comprising 355 children born to HBsAg-positive mothers (226 HBV-infected children and 129 controls). Intriguingly, SLC10A1 AA was observed only in the unexposed group, but not in the exposed group. The SLC10A1 A allele consistently decreased HBV infection risk compared with the G allele (OR = 0.76, 95% CI: 0.64-0.90 in combined samples). In addition, children with the SLC10A1 GA genotype had a reduced risk of perinatal transmission (OR = 0.31, 95% CI: 0.14-0.71). Moreover, unexposed subjects with the SLC10A1 AA genotype exhibited decreased serum total cholesterol and low-density lipoprotein cholesterol compared to those with the GG or GA genotypes (P = 2.975 × 10 and 0.004, respectively). The study highlighted the role of the SLC10A1 S267F variant in the loss of the ability to support HBV infection and taurocholate transport activity. Subjects with the AA genotype may escape from HBV infection and present decreased cholesterol levels as a consequence of impaired bile acid uptake.
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http://dx.doi.org/10.1111/jvh.13157DOI Listing
October 2019

Integrative analysis identifies genetic variant modulating MICA expression and altering susceptibility to persistent HBV infection.

Liver Int 2019 10 14;39(10):1927-1936. Epub 2019 May 14.

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

Background & Aims: Genome-wide association studies have identified multiple genetic signals associated with the risk of persistent hepatitis B virus (HBV) infection and HBV-related hepatocellular carcinoma. However, the majority of the associated variants may only be markers of functional variants and the underlying biological mechanisms remain elusive. We hypothesized that the functional variants with modulating transcription factor (TF) binding affinity in genome-wide association studies-identified loci may influence the risk of persistent HBV infection in Chinese people.

Methods: A systematic bioinformatics approach was implemented to prioritize potential functional variants that may influence TF binding. A two-stage case-control study, including 1595 HBV-persistent carriers and 1590 subjects with HBV natural clearance, was conducted to examine the associations between candidate variants and susceptibility to persistent HBV infection. Biological assays were carried out to elucidate the underlying mechanism of the associated genetic variants.

Results: Twelve candidate variants were identified, and rs2523454 G > A increased the risk of persistent HBV infection (dominant model: OR  = 1.37, 95% CI = 1.19-1.58, P = 1.610 × 10 ). Functional assays indicated that the rs2523454 A allele significantly decreased transcriptional activity compared to the G allele by influencing TF-binding affinity. In addition, expression quantitative trait loci analyses revealed that the A allele was associated with the reduced expression of MICA (P < 0.01).

Conclusions: Our findings suggest that the germline G > A variation at rs2523454 may influence TF-DNA interaction, downregulate the expression of MICA and play an important role in the development of persistent HBV infection in the Chinese population.
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http://dx.doi.org/10.1111/liv.14127DOI Listing
October 2019

Functional polymorphisms on chromosome 5p15.33 disturb telomere biology and confer the risk of non-small cell lung cancer in Chinese population.

Mol Carcinog 2019 06 11;58(6):913-921. Epub 2019 Feb 11.

Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The chromosome 5p15.33 has been reported as a susceptibility locus for lung cancer. However, causal variants in this region have not been fully uncovered. In this study, we intended to identify functional polymorphisms associated with non-small cell lung cancer (NSCLC) susceptibility in Chinese population. A targeted sequencing on 5p15.33 region was conducted in 400 NSCLC cases. We selected candidate variants by comparing genotypic frequency with data from 1000 Genomes Project, and their associations with NSCLC were validated in 985 cases and 970 controls. The relationships between risk variants and telomere length were evaluated in 774 healthy subjects. Luciferase assays and electrophoretic mobility shift assays (EMSA) were performed to explore potential functions and reveal carcinogenic mechanisms. As a result, we identified 1478 variants through targeted sequencing and selected 17 candidates. Four polymorphisms exhibited prominent associations with lung cancer risk, including rs7726159 (OR = 1.34, 95%CI: 1.18-1.52, P = 7.78 × 10 ), rs10054203 (OR = 1.29, 95%CI: 1.13-1.46, P = 1.37 × 10 ), rs2736107 (OR = 1.28, 95%CI: 1.11-1.47, P = 5.14 × 10 ), and rs2853677 (OR = 1.23, 95%CI: 1.08-1.39, P = 0.002). The minor allele of rs7726159 and rs10053203 were associated with long telomeres (P = 0.008 and 0.036, respectively). Mechanistically, the rs7726159-A increased TERT transcription through mediating allele-specific MYC binding. In conclusion, the functional variant rs7726159 confers lung cancer susceptibility might by affecting MYC binding and inducing telomere lengthening, which provides a new insight into the crucial role of telomere biology in tumorigenesis.
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http://dx.doi.org/10.1002/mc.22980DOI Listing
June 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

A study on Chinese consumer preferences for food traceability information using best-worst scaling.

