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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

批准号：
7734521
负责人：
Frederick Miller
金额：
$ 136.9万
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
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/7734521
关键词：
14q32.33 2p12 3-Dimensional Acanthosis Nigricans Adolescent Adult Affect African American Age Air Alleles American Amino Acid Sequence Animal Model Area Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Binding Biopsy Calcinosis Candidate Disease Gene Cause of Death Child Childhood Chromosomes Chronic Classification Clinical Collaborations Complement Complex Complication Data Date of birth Dermatomyositis Development Diagnostic Disease Disease Association Dust Environmental Exposure Environmental Risk Factor Epigenetic Process Estrogens Ethnic Origin European Evaluation Event Exposure to Familial generalized lipodystrophy Family Fatty acid glycerol esters Food Frequencies Gene Expression Genes Genetic Genetic Polymorphism Genetic Risk Genome Genotype Goals HLA-A Antigens HLA-A gene HLA-A2 Antigen Haplotypes Herpesvirus Type 3 Hirsutism Histone Deacetylase Hormones Hypertriglyceridemia Immune Immune Response Genes Immune response Immunoglobulin Genes Immunologics Individual Infectious Agent Inflammation Inflammatory Insulin Resistance Interleukin-1 alpha International Investigation Laboratories Lead Learning Life Light Lipoatrophy Lipodystrophy Mi-2 antibodies Molecular Molecular Genetics Monozygotic Twinning Monozygotic twins Morbidity - disease rate Muscle Myopathy Myositis Nucleosomes Occupational Exposure Onset of illness Organic solvent product Outcome Panniculitis Pathogenesis Pathologic Pathology Patients Pattern Peptides Pharmaceutical Preparations Phenotype Play Polymyositis Population Population Study Pregnancy Prevalence Proteomics Purpose Rate Recurrence Relative (related person)Rheumatoid Arthritis Risk Risk Factors Role Scleroderma Severities Severity of illness Siblings Signal Recognition Particle Silicon Dioxide Skin Smoking Subcutaneous Tissue Subgroup Syndrome Systemic Lupus Erythematosus Therapeutic Threonine-tRNA Ligase Tobacco smoke Tumor Necrosis Factor-alpha Twin Studies Ultraviolet Rays United States Vaccination Water Woman base cohort comparative concept cytokine dietary supplements disease phenotype environmental agent forest gamma-Chain Immunoglobulins gene environment interaction genetic analysis genetic risk factor genome wide association study helicase interest member metabolic abnormality assessment mortality multidisciplinary nonalcoholic steatohepatitis novel prognostic subcutaneous

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 are defined by chronic muscle inflammation and weakness and 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. Our worldwide studies suggested that ultraviolet radiation exposure may modulate the clinical and immunologic expression of myositis in different populations and studies in the United States this year demonstrated similar findings. Ultraviolet radiation exposure strongly correlated with the prevalence of dermatomyositis and the associated anti-Mi-2 autoantibodies directed against a 220 KD member of the SNF2/RAD54 helicase family, which is a major component of the nucleosome remodeling and histone deacetylase (NuRD) complex. Studies in collaboration with Trevor Archer are ongoing to understand the molecular effects of ultraviolet radiation and estrogen on the expression and function of the Mi-2 target autoantigen. We are also assessing the pathogenesis of certain disease features that result in poor clinical outcomes. For example, inflammation of subcutaneous tissue, called panniculitis, and the loss of fat in the subcutaneous tissue, called lipodystrophy, are major problems for some patients with myositis, especially children. To understand possible risk factors for their development, we performed extensive clinical, laboratory and genetic assessments on subjects with these disorders. Panniculitis was associated with focal lipoatrophy, while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more commonly associated with generalized lipodystrophy. Features such as acanthosis nigricans, hirsutism, fat redistribution, and steatosis/nonalcoholic steatohepatitis were frequent in patients with lipodystrophy, in a gradient of frequency and severity among the sub-phenotypes of disease. Metabolic studies revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial lipodystrophy. We conclude that lipodystrophy is an under-recognized complication of juvenile dermatomyositis, and certain patients with a severe, prolonged clinical course and a high frequency of subcutaneous calcinosis appear to be at greater risk for the development of this problem. Regarding our genetic studies, we have defined new genetic risk and protective factors for myositis in African Americans and children. Previously, molecular genetic analyses of HLA-A, B, Cw, DRB1, and DQA1 polymorphisms were assessed in a large population of African American patients with myositis. We showed that in contrast to European American patients with polymyositis, African American patients with polymyositis had no strong disease associations with HLA alleles of the 8.1 ancestral haplotype. Additionally, we detected novel HLA risk factors in African American patients producing anti-signal recognition particle (DQA1*0102) and anti-Mi-2 autoantibodies (DRB1*0302). Of interest, the African American HLA risk factor for anti-Mi-2 autoantibodies, DRB1*0302, and the European American anti-Mi-2-associated risk factor, DRB1*0701, were found to share a 4-amino-acid sequence motif, which was predicted by comparative homology analyses to have identical 3-dimensional orientations within the peptide-binding groove. This year we extended these studies to polymorphic determinants of genes encoding regions of immunoglobulin gamma heavy and kappa light chains (GM and KM loci on chromosomes 14q32.33 and 2p12, respectively), which have been associated with different immune responses in a variety of infectious and autoimmune diseases. In European American dermatomyositis patients the GM 3 23 5,13 phenotype was a risk factor for both adults and children. The GM 13 allotype, however, was a risk factor for juvenile dermatomyositis for both European Americans and African Americans. Among the myositis autoantibody groups, GM 3 23 5,13 was a risk factor for adults with anti-Jo-1 autoantibodies, while the GM 3 allotype was protective for adults with anti-threonyl-tRNA synthetase or anti-RNP autoantibodies. In contrast, GM 6 was a risk factor for African American adults with autoantibodies to the signal recognition particle. Because cytokines appear to play important role in the pathogenesis of inflammatory myopathies, and the expressions of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF) and interleukin 1alpha (IL-1)are increased in muscle biopsies from myositis patients, we investigated polymorphisms in these genes as possible risk and severity factors for childhood myositis. We found that the genotypes TNF -308AG, TNF -238GG, and IL-1+4845TT were risk factors, and TNF -308GG as well as TNF -238AG were protective for the development of juvenile dermatomyositis. Random Forests classification analysis showed HLA DRB1*03 and TNF -308A to have highest relative importance as risk factors for myositis in children compared to the other alleles. Also, TNF -308AA was a risk factor, and carriage of the TNF-308G and IL1-889T alleles were protective for the development of calcinosis. Thus, TNF and IL-1 genetic polymorphisms contribute to the development of juvenile myositis and may also be indicators of disease severity. These data, taken together, suggest that polymorphic alleles of MHC genes, pro-inflammatory cytokines, as well as the GM and KM loci for immunoglobulin genes, are differentially associated with myositis subgroups defined by age, ethnicity, clinical features and autoantibodies, and expand the list of immune response genes possibly important in the pathogenesis of myositis. Explanations for these findings require additional investigations into the molecular mechanisms of how these genes regulate immune responses, and which environmental agents may be triggering them. Our findings, obtained from the largest cohort of patients with myositis studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms as a result of different gene-environment interactions. Genetic investigations are now focusing on genome-wide association studies in myositis, which will be facilitated by the International Myositis Genetic Consortium (MYOGEN) that we have formed to define additional genetic risk and protective factors in adults and children with these incurable and life-threatening diseases.

