Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 201
Filtrar
1.
Gene ; 767: 145287, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33181258

RESUMO

BACKGROUND: Chronic respiratory diseases have become a non-negligible cause of death globally. Although smoking and environmental exposures are primary risk factors for chronic respiratory diseases, genetic factors also play an important role in determining individual's susceptibility to diseases. Here we performed integrated gene-based and pathway analyses to systematically illuminate the heritable characteristics of chronic respiratory diseases. METHODS: UK (United Kingdom) Biobank is a very large, population-based prospective study with over 500,000 participants, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases. Utilizing the GWAS-summarized data downloaded from UK Biobank, we conducted gene-based analysis to obtain associations of susceptibility genes with asthma, chronic obstructive pulmonary disease(COPD) and pneumonia using FUSION and MAGMA software. Across the identified susceptibility regions, functional annotation integrating multiple functional data sources was performed to explore potential regulatory mechanisms with INQUISIT algorithm. To further detect the biological process involved in the development of chronic respiratory diseases, we undertook pathway enrichment analysis with the R package (clusterProfiler). RESULTS: A total of 195 susceptibility genes were identified significantly associated with chronic respiratory diseases (Pbonferroni < 0.05), and 24/195 located out of known susceptibility regions (e.g. WDPCP in 2p15). Within the identified susceptibility regions, functional annotation revealed an aggregation of credible variants in promoter-like and enhancer-like histone modification regions and such regulatory mechanisms were specific to lung tissues. Furthermore, 110 genes with INQUISIT score ≥1 may influence diseases susceptibility through exerting effects on coding sequences, proximal promoter and distal enhancer regulations. Pathway enrichment results showed that these genes were enriched in immune-related processes and nicotinic acetylcholine receptors pathways. CONCLUSIONS: This study implemented an integrated gene-based and pathway strategy to explore the underlying biological mechanisms and our findings may serve as promising targets for future clinical treatments of chronic respiratory diseases.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Transtornos Respiratórios/genética , Asma/genética , Bancos de Espécimes Biológicos , Doença Crônica/epidemiologia , Bases de Dados Genéticas , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Reino Unido
2.
Artigo em Inglês | MEDLINE | ID: mdl-33203726

RESUMO

INTRODUCTION: Both environmental and genetic factors contribute to type 2 diabetes (T2D) risk. Dozens of T2D susceptibility loci have been identified by genome-wide association study. However, these loci account for only a small fraction of the familial T2D risk. We hypothesized that the gene-obesity interaction may contribute to the missing heritability. RESEARCH DESIGN AND METHOD: Forty-eight T2D-associated variants were genotyped using the TaqMan OpenArray Genotyping System and iPLEX Sequenom MassARRAY platform in two separate studies. Obesity was defined according to multiple indexes (body mass index (BMI), waist circumference and waist-hip ratio). Multiplicative interactions were tested using general logistic regression to assess the gene-obesity interaction effect on T2D risk among a total of 6206 Chinese Hans. RESULTS: After adjusting for the main effects of genes and obesity, as well as covariates (age, sex, smoking and alcohol consumption status), robust multiplicative interaction effects were observed between rs10811661 in CDKN2A/CDKN2B and multiple obesity indices (p ranged from 0.001 to 0.043 for BMI, waist circumference and waist-hip ratio). Obese individuals with the TT genotype had a drastically higher risk of T2D than normal weight individuals without the risk allele (OR=17.58, p<0.001). There were no significant differences between subgroups in the stratification analysis. Plausible biological explanations were established using a public database. However, there were no significant interaction effects between the other 47 single nucleotide polymorphism (SNPs) and obesity. CONCLUSION: Our findings indicated that the CDKN2A/CDKN2B gene-obesity interaction significantly increases T2D risk in Chinese Hans. The interaction effect identified in our study may help to explain some of the missing heritability in the context of T2D susceptibility. In addition, the interaction effect may play a role in the precise prevention of T2D in Chinese individuals.

