Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease

环境/遗传风险因素与自身免疫性疾病的发病机制

基本信息

项目摘要

Multidisciplinary studies - including clinical, immunologic, pathologic, epidemiologic and molecular genetic investigations - are being used to complement findings in each area and overcome limitations inherent in each approach. Current studies are focusing on: exploring possible environmental risk and protective factors; identifying genetic risk and protective factors by candidate gene and whole genome SNP analyses; defining the associations among clinical, laboratory and immunologic features of autoimmune diseases for diagnostic, prognostic and pathogenic purposes; and understanding differences in epigenetics, gene expression and proteomic patterns between monozygotic twins discordant for disease. Evaluation of exposures to silica, organic solvents, ultraviolet light, vaccinations, selected drugs and dietary supplements, hormones and pregnancy, tobacco smoke, stressful life events and infectious agents in the development of systemic autoimmune diseases are being conducted via a study of twins and close siblings discordant for systemic autoimmune disease. A group of poorly-understood, life-threatening autoimmune muscle diseases called the myositis syndromes or idiopathic inflammatory myopathies (IIM) are defined by chronic muscle inflammation and weakness and are associated with specific autoantibodies. The major forms of myositis are polymyositis, in which multiple muscles are affected by inflammation, and dermatomyositis, in which patients also develop skin inflammation. Yet there appear to be other types of myositis based on the clinical presentations, pathology and autoantibodies. We are studying both the adult (IIM) and juvenile (JIIM) forms of these diseases to understand possible differences in pathogenesis and risk factors. One area of investigation in which we have made recent advances involves identifying new genetic associations with juvenile and adult IIM. To accomplish this goal, we formed collaborations with many investigators around the world called the Myositis Genetic Consortium (MYOGEN). Using samples from MYOGEN, we performed a genome-wide association study (GWAS) of adult and juvenile myositis patients of European ancestry and controls. To identify genetic risk factors , we conducted GWAS of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis; 532 polymyositis, and 206 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P < 5 X 10-8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. We are continuing these investigations using Immunochip approaches and assessing additional phenotypes.
多学科研究——包括临床、免疫学、病理学、流行病学和分子遗传学研究——正在被用来补充每个领域的发现,并克服每种方法固有的局限性。目前的研究主要集中在:探索可能的环境风险和保护因素;通过候选基因和全基因组SNP分析识别遗传风险和保护因素;确定自身免疫性疾病的临床、实验室和免疫学特征之间的关系,以用于诊断、预后和致病目的;了解表观遗传学、基因表达和蛋白质组学模式在同卵双胞胎之间的差异。通过对患有系统性自身免疫性疾病的双胞胎和近亲兄弟姐妹进行的一项研究,正在评估暴露于二氧化硅、有机溶剂、紫外线、疫苗接种、选定药物和膳食补充剂、激素和妊娠、烟草烟雾、压力生活事件和感染因子在系统性自身免疫性疾病发展中的作用。

项目成果

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Frederick Miller其他文献

Frederick Miller的其他文献

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{{ truncateString('Frederick Miller', 18)}}的其他基金

Program in Clinical Research, Clinical Support Services and Clinical Training
临床研究、临床支持服务和临床培训项目
  • 批准号:
    8929844
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:
Assessment, Therapy and Prevention Of Autoimmune Disease
自身免疫性疾病的评估、治疗和预防
  • 批准号:
    10012666
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:
Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease
环境/遗传风险因素与自身免疫性疾病的发病机制
  • 批准号:
    8929773
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:
Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease
环境/遗传风险因素与自身免疫性疾病的发病机制
  • 批准号:
    8336614
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:
Assessment, Therapy and Prevention Of Autoimmune Disease
自身免疫性疾病的评估、治疗和预防
  • 批准号:
    7734522
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:
Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease
环境/遗传风险因素与自身免疫性疾病的发病机制
  • 批准号:
    10012665
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:
Program in Clinical Research, Clinical Support Services and Clinical Training
临床研究、临床支持服务和临床培训项目
  • 批准号:
    8554185
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:
Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease
环境/遗传风险因素与自身免疫性疾病的发病机制
  • 批准号:
    9550108
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:
Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease
环境/遗传风险因素与自身免疫性疾病的发病机制
  • 批准号:
    10252585
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:
Assessment, Therapy and Prevention Of Autoimmune Disease
自身免疫性疾病的评估、治疗和预防
  • 批准号:
    8336615
  • 财政年份:
  • 资助金额:
    $ 212.9万
  • 项目类别:

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