Insights Into Immune-Related Diseases Born from Population Genomics

对群体基因组学产生的免疫相关疾病的见解

• 批准号: 10656300
• 负责人: Paul John Norman
• 金额: $ 72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656300
• 关键词: Acceleration; Affect; African American; African ancestry; Algorithms; Alleles; Allergic Disease; American; Amerindian; Antibody Formation; Asthma; Atopic Dermatitis; Autoimmune; Autoimmune Diseases; Bioinformatics; Cell physiology; Cell-Mediated Cytolysis; Cells; Cessation of life; Child; Chromosome 19; Chromosome 6; Chronic; Communicable Diseases; Complex; Country; DNA; Data; Development; Disease; Disease Resistance; Disparate; Disparity; Education; European; Exhibits; Extrinsic asthma; Family; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomic Segment; Genomics; Genotype; Goals; Graph; HLA Antigens; Haplotypes; Health; Heterozygote; High Prevalence; Hispanic; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Homozygote; Human; Human Genome; Hypersensitivity; IgE; Immune; Immune response; Immunity; Immunoglobulins; Immunologics; Incidence; Individual; Infection; Inflammatory; Intervention; Killer Cells; Knowledge; Link; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Measures; Mediating; Medical; Methodology; Methods; Natural Immunity; Natural Killer Cells; Nature; Outcome; Pathway interactions; Patients; Population; Population Group; Predisposition; Pregnancy; Prevalence; Production; Prognosis; Property; Proteins; Receptor Cell; Reproduction; Resolution; Respiratory physiology; Role; Serum; Severities; Signal Transduction; Specificity; Structure; Study Subject; Syndrome; T-Lymphocyte; Testing; Transplantation; Variant; Work; adaptive immunity; allergic response; arm; bioinformatics pipeline; causal variant; chronic inflammatory lung disease; cohort; combinatorial; cost effective; cost estimate; design; flexibility; genome-wide; hematopoietic cell transplantation; insight; novel; pathogen; pressure; receptor; reproductive success; response; targeted sequencing; tool; user-friendly

The major histocompatibility complex (MHC) of chromosome 6 and the killer cell immunoglobulin-like receptor (KIR) region of chromosome 19 are among the most variable and medically important regions of the human genome. The MHC encodes the highly polymorphic human leukocyte antigens (HLA) that are central to immunity and reproduction, and another 140 genes, many with supporting roles in immunity. A subset of HLA allotypes interact with KIR, which are expressed by Natural Killer (NK) cells, modulating their activities in initiating and controlling the immune response. Specific alleles as well as compound genotypes of MHC and KIR have been implicated in susceptibility or resistance to infectious, allergic, inflammatory, and autoimmune diseases, as well as to outcomes of hematopoietic cell transplantation and reproductive success. Asthma is one of the most common inflammatory diseases affecting over 30 million Americans, with 5,000 deaths per year. Atopic dermatitis (AD) occurs in 20% of children and predisposes to asthma. Together they pose significant burden on the health and economy of the country, costing an estimated $82 billion per year. Common to these diseases are a strong genetic component, an environmental or infection trigger, and complex interplay between innate and adaptive immunity. Accordingly, there are long standing associations with MHC diversity and asthma susceptibility, which have been confirmed by recent large scale genome studies, but they remain poorly refined due to the complexity and difficulty of sequencing the region. For the same reasons, the KIR region has never been studied to high resolution in AD or asthma. To overcome difficulties in analyzing these complex genomic regions, we developed a targeted sequencing and bioinformatics approach to analyze MHC and KIR regions at high throughput and resolution. In Aim 1 we will use the methods to analyze the complete MHC genomic regions from 5,000 patients and 5,000 controls, investigating each gene as well as their pathways of interaction. We will study well defined cohorts of individuals from diverse backgrounds, focusing on African ancestry, which associates with the highest prevalence and poorest outcome. We will sequence the entire MHC with high accuracy to determine the full context of any variants associated with asthma susceptibility. In Aim 2 we will perform the first high resolution analysis of NK cell diversity in asthma, supported by directed functional analyses of the activity and specificity of NK cells in disease. By combining high- resolution analysis of KIR and HLA genes with known functional properties of these interactions, we will be able to determine the role of NK cell diversity in asthma. To enhance our methodology and solve the most difficult genomic structural variation, in Aim 3 we will design and implement the first methods to target long-read sequencing specifically to the MHC and KIR regions, and a bioinformatics pipeline to annotate and analyze the data. In doing so we will expand the MHC reference set and tools for large-scale analysis. Through these three Aims we will accelerate understanding of the natural immunity of atopic asthma and begin to identify novel targets for intervention

6号染色体的主要组织相容性复合体（MHC）和杀伤细胞免疫球蛋白样受体

项目成果

Estimating HLA haplotype frequencies from homozygous individuals - A Technical Report.

• DOI: 10.1111/iji.12553
• 发表时间: 2021-12
• 期刊: International journal of immunogenetics
• 影响因子: 2.2

High-Resolution Characterization of KIR Genes in a Large North American Cohort Reveals Novel Details of Structural and Sequence Diversity.

大型北美队列中 KIR 基因的高分辨率表征揭示了结构和序列多样性的新细节。

• DOI: 10.3389/fimmu.2021.674778
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Amorim LM;Augusto DG;Nemat-Gorgani N;Montero-Martin G;Marin WM;Shams H;Dandekar R;Caillier S;Parham P;Fernández-Viña MA;Oksenberg JR;Norman PJ;Hollenbach JA
• 通讯作者: Hollenbach JA

Behçet disease, new insights in disease associations and manifestations: a next-generation sequencing study.

白塞病，疾病关联和表现的新见解：下一代测序研究。

• DOI: 10.1111/cei.13571
• 发表时间: 2021
• 期刊: Clinical and experimental immunology
• 影响因子: 4.6
• 作者: Elfishawi,M;Mossallam,G;Augusto,DG;Montero-Martin,G;deBruin,H;VandePasch,L;Norman,PJ;Rozemuller,E;Fernandez-Vina,M;Abrudescu,A;Hollenbach,JA;Zaky,K;Elfishawi,S
• 通讯作者: Elfishawi,S

Deciphering the killer-cell immunoglobulin-like receptor system at super-resolution for natural killer and T-cell biology.

• DOI: 10.1111/imm.12684
• 发表时间: 2017-03
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Béziat V;Hilton HG;Norman PJ;Traherne JA
• 通讯作者: Traherne JA

Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop.

第 17 届国际 HLA 和免疫遗传学研讨会杀伤细胞免疫球蛋白样受体 (KIR) 部分的报告。

• DOI: 10.1016/j.humimm.2018.10.003
• 发表时间: 2018
• 期刊: Human immunology
• 影响因子: 2.7
• 作者: Misra,ManeeshK;Augusto,DanilloG;Martin,GonzaloMontero;Nemat-Gorgani,Neda;Sauter,Jürgen;Hofmann,JanA;Traherne,JamesA;González-Quezada,Betsy;Gorodezky,Clara;Bultitude,WillP;Marin,Wesley;Vierra-Green,Cynthia;Anderson,KirstenM