3.
Theranostics ; 10(24): 11264-11277, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042282

RESUMO

Rationale: As the transcriptional products of active enhancers, enhancer RNAs (eRNAs) are essential for the initiation of tumorigenesis. However, the landscape and functional characteristics of eRNAs in Chinese lung adenocarcinoma, and the clinical utility of eRNA-based molecular subtypes remain largely unknown. Methods: A genome-wide profiling of eRNAs was performed in 80 Chinese lung adenocarcinoma patients with RNA-seq data. Functional eRNAs and associated genes were identified between paired adenocarcinoma and adjacent samples. Unsupervised clustering of functional eRNAs was conducted and the associations with molecular characteristics and clinical outcomes were accessed by integrating whole-genome sequencing data and clinical data. Additionally, 481 lung adenocarcinoma patients were used for the validation based on The Cancer Genome Atlas (TCGA) dataset. Results: A total of 3297 eRNAs with sufficient expression were identified, which were globally upregulated in adenocarcinoma samples compared to matched-adjacent pairs (P = 7.61×10-3). Further analyses indicated that these upregulated eRNAs were correlated with copy number amplification (CNA) status (Cor = 0.22, P = 0.045), and eRNA-correlated genes were primarily involved in cell cycle and immune system-related pathways. Based on the co-expression analysis of eRNAs with protein-coding genes, we defined 188 functional eRNAs and their correlated genes were overrepresented in cancer driver genes (ER = 1.98, P = 5.95×10-12) and clinically-actionable genes (ER = 2.19, P = 3.44×10-4). The eRNA-based consensus clustering further identified a novel molecular subtype with immune deficiency and a high-level of genomic alterations, which was associated with poor clinical outcomes of lung adenocarcinoma patients (OS: HR = 1.91, P = 0.015; PFI: HR = 1.64, P = 0.034). Conclusions: The genome-wide identification and characterization of eRNAs reveal novel regulators for the development of lung cancer, which provides a new biological dimension for the understanding of eRNAs during lung carcinogenesis and emphasize the clinical utility of eRNA-based molecular subtypes in the treatment of lung adenocarcinoma.

4.
J Biomol Struct Dyn ; : 1-11, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33030111

RESUMO

Hepatitis B virus (HBV) infection is an important problem threatening human health. After HBV virus invades human body, it may assemble a complete virus particle in the cytoplasm to trigger the immune reaction, especially the interaction between the HBV virus and the host that mediated by CD8+ T cell. We collected the sequences of HBV from the HBVdb database, then screened candidate mutation sites in Chinese, European and American populations based on conservation and physicochemical properties. After that we constructed the three-dimensional structure of Major histocompatibility complex class I (MHC I) -peptide complexes, performed molecular docking, run molecular dynamics to compare the binding free energy, stability, and affinity of MHC I-peptide complexes with the aim to estimate the effect of peptide mutation. The specific HBV virus subtypes of the Chinese, European and American population were studied and the candidate mutation sites were used to predict the mutant peptide antigen. Finally, based on physical and chemical properties and peptide antigen prediction scores, 21 HBV mutation sites were selected. Then combined with specific Human lymphocyte antigen (HLA) subtypes, 11 mutations were found to have a significant negative impact on affinity, stability and binding free energy. Overall, our work found important potential mutations, which provide an evaluation of HBV mutations and a clue of it in immunotherapy. Communicated by Ramaswamy H. Sarma.

5.
Lancet Oncol ; 21(10): 1378-1386, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002439

RESUMO

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.


