CIP Genomics Core

CIP 基因组学核心

基本信息

批准号：
8938473
负责人：
Colm Ohuigin
金额：
$ 102.59万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8938473
关键词：
3&apos Untranslated Regions ATP-Binding Cassette Transporters Acquired Immunodeficiency Syndrome Alleles Area Autoimmune Diseases Autoimmunity Binding Binding Sites Bioinformatics Biological Assay CCR5 gene Case-Control Studies Castration Cells Cervix Neoplasms Childhood Chinese People Chromosomes, Human, Pair 7 Chronology Cohort Analysis Colon Carcinoma Communicable Diseases Copy Number Polymorphism Crohn&apos s disease Data Development Disease Embryo Epidemiology Event Evolution Exons Female Gagging Gelatinase B Gene Conversion Genes Genetic Genetic Polymorphism Genetic Programming Genomics Genotype Guatemala HIV HIV-1 HLA Antigens HLA-B Antigens HLA-C Antigens HLA-DPB1 gene Health Hepatitis B Virus Hepatitis C virus Heterogeneity High-Throughput Nucleotide Sequencing Human Human papillomavirus 16 Human papillomavirus 18 Hypermethylation Immune response Incidence Individual Infection Inflammation Integration Host Factors Ligands MHC Class II Genes MSMB gene Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of prostate Maps Mediating Methods Mexican Missense Mutation Mission Modeling Mus Mutation NCOA4 gene Neoplasm Metastasis Odds Ratio Outcome Pathway interactions Patients Peptides Phylogeny Play Population Predisposition Preparation Prostatic Neoplasms Pseudoxanthoma Elasticum RB1 gene Recovery Regulation Research Personnel Resistance Retinoblastoma Risk Risk Factors Role Sampling Sequence Analysis Severities Signal Transduction Site Somatic Mutation Specificity Testing Tissues Transcript Variant Viral Load result Virus Replication Woman Work Zebrafish cohort comparative exome exome sequencing genetic variant genome sequencing killer immunoglobulin-like receptor mouse model mutant novel premature atherosclerosis programs promoter receptor risk variant tapasin transmission process tumor

3&apos Untranslated Regions ATP-Binding Cassette Transporters Acquired Immunodeficiency Syndrome Alleles Area Autoimmune Diseases Autoimmunity Binding Binding Sites Bioinformatics Biological Assay CCR5 gene Case-Control Studies Castration Cells Cervix Neoplasms Childhood Chinese People Chromosomes, Human, Pair 7 Chronology Cohort Analysis Colon Carcinoma Communicable Diseases Copy Number Polymorphism Crohn&apos s disease Data Development Disease Embryo Epidemiology Event Evolution Exons Female Gagging Gelatinase B Gene Conversion Genes Genetic Genetic Polymorphism Genetic Programming Genomics Genotype Guatemala HIV HIV-1 HLA Antigens HLA-B Antigens HLA-C Antigens HLA-DPB1 gene Health Hepatitis B Virus Hepatitis C virus Heterogeneity High-Throughput Nucleotide Sequencing Human Human papillomavirus 16 Human papillomavirus 18 Hypermethylation Immune response Incidence Individual Infection Inflammation Integration Host Factors Ligands MHC Class II Genes MSMB gene Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of prostate Maps Mediating Methods Mexican Missense Mutation Mission Modeling Mus Mutation NCOA4 gene Neoplasm Metastasis Odds Ratio Outcome Pathway interactions Patients Peptides Phylogeny Play Population Predisposition Preparation Prostatic Neoplasms Pseudoxanthoma Elasticum RB1 gene Recovery Regulation Research Personnel Resistance Retinoblastoma Risk Risk Factors Role Sampling Sequence Analysis Severities Signal Transduction Site Somatic Mutation Specificity Testing Tissues Transcript Variant Viral Load result Virus Replication Woman Work Zebrafish cohort comparative exome exome sequencing genetic variant genome sequencing killer immunoglobulin-like receptor mouse model mutant novel premature atherosclerosis programs promoter receptor risk variant tapasin transmission process tumor