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

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Is occupational exposure to mineral oil a risk factor for rheumatoid arthritis?

职业接触矿物油是类风湿性关节炎的危险因素吗？

DOI：
10.1038/ncprheum0137
发表时间：
2006
期刊：
Nature clinical practice. Rheumatology
影响因子：
0
作者：
Miller,FrederickW
通讯作者：
Miller,FrederickW

Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders.

DOI：
10.1002/art.38137
发表时间：
2013-12
期刊：
ARTHRITIS AND RHEUMATISM
影响因子：
0
作者：
Miller, Frederick W.;Cooper, Robert G.;Vencovsky, Jiri;Rider, Lisa G.;Danko, Katalin;Wedderburn, Lucy R.;Lundberg, Ingrid E.;Pachman, Lauren M.;Reed, Ann M.;Ytterberg, Steven R.;Padyukov, Leonid;Selva-O'Callaghan, Albert;Radstake, Timothy R. D. J.;Isenberg, David A.;Chinoy, Hector;Ollier, William E. R.;O'Hanlon, Terrance P.;Peng, Bo;Lee, Annette;Lamb, Janine A.;Chen, Wei;Amos, Christopher I.;Gregersen, Peter K.
通讯作者：
Gregersen, Peter K.

Validation of the Childhood Health Assessment Questionnaire in the juvenile idiopathic myopathies. Juvenile Dermatomyositis Disease Activity Collaborative Study Group.

青少年特发性肌病儿童健康评估问卷的验证。

DOI：
发表时间：
2001
期刊：
The Journal of rheumatology
影响因子：
0
作者：
Huber,AM;Hicks,JE;Lachenbruch,PA;Perez,MD;Zemel,LS;Rennebohm,RM;Wallace,CA;Lindsley,CB;Passo,MH;Ballinger,SH;Bowyer,SL;Reed,AM;White,PH;Katona,IM;Miller,FW;Rider,LG;Feldman,BM;JuvenileDermatomyositisDis
通讯作者：
JuvenileDermatomyositisDis

HLA-DQA1 is not an apparent risk factor for microchimerism in patients with various autoimmune diseases and in healthy individuals.

HLA-DQA1 并不是各种自身免疫性疾病患者和健康个体中微嵌合现象的明显危险因素。

DOI：
10.1002/art.11235
发表时间：
2003
期刊：
Arthritis and rheumatism
影响因子：
0
作者：
Artlett,CarolM;O'Hanlon,TerrenceP;Lopez,AnaM;Song,YeongWook;Miller,FrederickW;Rider,LisaG
通讯作者：
Rider,LisaG

Prevalence and sociodemographic correlates of antinuclear antibodies in the United States.

DOI：
10.1002/art.34380
发表时间：
2012-07
期刊：
ARTHRITIS AND RHEUMATISM
影响因子：
0
作者：
Satoh, Minoru;Chan, Edward K. L.;Ho, Lindsey A.;Rose, Kathryn M.;Parks, Christine G.;Cohn, Richard D.;Jusko, Todd A.;Walker, Nigel J.;Germolec, Dori R.;Whitt, Irene Z.;Crockett, Patrick W.;Pauley, Brad A.;Chan, Jason Y. F.;Ross, Steven J.;Birnbaum, Linda S.;Zeldin, Darryl C.;Miller, Frederick W.
通讯作者：
Miller, Frederick W.