Assuntos
Predisposição Genética para Doença/genética , Estilo de Vida Saudável , Neoplasias Gástricas/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/psicologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/psicologia
6.
Biomed Res Int ; 2020: 6739823, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879886

RESUMO

BRCA1 and BRCA2 as important DNA repair genes have been thoroughly investigated in abundant studies. The potential relationships of BRCA1/2 pathogenic variants between multicancers have been verified in Caucasians but few in Chinese. In this study, we performed a two-stage study to screen BRCA1/2 pathogenic variants or variants of uncertain significance (VUS) with 7580 cancer cases and 4874 cancer-free controls, consisting of a discovery stage with 70 familial breast cancer cases and a subsequent validation stage with 7510 cases (3217 breast cancer, 1133 cervical cancer, 2044 hepatocellular carcinoma, and 1116 colorectal cancer). 48 variants were obtained from 70 familial breast cancer cases after BRCA1/2 exon detection, and finally, 20 pathogenic variants or VUS were selected for subsequent validation. Four recurrent variants in sporadic cases (BRCA1 c.4801A>T, BRCA1 c.3257del, BRCA1 c.440del, and BRCA2 c.7409dup) were identified and three of them were labeled Class 5 by ENIGMA. Two variants (BRCA1 c.3257del and c.440del) were specific in breast cancer cases, while BRCA2 c.7409dup and c.4307T>C were detected in two hepatocellular carcinoma patients and the BRCA1 c.4801A>T variant in one cervical cancer patient, respectively. Moreover, BRCA1 c.3257del was the most frequent variant observed in Chinese sporadic breast cancer and showed increased proliferation of BRCA1 c.3257del-overexpressing triple-negative breast cancer cell lines (MDA-MB-231) in vitro. In addition to the known founder deleterious mutations, our findings highlight that the recurrently pathogenic variants in breast cancer cases could be taken as candidate genetic screening loci for a more efficient genetic screening of the Chinese population.

7.
Front Med ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32889700

RESUMO

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

9.
Liver Int ; 40(9): 2117-2127, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32574393

RESUMO

BACKGROUND & AIMS: Previous genome-wide association studies (GWAS) have identified multiple susceptible variants associated with persistent hepatitis B virus (HBV) infection. However, most of these variants are located in the noncoding regions, which make it difficult to determine the effective genes underlying these associations. We performed a two-stage study, in the first stage we integrated RNA sequencing data of liver tissues and high-density genotyping data from the Genotype-Tissue Expression (GTEx) project with our previous GWAS data to conduct a transcriptome-wide association study (TWAS) on HBV infection. Firstly, the cis-heritable genes were screened by a genetic relatedness matrix of genome-wide complex trait analysis (GCTA) from GTEx data. Then, the genetic expression of 2587 cis-heritable genes was predicted by restricted maximum likelihood (REML) of genome-wide efficient mixed-model association (GEMMA) in our GWAS data with 951 HBV carrier cases and 937 HBV cleared controls. Next, we investigated the associations between predictive expression levels and persistent HBV infection risk. Gene set enrichment analysis (GSEA) was applied to infer the function of the identified genes. To identify the causal single nucleotide polymorphisms (SNPs) of HBV infection risk, we conducted the expression quantitative trait loci (eQTL)-based stepwise logistic regression analysis in the regions around 1 Mb of these genes and validated the association between 994 health controls and 994 HBV-persistent infection cases by genotyping experiment. In the second stage, 1538 HBV-related hepatocellular carcinoma (HCC) cases and 1465 persistent HBV infection controls were collected to determine the effect of these variants on HBV-related HCC as well, which were examined by the additive model in logistic regression analysis. We identified seven genes associated with HBV infection. In the classic human leukocyte antigen (HLA) region, three novel genes BAK1, HLA-DOB and C4A (Z range from -3.95 to -3.64, P range from 7.84 × 10-5 to 2.00 × 10-4 ), as well as two genes (HLA-DPA1 and HLA-DPB1) were reported by previous GWAS. In the non-HLA region, immune related at newly identified loci, PARP9 (Z = 3.69, P = 2.20 × 10-4 ) at 3q21.1. At 22q11.21, we identified TMEM191A (Z = 3.55, P = 3.80 × 10-4 ) as a target gene in addition to the reported non-cis-heritable gene UBE2L3. After further stepwise logistic regression analysis and validation, we identified eight variants independently associated with persistent HBV infection. Among those variants, the additive model showed that two SNPs associated with HBV-related HCC risk (rs9272714 and rs9394194, OR range from 1.20 to 1.25, P range from 1.19 × 10-4 to 3.97 × 10-4 ). By integrating transcriptome data, our study not only identified new susceptibility loci of persistent HBV infection but also determined the potential target genes at reported loci, which provided insight into the genetic aetiology of persistent HBV infection and related HCC.