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项目摘要

The genetic epidemiological characterization of variants associated with HIV control was investigated using a variety of statistical approaches. The Genetic Core was responsible for part of the statistical analysis in a case-control study which, apart from CCR5 polymorphism, revealed little or no association of common genetic variants associated with HIV-1 acquisition. The Genetic Core statistical expertise was utilized in another large study, which determined that much of both protective and risk associations between HLA and HIV progression can be explained by the binding specificity conferred by polymorphisms at specific sites of HLA. The study of individual gene effects was also supported by the core epidemiological expertise. Much of the association between HLA-C variants and HIV viral load, could be shown to be attributable to differences in expression governed by miR148A binding to certain HLA-C alleles. The Genetic Core supported both the experimental and epidemiological work that underlie this finding. Additional uncharacterized differences give rise to a continuum of allelic lineage specific HLA-C expression levels. The work of the core was used to demonstrate that both infectious disease (HIV viral load) and autoimmunity (risk of Crohn's disease) can be associated with this continuum, treating HLA-C allelic effects as a continuous rather than a categorical variable. Both tapasin-dependent and independent folding is used by different HLA-B allotypes and the core could help show that the independent pathways associate with more rapid progression to multiple AIDS outcomes using statistical epidemiology. HLA class II genes appear less prominent in control of HIV. Nevertheless, DRB1*13:03 could be shown to associate with lower viral load in two independent populations. Furthermore DRB1 genes could be shown to exert effects on viral load through control of HIV replication mediated through peptide presentation primarily involving HIV Gag and Nef products. The Genetic Core was also involved in showing that polymorphisms of myelomonocytic cell HLA receptors (specifically LILRB2) have a role in the determination of HIV viral load through the strength of their interaction with HLA-B. The Genetic Core is quite active in the area of regulation of HLA-C expression. The HLA is central to immune responses and provides among the strongest epidemiological association signals in studies of both infectious and autoimmune diseases as well as for some cancers. The core participated in bioinformatic analyses of HLA-C sequences in Chinese populations, characterizing two new variants and showing that gene conversion is a rare event in the evolution of HLA-C with different regions of the gene showing congruent phylogenies. The core have also been prominent in showing that HLA-C expression (rather than binding repertoire) is an important determinant of HIV viral load and that a polymorphism of a miR148A binding site can control such expression. We were able to show that the miR binding site was originally present on all HLA-C alleles but that a rare gene conversion from HLA-B some 4 MYA generated a HLA-C allele without the binding site. The allele gave rise to half the lineages and 33% of extant HLA-C allele in a manner that independently recapitulated known functional HLA-C polymorphisms on a high expression background. Mir148A maps to chromosome 7 and is itself polymorphic, having high and low expression variants. It was possible to show that miR148A genotype influenced both autoimmune status (Crohn's disease) and infectious disease (HIV) severity in a manner indicative of action through HLA-C expression control. Since tight linkage to HLA-B generally confounds determination of HLA-C specific effects but HLA-B has no miR148A binding site, the miR148A influence are attributable to HLA-C specific disease effects. Staff of the Genetic Core played the leading role in characterizing a fusion transcript of MSMB (exons 1-2) with NCOA4 (exons 2-10). The fusion transcript is associated with MSMB promoter variants involved in increased risk of prostate cancer. Five metastatic castration-resistant prostate tumors as well as healthy tissue were exome sequenced to enabled comparison of shared and unique somatic mutations between tumors. The sequencing of the mutant genes in other metastatic tumors, allowed inference of the chronology of mutations. The core was particularly involved in characterizing the TET2 missense mutations. The heterogeneity in worldwide incidence of prostate cancer is considered as evidence of undiscovered risk factors. Exome and whole genome sequencing are argued to be methods by which the indeterminate risk factors may be identified (14). The core was involved in the characterization by sequence analysis of retinoblastomas in pediatric patients from Guatemala. Five of nine mutations described were novel and the core was responsible for sample preparation and for characterizing the hypermethylation of RB1 that was found to associate with development of the retinablastomas. A transmission disequilibrium test was used to identify risk alleles of KIR and HLA in familial trios of women with cervical cancer or neoplasia. Certain HLA-C alleles that act as ligands for KIR were found to increase risk, particularly for HPV16 or HPV18 subtype infections. The core undertook the statistical analysis for these findings. Three SNPs in the MMP-9 gene were found to associate with childhood athsma in a case-control study in a Mexican population. Two of the SNP had Odds-ratios 2.0 and one was found to associate with higher athsma risk in females. The Genetic Core was responsible for the sample preparation and SNP characterization. A novel variant of HLA-DPB1 3'UTR was found to significantly associate with HBV recovery in two populations. Analysis by the core demonstrated that the SNP distinguished high and low risk alleles and that risk itself is associated with higher allelic expression levels of DPB1. Mutations in the ATP-binding cassette transporter gene, ABCC6, cause Pseudoxanthoma elasticum (PXE) and premature atherosclerosis in humans. The zebrafish abcc6 genes was used to model knockdown using morpholinos. Knockdown of the abcc6a gene was found to be embryonic lethal, but could be rescued using a mouse ABCC6 transcript.

