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
• 负责人: Frederick Miller
• 金额: $ 189.12万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 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/9550108
• 关键词: Adolescent; Adult; Affect; Air; Alleles; American; Animal Model; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Candidate Disease Gene; Caucasians; Cause of Death; Chronic; Clinical; Collaborations; Complement; Complex; Data; Date of birth; Dermatomyositis; Development; Diagnostic; Disease; Dust; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epigenetic Process; Estrogens; European; Evaluation; Event; Exposure to; Flare; Food; Gene Expression; Genes; Genetic; Genetic Risk; Geography; Goals; HLA Antigens; Haplotypes; Herpesvirus Type 3; Histidine-tRNA Ligase; Hormones; Idiopathic Inflammatory Myopathies; Immune; Immunologics; Individual; Infectious Agent; Inflammation; Investigation; Laboratories; Lead; Life; Major Histocompatibility Complex; Molecular Genetics; Monozygotic twins; Morbidity - disease rate; Muscle; Myopathy; Myositis; Occupational Exposure; Onset of illness; Organic solvent product; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Play; Polymyositis; Population; Pregnancy; Prevalence; Prevention strategy; Proteomics; Recurrence; Regression Analysis; Research Personnel; Rheumatoid Arthritis; Risk; Risk Factors; Role; Sampling; Scleroderma; Siblings; Silicon Dioxide; Single Nucleotide Polymorphism; Skin; Smoking; Subgroup; Syndrome; Systemic Lupus Erythematosus; Therapeutic; Tobacco smoke; Twin Studies; Ultraviolet Rays; Vaccination; Water; Xenobiotics; base; dietary supplements; environmental agent; genetic association; genetic risk factor; genome wide association study; immune activation; mortality; multidisciplinary; novel; prognostic; systemic autoimmune disease; whole genome; young woman

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 and sequencing 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 and other xenobiotics, 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. We are also assessing environmental agents associated with disease flares. 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 adult dermatomyositis, juvenile dermatomyositis; polymyositis, and adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 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. Other studies have found that genes associated with other autoimmune diseases are also seen in myositis phenotypes. We are continuing these investigations using Immunochip and other 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调查-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和测序分析确定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联，以用于诊断、预后和致病目的;并了解疾病不一致的同卵双胞胎之间表观遗传学、基因表达和蛋白质组模式的差异。通过对双胞胎和与系统性自身免疫性疾病不一致的近亲兄弟姐妹的研究，正在评估接触二氧化硅、有机溶剂和其他外源性物质、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、压力性生活事件和传染性病原体在系统性自身免疫性疾病发展中的作用。 我们还在评估与疾病爆发有关的环境因素。 一组被称为肌炎综合征或特发性炎性肌病（IIM）的、知之甚少的、危及生命的自身免疫性肌肉疾病被定义为慢性肌肉炎症和无力，并且与特异性自身抗体相关。肌炎的主要形式是多发性肌炎，其中多个肌肉受到炎症的影响，以及皮肌炎，其中患者也发生皮肤炎症。然而，似乎有其他类型的肌炎的基础上的临床表现，病理和自身抗体。我们正在研究这些疾病的成人（IIM）和青少年（JIM）形式，以了解发病机制和风险因素的可能差异。 我们最近取得进展的一个调查领域涉及识别与青少年和成人IIM的新遗传关联。为了实现这一目标，我们与世界各地的许多研究人员合作，称为肌炎遗传联盟（MYOGEN）。使用来自MYOGEN的样本，我们对欧洲血统的成人和青少年肌炎患者和对照组进行了全基因组关联研究（GWAS）。为了确定遗传风险因素，我们对成人皮肌炎、青少年皮肌炎、多发性肌炎和成人皮肌炎、青少年皮肌炎或多发性肌炎患者中主要肌炎表型进行了GWAS，并将其与对照组进行了比较。对于所有肌炎表型以及分别研究的四种临床和自身抗体表型，在主要组织相容性复合体（MHC）区域中发现了在GWAS中显示出强相关性（P < 5 X 10-8）的单核苷酸多态性。插补和回归分析发现，等位基因包括人类白细胞抗原（HLA）8.1祖先单倍型（AH8.1）定义基本上所有的遗传风险的表型研究。尽管HLA DRB 1 *03：01等位基因与成人和青少年皮肌炎的相关性略强，HLA B*08：01与多发性肌炎和抗Jo-1自身抗体阳性肌炎的相关性略强，但AH8.1的多个等位基因需要完全的风险效应。我们的研究结果表明，AH8.1的等位基因构成了地理上不同的高加索人群中与主要肌炎表型相关的主要遗传危险因素。 其他研究发现，与其他自身免疫性疾病相关的基因也见于肌炎表型。我们正在继续使用免疫芯片和其他方法进行这些研究，并评估其他表型。