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
• 负责人: Frederick Miller
• 金额: $ 181.13万
• 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/8929773
• 关键词: Adolescent; Adult; Adult Dermatomyositis; Affect; Air; American; Animal Model; Area; Arthralgia; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Blood capillaries; CCL21 gene; Candidate Disease Gene; Carpal Tunnel Syndrome; Cause of Death; Characteristics; Chronic; Classification; Clinical; Collaborations; Complement; Complex; Creatine Kinase; Data; Date of birth; Dermatomyositis; Development; Diagnostic; Disease; Dust; Enrollment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epigenetic Process; Estrogens; European; Evaluation; Event; Exanthema; Exposure to; Food; Frequencies; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genome; Genotype; Goals; Hand; Heart Diseases; Herpesvirus Type 3; Hormones; Hospitalization; Idiopathic Inflammatory Myopathies; Immune; Immunologics; Individual; Infectious Agent; Inflammation; Interstitial Lung Diseases; Investigation; Laboratories; Lead; Learning; Life; Ligands; Link; Logistic Regressions; Lymphoid; Major Histocompatibility Complex; Measures; Mechanics; Mi-2 antibodies; Modeling; Molecular Genetics; Monozygotic Twinning; Monozygotic twins; Morbidity - disease rate; Muscle; Myopathy; Myositis; Natural History; Occupational Exposure; Onset of illness; Organic solvent product; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phospholipase C; Play; Polymyositis; Population; Pregnancy; Prevalence; Protein Tyrosine Kinase; Proteomics; Publishing; Raynaud Phenomenon; Recurrence; Registries; Reporting; Research Personnel; Rheumatoid Arthritis; Risk Factors; Role; Sampling; Scleroderma; Siblings; Signal Recognition Particle; Signal Transduction; Silicon Dioxide; Single Nucleotide Polymorphism; Skin; Smoking; Subgroup; Syndrome; Systemic Lupus Erythematosus; Therapeutic; Tobacco smoke; Twin Studies; Ultraviolet Rays; Vaccination; Water; Wheelchairs; base; beta-Chemokines; capillary; demographics; dietary supplements; environmental agent; falls; forest; genetic association; genetic risk factor; genome wide association study; immune activation; mortality; multidisciplinary; novel; novel diagnostics; novel therapeutic intervention; prognostic; risk variant; systemic autoimmune disease; 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 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. We enrolled 436 patients with JIIM, including 354 classified as JDM, 33 as JPM, and 49 as JCTM, in a nationwide registry study. The aim of the study was to compare demographics; clinical features; laboratory measures, including myositis autoantibodies; and outcomes among these clinical subgroups, as well as with published data on adult patients with idiopathic inflammatory myopathies (IIM) enrolled in a separate natural history study. We used random forest classification and logistic regression modeling to compare clinical subgroups, following univariate analysis. JDM was characterized by typical rashes, including Gottrons papules, heliotrope rash, malar rash, periungual capillary changes, and other photosensitive and vasculopathic skin rashes. JPM was characterized by more severe weakness, higher creatine kinase levels, falling episodes, and more frequent cardiac disease. JCTM had more frequent interstitial lung disease, Raynaud phenomenon, arthralgia, and malar rash. Differences in autoantibody frequency were also evident, with anti-p155/140, anti-MJ, and anti-Mi-2 seen more frequently in patients with JDM, anti-signal recognition particle and anti-Jo-1 in JPM, and anti-U1-RNP, PM-Scl, and other myositis-associated autoantibodies more commonly present in JCTM. Mortality was highest in patients with JCTM, whereas hospitalizations and wheelchair use were highest in JPM patients. Several demographic and clinical features were shared between juvenile and adult IIM subgroups. However, JDM and JPM patients had a lower frequency of interstitial lung disease, Raynaud phenomenon, "mechanic's hands" and carpal tunnel syndrome, and lower mortality than their adult counterparts. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct clinical subgroups, defined by varying clinical and demographic characteristics, laboratory features, and outcomes. To identify new genetic associations with juvenile and adult dermatomyositis (DM), 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 DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

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，用于诊断，预后和致病目的;以及了解单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，正在评估暴露于二氧化硅、有机溶剂、紫外线、疫苗接种、选定的药物和膳食补充剂、激素和妊娠、烟草烟雾、压力性生活事件和感染因子在系统性自身免疫性疾病发展中的作用。 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。 在一项全国性的登记研究中，我们招募了436例JIIM患者，包括354例JDM，33例JPM和49例JCTM。该研究的目的是比较人口统计学;临床特征;实验室指标，包括肌炎自身抗体;和这些临床亚组之间的结果，以及在一项单独的自然史研究中登记的特发性炎性肌病（IIM）成人患者的已发表数据。我们使用随机森林分类和逻辑回归模型比较临床亚组，单变量分析。JDM的特征是典型的皮疹，包括Gottrons丘疹、日光性皮疹、颧骨皮疹、甲周毛细血管改变以及其他光敏性和血管性皮疹。JPM的特征是更严重的虚弱，更高的肌酸激酶水平，下降的发作，更频繁的心脏病。JCTM更常见间质性肺病、雷诺现象、关节痛和颧骨皮疹。自身抗体频率的差异也很明显，抗p155/140、抗MJ和抗Mi-2在JDM患者中更常见，抗信号识别颗粒和抗Jo-1在JPM中更常见，抗U1-RNP、PM-Scl和其他肌炎相关自身抗体在JCTM中更常见。JCTM患者的死亡率最高，而JPM患者的住院率和轮椅使用率最高。青少年和成人IIM亚组之间有一些共同的人口统计学和临床特征。然而，JDM和JPM患者的间质性肺病、雷诺现象、“机械手”和腕管综合征的发生率较低，死亡率也低于成年患者。我们的结论是，青少年肌炎是一组异质性疾病，不同的临床亚组，定义不同的临床和人口统计学特征，实验室特征和结果。 为了确定与青少年和成人皮肌炎（DM）的新的遗传关联，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DM患者（n = 1，178）和对照组（n = 4，724）进行了全基因组关联研究（GWAS）。为了评估与其他自身免疫性疾病的遗传重叠，我们研究了主要组织相容性复合体（MHC）基因座外的141个单核苷酸多态性（SNP）是否与自身免疫性疾病相关，易患DM。与对照组相比，DM患者在MHC区域有一个强信号，在80个基因型SNP上具有GWAS水平的显著性（P < 5 10（-8））。对先前与自身免疫性疾病相关的141个非MHC SNPs的分析显示，与3个基因连锁的3个SNPs与DM相关，错误发现率（FDR）<0.05。这些基因是磷脂酶C样1（PLCL 1; rs6738825，FDR = 0.00089）、B淋巴酪氨酸激酶（BLK; rs 2736340，FDR = 0.0031）和趋化因子（C-C基序）配体21（CCL 21; rs 951005，FDR = 0.0076）。这些基因中没有一个先前被报道与DM相关。我们的研究结果证实了MHC是与DM相关的主要遗传区域，并表明DM与其他自身免疫性疾病具有非MHC遗传特征，表明存在其他新的风险位点。这一首次发现的自身免疫性疾病遗传易感性与糖尿病共享，可能会导致增强了解的发病机制和新的诊断和治疗方法。