PLoS One 2018 2;13(11):e0206793. Epub 2018 Nov 2.

College of Economics and Management, China Agricultural University, Beijing, China.

Food safety is a global public health issue, which often arises from asymmetric information between consumers and suppliers. With the development of information technology in human life, building a food traceability information sharing platform is viewed as one of the best ways to overcome the trust crisis and resolve the problem of information asymmetry in China. However, among the myriad information available from the food supply chain, there is a lack of knowledge on consumer preference. Based on the best-worst scaling approach, this paper investigated consumer preferences for vegetable, pork, and dairy product traceability information. Specifically, this paper measured the relative importance that consumers place on the traceable information. The results indicate that consumers have varying priorities for information in different cases. "Pesticide/veterinary use," "picking/slaughtering date," and "fertilizer/feed use" are the most preferred traceable information for Chinese consumers in the case of vegetables, while "picking/slaughtering date" and "history of illness and taking protective measures" are the most preferred information in the case of pork. In the case of dairy products, consumers prefer "processing information," "environmental information of the origin," and "traceable tag certification information" most. The results of this study call for the direct involvement of the Chinese government in the food safety information sharing system as following. First, given consumers' diverse preferences, different types of traceable information should be recorded into the information sharing platform depending on food types. Second, the government could promote the step-by-step construction of such a platform based on the priority of consumers' preferences. Third, new technology should be applied to guarantee the reliability of traceable information. Finally, local preferences in terms of the way consumers receive and understand information should be taken into consideration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206793PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214548PMC
April 2019

AWESOME: a database of SNPs that affect protein post-translational modifications.

Nucleic Acids Res 2019 01;47(D1):D874-D880

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, 430030, China.

Protein post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, acetylation, glycosylation et al, are very important biological processes. PTM changes in some critical genes, which may be induced by base-pair substitution, are shown to affect the risk of diseases. Recently, large-scale exome-wide association studies found that missense single nucleotide polymorphisms (SNPs) play an important role in the susceptibility for complex diseases or traits. One of the functional mechanisms of missense SNPs is that they may affect PTMs and leads to a protein dysfunction and its downstream signaling pathway disorder. Here, we constructed a database named AWESOME (A Website Exhibits SNP On Modification Event, http://www.awesome-hust.com), which is an interactive web-based analysis tool that systematically evaluates the role of SNPs on nearly all kinds of PTMs based on 20 available tools. We also provided a well-designed scoring system to compare the performance of different PTM prediction tools and help users to get a better interpretation of results. Users can search SNPs, genes or position of interest, filter with specific modifications or prediction methods, to get a comprehensive PTM change induced by SNPs. In summary, our database provides a convenient way to detect PTM-related SNPs, which may potentially be pathogenic factors or therapeutic targets.
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http://dx.doi.org/10.1093/nar/gky821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324025PMC
January 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

A Rare Variant P507L in TPP1 Interrupts TPP1-TIN2 Interaction, Influences Telomere Length, and Confers Colorectal Cancer Risk in Chinese Population.

Cancer Epidemiol Biomarkers Prev 2018 09 11;27(9):1029-1035. Epub 2018 Jun 11.

Department of Epidemiology and Biostatistics, and State Key Laboratory of Environment Health, MOE (Ministry of Education) Key Laboratory of Environment & 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, China.