10.
J Biomed Res ; 34(2): 129-138, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32305967

RESUMO

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that currently lacks effective biomarkers and therapeutic targets required to investigate the diagnosis and treatment of TNBC. Here we performed a comprehensive differential analysis of 165 TNBC samples by integrating RNA-seq data of breast tumor tissues and adjacent normal tissues from both our cohort and The Cancer Genome Atlas (TCGA). Pathway enrichment analysis was conducted to evaluate the biological function of TNBC-specific expressed genes. Further multivariate Cox proportional hazard regression was performed to evaluate the effect of these genes on TNBC prognosis. In this report, we identified a total of 148 TNBC-specific expressed genes that were primarily enriched in mammary gland morphogenesis and hormone levels related pathways, suggesting that mammary gland morphogenesis might play a unique role in TNBC patients differing from other breast cancer types. Further survival analysis revealed that nine genes ( FSIP1, ADCY5, FSD1, HMSD, CMTM5, AFF3, CYP2A7, ATP1A2, and C11orf86) were significantly associated with the prognosis of TNBC patients, while three of them ( ADCY5, CYP2A7, and ATP1A2) were involved in the hormone-related pathways. These findings indicated the vital role of the hormone-related genes in TNBC tumorigenesis and may provide some independent prognostic markers as well as novel therapeutic targets for TNBC.

11.
Biomed Res Int ; 2020: 8781348, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32309442

RESUMO

MicroRNAs (miRNAs) of the miR-30 family are closely linked with tumor metastasis and play key roles in the complex malignant phenotypes of cancers by targeting many tumor-related genes. Deregulated expression of miR-30 family members has been commonly observed in breast cancer. However, associations between the genetic variants in the regulatory region of miR-30 family and the risk of breast cancer are still limited, especially in the Chinese Han population. In the present study, we conducted a case-control analysis wherein 1064 breast cancer patients and 1073 healthy controls underwent genotyping of 10 SNPs in the regulatory region of miR-30 family members. Multivariate logistic regression analyses illustrated that the rs763354 variant in the miR-30a regulatory region was linked with a significant decrease in breast cancer risk in an additive model (adjusted OR = 0.86, 95% CI: 0.75-0.98, P = 0.022). Further, eQTL analyses also indicated that this SNP was associated with miR-30a expression levels in breast cancer samples compiled in the TCGA database (P = 0.020). The Kaplan-Meier plotter showed that breast cancer patients with higher miR-30a expression have significantly better outcomes than do patients expressing low levels of this miRNA (HR = 0.75, 95% CI: 0.61-0.91, P = 0.0041). Together, these findings suggest that the miR-30a rs763354 SNP is an important regulator of breast cancer risk, thus making it a potentially viable prognostic biomarker and one that can be used to guide therapeutic treatment in affected patients.

12.
Cancer Epidemiol Biomarkers Prev ; 29(7): 1423-1429, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32277007

RESUMO

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. RESULTS: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3). CONCLUSIONS: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. IMPACT: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.