使用多种统计方法研究了与HIV控制相关的变体的遗传流行病学表征。在一项病例对照研究中，遗传核心是统计分析的一部分，除了CCR5多态性外，几乎没有或没有与HIV-1获取相关的常见遗传变异的关联。遗传核心统计专业知识是在另一项大型研究中使用的，该研究确定HLA和HIV进展之间的许多保护性和风险关联可以通过HLA特定部位的多态性赋予的结合特异性来解释。核心流行病学专业知识也支持了单个基因效应的研究。 HLA-C变体与HIV病毒载量之间的大部分关联可以证明归因于由miR148a与某些HLA-C等位基因结合的表达差异。遗传核心支持这一发现的基础的实验和流行病学工作。其他未表征的差异导致等位基因谱系特定的HLA-C表达水平的连续体。核心的工作用于证明传染病（HIV病毒负荷）和自身免疫性（克罗恩病的风险）都可以与此连续体有关，从而将HLA-C等位基因效应视为连续的，而不是分类变量。不同HLA-B同种型都使用了帕替蛋白依赖性和独立的折叠，并且核心可以帮助表明，独立途径使用统计流行病学促进了更快地与多种辅助结果相关联。 HLA II类基因在HIV控制中似乎不太明显。然而，DRB1*13：03可以证明在两个独立人群中与较低的病毒载荷相关。此外，DRB1基因可以证明通过控制通过肽表现介导的HIV GAG和NEF产物介导的HIV复制来对病毒负荷发挥影响。遗传核还参与表明脊髓细胞细胞HLA受体的多态性（特别是LILRB2）通过与HLA-B的相互作用的强度在测定HIV病毒载量中起作用。遗传核心在HLA-C表达的调节领域非常活跃。 HLA是免疫反应的核心，在对感染和自身免疫性疾病以及某些癌症的研究中提供了最强的流行病学关联信号之一。核心参与了中国人群中HLA-C序列的生物信息学分析，表征了两种新变体，并表明基因转化是HLA-C的进化中的罕见事件，其基因的不同区域显示出一致的系统发育。核心在表明HLA-C表达（而不是结合曲目）是HIV病毒载量的重要决定因素，并且MiR148A结合位点的多态性可以控制这种表达。我们能够证明MIR结合位点最初存在于所有HLA-C等位基因上，但是HLA-B的罕见基因转化约4 mya产生了HLA-C等位基因，而没有结合位点。等位基因产生了一半的谱系，而现存的HLA-C等位基因的33％则以高表达背景下独立概括的已知功能HLA-C多态性的方式产生了一半。 miR148a映射到7染色体，其本身是多态性的，具有高表达变体。可以证明MIR148A基因型以通过HLA-C表达控制来表明作用的方式影响了自身免疫状态（克罗恩病）和传染病（HIV）严重程度。由于与HLA-B的紧密连接通常会混淆HLA-C特异性效应的测定，但HLA-B没有MIR148A结合位点，因此MIR148A的影响归因于HLA-C特异性疾病效应。遗传核心的工作人员在表征MSMB（外显子1-2）与NCOA4（外显子2-10）的融合转录方面发挥了领先作用。融合转录本与MSMB启动子变体有关，涉及增加前列腺癌风险。五个转移性cast割的前列腺肿瘤以及健康的组织被测序，可以比较肿瘤之间共享和独特的体细胞突变。突变基因在其他转移性肿瘤中的测序允许突变的年代学。核心特别参与表征TET2错义突变。前列腺癌发生率的异质性被认为是未被发现的危险因素的证据。外显子和整个基因组测序被认为是可以鉴定出不确定风险因素的方法（14）。核心通过对危地马拉小儿患者的视网膜细胞瘤的序列分析进行了表征。描述的九个突变中有五个是新颖的，核心负责样品制备和表征RB1的高甲基化，这被发现与视网膜腔的发展相关。使用传播不平衡测试来鉴定宫颈癌或肿瘤妇女家族三重点的KIR和HLA风险等位基因。发现某些充当KIR配体的HLA-C等位基因会增加风险，特别是对于HPV16或HPV18亚型感染。核心对这些发现进行了统计分析。在墨西哥人群中，发现MMP-9基因中的三个SNP与童年Athsma相关。其中两个SNP的赔率比例为2.0，发现女性的ATHSMA风险更高。遗传核心负责样品制备和SNP表征。发现HLA-DPB1 3'UTR的一种新型变体与两个人群中的HBV恢复显着相关。核心的分析表明，SNP区分了高风险等位基因，并且风险本身与DPB1的等位基因表达水平较高有关。 ABCC6的ATP结合磁带转运蛋白基因中的突变导致人类的假氧质瘤（PXE）和早产动脉粥样硬化。斑马鱼ABCC6基因用于使用形态学模拟敲低。发现ABCC6A基因的敲低是胚胎致死的，但可以使用小鼠ABCC6转录本进行营救。