Telomere dysfunction triggers cellular senescence and constitutes a driving force for cancer initiation. Genetic variants in genes involved in telomere maintenance may contribute to colorectal cancer susceptibility. In this study, we firstly captured germline mutations in 192 patients with colorectal cancer by sequencing the coding regions of 13 core components implicated in telomere biology. Five potential functional variants were then genotyped and assessed in a case-control set with 3,761 colorectal cancer cases and 3,839 healthy controls. The promising association was replicated in additional 6,765 cases and 6,906 controls. Functional experiments were used to further clarify the potential function of the significant variant and uncover the underlying mechanism in colorectal cancer development. The two-stage association studies showed that a rare missense variant rs149418249 (c.1520 and p.P507L) in the 11th exon of (also known as , gene ID 65057) was significantly associated with colorectal cancer risk with the ORs being 2.90 [95% confidence interval (CI), 1.04-8.07; = 0.041], 2.50 (95% CI, 1.04-6.04; = 0.042), and 2.66 (95% CI, 1.36-5.18; = 0.004) in discovery, replication, and the combined samples, respectively. Further functional annotation indicated that the TPP1 P507L substitution interrupted TPP1-TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted colorectal cancer development. A rare variant P507L in TPP1 confers increased risk of colorectal cancer through interrupting TPP1-TIN2 interaction, impairing telomerase processivity, and shrinking telomere length. These findings emphasize the important role of telomere dysfunction in colorectal cancer development, and provide new insights about the prevention of this type of cancer. .
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0099DOI 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 functional variant in GREM1 confers risk for colorectal cancer by disrupting a hsa-miR-185-3p binding site.

Oncotarget 2017 Sep 23;8(37):61318-61326. Epub 2017 May 23.

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

The transforming growth factor beta (TGF-β) pathway has been implicated in carcinogenesis of intestinal canal. Except for common variants indentified by genome-wide association studies, variants with lower frequency can also explain a part of the disease heritability, especially those in gene regulatory regions. In this study, we searched for colorectal cancer (CRC) related functional low-frequency variants (minor allele frequency 1-5%) in untranslated regions (UTR) involved in the TGF-β signaling using a next-generation sequencing based approach. A case-control study including 1,841 CRC cases and 1,837 controls was performed to identify CRC associated variants and biological experiments were applied to further explore the potential functions of the significant variants. Three low-frequency UTR variants were selected as our candidates and subsequent association analyses showed that a low-frequency variant rs12915554 in the 3' UTR of GREM1 was significantly associated with CRC risk (Additive model: OR=1.43, 95%CI: 1.04-1.95, =0.026). Functional annotations suggested that rs12915554 variation increased the expression of GREM1 by perturbing a hsa-miR-185-3p binding site. Moreover, higher expression level of GREM1 was investigated in colon tumor tissues compared with adjacent normal tissues using TCGA data. In conclusion, low-frequency UTR variant rs12915554 in the gene GREM1 was in relation to CRC susceptibility in a Chinese population and this variation might promote CRC development through enhancing GREM1 expression in a miRNA-mediated posttranscriptional manner.
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http://dx.doi.org/10.18632/oncotarget.18095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617425PMC
September 2017

The relationships between violence in childhood and educational outcomes: A global systematic review and meta-analysis.

Child Abuse Negl 2018 01 12;75:6-28. Epub 2017 Jul 12.

Moray House School of Education, Holyrood Road, University of Edinburgh, Edinburgh, Scotland, UK.

This is the first study to estimate the association globally between violence in childhood on educational outcomes, addressing a significant gap in the current evidence base. Systematic reviews and meta-analyses were conducted to identify 67 and 43 studies respectively from 21 countries to estimate the relationship between different types of violence in childhood on educational outcomes including school dropout/graduation, school absence, academic achievement and other educational outcomes such as grade retention, learning outcomes and remedial classes. Findings show that all forms of violence in childhood have a significant impact on educational outcomes. Children who have experienced any form of violence in childhood have a 13% predicted probability that they will not graduate from school. Males who are bullied are nearly three times more likely to be absent from school and girls who have experienced sexual violence have a three-fold increased risk of being absent, AOR 2.912, 95% CI (0.904-4.92) and AOR 3.147, 95% CI (0.033-4.57) respectively. Violence in childhood also has a significant impact on children's academic achievement on standardized tests. This study shows how different forms of violence in childhood contribute to inequalities in education-for both boys and girls and that an increased investment in prevention is needed in order to meet the global Sustainable Development Goals of ending violence, raising learning outcomes and creating safe, non-violent and inclusive learning environments. More work is also needed to further define, monitor and measure the link between violence in childhood and educational outcomes in order to achieve the Sustainable Development Goals.
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http://dx.doi.org/10.1016/j.chiabu.2017.06.021DOI Listing
January 2018

BRCA1 missense polymorphisms are associated with poor prognosis of pancreatic cancer patients in a Chinese population.