13.
Gene ; 740: 144570, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32165298

RESUMO

Recent studies have found multiple single nucleotide variants (SNVs) associated with DNA damage. However, previous association analysis may ignore the potential interaction effects between SNVs. Therefore, we used an improved random forest (RF) analysis to identify the SNVs related to personal DNA damage in exon-focused genome-wide association study (GWAS). A total of 301 subjects from three independent centers (Zhuhai, Wuhan, and Tianjin) were retained for analysis. An improved RF procedure was used to systematically screen key SNVs associated with DNA damage. Furthermore, we used genetic risk score (GRS) and mediation analysis to investigate the integrative effect and potential mechanism of these genetic variants on DNA damage. Besides, gene set enrichment analysis was conducted to identify the pathways enriched by key SNVs using the Data-driven Expression Prioritized Integration for Complex Traits (DEPICT). Finally, a set of 24 SNVs with the lowest mean square errors (MSE) were identified by improved RF analysis. Both weighted and unweighted GRSs were associated with increased DNA damage levels (Pweight < 0.001 and Punweight < 0.001). Gene set enrichment analysis indicated that these loci were significantly enriched in several biological features associated with DNA damage. These findings suggested the role of SNVs in modifying DNA damage levels. It may be convincing that this improved RF analysis can effectively identify SNVs associated with DNA damage levels.


Assuntos
Dano ao DNA , Material Particulado/toxicidade , China , Dano ao DNA/genética , Dano ao DNA/fisiologia , Interpretação Estatística de Dados , Humanos , Material Particulado/sangue , Material Particulado/metabolismo , Polimorfismo de Nucleotídeo Único
14.
Gene ; 741: 144555, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32165302

RESUMO

Tetralogy of Fallot (TOF) is one of most serious cyanotic congenital heart disease (CHD) and the prevalence is estimated to be 1 in 3000 live births worldwide. Though multiple studies have found genetic variants as risk factors for TOF, they could only explain a small fraction of the pathogenesis. Here, we performed whole genome sequencing (WGS) for 6 individuals derived from 2 families to evaluate pathogenic mutations located in both coding and noncoding regions. We characterized the annotated deleterious coding mutations and impaired noncoding mutations in regulatory elements by various data analysis. Additionally, functional assays were conducted to validate function regulatory elements and noncoding mutations. Interestingly, a compound heterozygous pattern with pathogenic coding and noncoding mutations was identified in probands. In proband 1, biallelic mutations (g.139409115A > T, encoding p.Asn685Ile; g.139444949C > A) in NOTCH1 exon and its regulatory element were detected. In vitro experiments revealed that the regulatory element acted as a silencer and the noncoding mutation decreased the expression of NOTCH1. In proband 2, we also found compound heterozygous mutations (g. 216235029C > T, encoding p.Val2281Met; g. 216525154A > C) which potentially regulated the function of FN1 gene. In summary, our study firstly reported an instance of newly identified noncoding mutation in regulatory element within the compound heterozygous pattern in TOF. The results provided a deeper understanding of TOF genetic architectures.


Assuntos
Éxons/genética , Fases de Leitura Aberta/genética , Tetralogia de Fallot/genética , Sequenciamento Completo do Genoma , Feminino , Heterozigoto , Humanos , Masculino , Mutação/genética , Linhagem , Tetralogia de Fallot/patologia
15.
J Cancer ; 11(5): 1075-1081, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31956354

RESUMO

Genome-wide association studies (GWAS) have reported 45 single-nucleotide polymorphisms (SNPs) that may contribute to the susceptibility of lung cancer, with the majority in non-coding regions. However, no study has ever systematically evaluated the association between SNPs in physical chromatin interaction regions and lung cancer risk. In this study, we integrated the chromatin interaction information (Hi-C data) of lung cancer cell line and conducted a meta-analysis with two Asian GWASs (7,127 cases and 6,818 controls) to evaluate the association of potentially functional SNPs in chromatin interaction regions with lung cancer risk. We identified four novel lung cancer susceptibility loci located at 1q21.1 (rs17160062, P=4.00×10-6), 2p23.3 (rs670343, P=4.87×10-7), 2p15 (rs9309336, P=3.24×10-6) and 17q21.2 (rs9252, P=1.51×10-5) that were significantly associated with lung cancer risk after correction for multiple tests. Functional annotation result indicated that these SNPs may contribute to the development of lung cancer by affecting the availability of transcription factor binding sites. The HaploReg analysis suggested that rs9309336 may affect binding motif of transcription factor Foxp1. Expression quantitative trait loci analysis revealed that rs9309336 and rs17160062 could regulate the expressions of cancer-related genes (PUS10 and CHD1L). Our results revealed that variants in chromatin interaction regions could contribute to the development of lung cancer by regulating the expression of target genes, which providing novel implications for the understanding of functional variants in the development of lung cancer.