Oncotarget 2017 May;8(22):36033-36039

Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Pancreatic cancer is a highly lethal disease with limited prognostic marker. BRAC1 and BRCA2 are two classic tumor suppressor genes which play an important role in DNA repair. Somatic mutations and germline genetic variants on BRCA1/2 have been found associated with the tumorigenesis of pancreatic cancer. However, the correlations between BRCA1/2 polymorphism and pancreatic cancer prognosis remained unknown. In this study, we genotyped three tag missense variants on BRCA1/2 in 603 sporadic pancreatic cancer patients in a Chinese population. We found rs1799966 on BRCA1 was associated with poor prognosis of pancreatic cancer patients with hazard ratio being 1.23 (95% CI: 1.09-1.40, P = 0.0010). Further stratification analyses showed that significant correlation was particularly in locally advanced stage patients with hazard ratio being 1.36 (95% CI: 1.13-1.64, P = 0.0014), but not in patients in local stage (P = 0.1139) or metastatic stage (P = 0.5185). Two missense variants (rs766173 and rs144848) on BRAC2 showed no significant correlation with pancreatic cancer patients' overall survival. In conclusion, we identified a germline missense variant on BRAC1 significantly associated with poor prognosis of pancreatic cancer patients with locally advanced stage. These results may contribute to the precision medicine of this disease.
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http://dx.doi.org/10.18632/oncotarget.16422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482636PMC
May 2017

Breast cancer risk-associated variants at 6q25.1 influence risk of hepatocellular carcinoma in a Chinese population.

Carcinogenesis 2017 04;38(4):447-454

Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of estrogens in HCC pathogenesis. In this study, we conducted a case-control study to investigate whether breast cancer risk-associated single nucleotide polymorphisms (SNPs) located at estrogens loci identified by genome-wide association studies (GWASs) also predispose to HCC in a Chinese population. Three candidate SNPs at 6q25.1 were genotyped in 2025 HCC cases and 2032 healthy controls. Differential expression analyses and expression quantitative trait loci (eQTL) analyses were conducted to further explore the potential function of significant SNPs and genes they reside in. Two of the three candidate SNPs (rs9383951 and rs9485372) were observed to be significantly associated with HCC risk. Under a dominant model, the odds ratios (OR) for rs9383951 and rs9485372 were 1.28 (95% CI: 1.10-1.49, P = 0.002) and 1.34 (95% CI: 1.17-1.53, P = 2.75 × 10-5), respectively. We also found a significant accumulative effect of these two SNPs and there was a gradual increase in OR with a greater number of hazard genotypes. Moreover, the association between rs9383951 and HCC risk was specific in males. Lower ESR1 and TAB2 expressions were investigated in hepatic tumor tissues than adjacent normal tissues. We found a significant association between rs9383951 and ESR1 expression (P = 0.047). Besides, ESR1 expression was significantly correlated with the expression of TAB2. Taken together, our study identified two genetic variants at 6q25.1 newly associated with HCC risk, suggesting ESR1 and estrogen signaling may play a role in mediating susceptibility to HCC in Chinese population.
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http://dx.doi.org/10.1093/carcin/bgx024DOI Listing
April 2017

Identification of a functional polymorphism affecting microRNA binding in the susceptibility locus 1q25.3 for colorectal cancer.

Mol Carcinog 2017 09 30;56(9):2014-2021. Epub 2017 Mar 30.

State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment & Health (Ministry of Education), 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.

Genome-wide association studies (GWASs) have identified dozens of susceptibility loci for colorectal cancer (CRC). However, most of them lack functional genetic variants and clear biological mechanisms. MicroRNAs (miRNAs) are small noncoding RNAs involved in a variety of physiological and tumorigenic processes. Here we hypothesized that single nucleotide polymorphisms (SNPs) that affect miRNAs biogenesis and binding, could contribute to CRC risk in the Chinese population. To locate miRNA-related SNPs in established GWAS loci, we initially screened out five candidate SNPs using a systematic bioinformatics analysis. Then, we performed a two-stage case-control study consisting of 2347 cases and 3390 controls, and found a positive polymorphism rs1062044, which presented consistently significant associations with CRC in both stages, and with an odds ratio (OR) = 1.32 (95% confidence interval (95%CI) = 1.18-1.49, P = 3.43E-06) under the dominant model in the combined study. Further luciferase reporter gene assays indicated that the variant G allele obviously improved the specific binding between miR-423-5p and the gene LAMC1. These findings suggested that the functional SNP rs1062044 at 1q25.3 might be a genetic modifier for the occurrence and development of CRC.
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http://dx.doi.org/10.1002/mc.22649DOI Listing
September 2017

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
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