16.
Gut ; 69(4): 641-651, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31383772

RESUMO

OBJECTIVE: Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development. DESIGN: We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies. RESULTS: The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10- 8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10- 9) and 4q28.1 (OR=1.14, p=3.33×10- 11) were associated with GC risk. CONCLUSION: We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Neoplasias Gástricas/genética , China , Estudo de Associação Genômica Ampla , Humanos
17.
Bioinformatics ; 36(5): 1382-1390, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593214

RESUMO

MOTIVATION: Reliable identification of expressed somatic insertions/deletions (indels) is an unmet need due to artifacts generated in PCR-based RNA-Seq library preparation and the lack of normal RNA-Seq data, presenting analytical challenges for discovery of somatic indels in tumor transcriptome. RESULTS: We present RNAIndel, a tool for predicting somatic, germline and artifact indels from tumor RNA-Seq data. RNAIndel leverages features derived from indel sequence context and biological effect in a machine-learning framework. Except for tumor samples with microsatellite instability, RNAIndel robustly predicts 88-100% of somatic indels in five diverse test datasets of pediatric and adult cancers, even recovering subclonal (VAF range 0.01-0.15) driver indels missed by targeted deep-sequencing, outperforming the current best-practice for RNA-Seq variant calling which had 57% sensitivity but with 14 times more false positives. AVAILABILITY AND IMPLEMENTATION: RNAIndel is freely available at https://github.com/stjude/RNAIndel. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Neoplasias/genética , RNA-Seq , Criança , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Software , Sequenciamento Completo do Exoma
18.
Int J Cancer ; 146(10): 2855-2864, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31577861

RESUMO

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.


Assuntos
Predisposição Genética para Doença/genética , Mutação INDEL/genética , Neoplasias Pulmonares/genética , Estudo de Associação Genômica Ampla , Humanos
19.
Clin Gastroenterol Hepatol ; 18(12): 2701-2709.e3, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31756444

RESUMO

BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. RESULTS: Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. CONCLUSIONS: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.

20.
Cancer Epidemiol Biomarkers Prev ; 29(2): 487-492, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31748259

RESUMO

BACKGROUND: The association of plasma homocysteine level (PHL) with gastric cancer risk was reported in observational studies. However, the causality is challenging due to confounding factors and the lack of evidence from well-designed cohort studies. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate whether PHL is causally related to gastric cancer risk. METHODS: We performed the MR analysis based on the results from genome-wide association studies consisting of 2,631 patients with gastric cancer and 4,373 controls. An externally weighted genetic risk score (wGRS) was constructed with 15 SNPs with well-established associations with PHL. We utilized logistic regression model to estimate associations of PHL-related SNPs and wGRS with gastric cancer risk in total population and in strata by sex, age, and study site, in addition to a series of sensitivity analyses. RESULTS: High genetically predicted PHL was associated with an increased gastric cancer risk (per SD increase in the wGRS: OR = 1.07; 95% confidence interval, 1.01-1.12; P = 0.011), which was consistent in sensitivity analyses. Subgroup analyses provided evidence of a stronger association with gastric cancer risk in women than in men. MR-Egger and weighted median regression suggested that potentially unknown pleiotropic effects were not biasing the association between PHL and gastric cancer risk. CONCLUSIONS: These results revealed that genetically predicted high PHL was associated with an increased gastric cancer risk, suggesting that high PHL may have a causal role in the etiology of gastric cancer. IMPACT: These findings provide causal inference for PHL on gastric cancer risk, suggesting a causal role of high PHL in the etiology of gastric cancer.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA