Autoimmune Conditions, Genetic Variations, and Lymphoma Etiology

自身免疫性疾病、遗传变异和淋巴瘤病因学

• 批准号: 8704140
• 负责人: Sophia S Wang
• 金额: $ 8.4万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-02 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704140
• 关键词: 6p21.3; Affect; Alleles; Antigen Presentation; Autoimmune Diseases; Autoimmune Process; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Binding; Biology; Case-Control Studies; Cell Lineage; Cells; Chromosomes; Chronic; Cleaved cell; Clinical Research; Data; Disease; Epidemiologic Studies; Epidemiology; Etiology; European; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; HLA Antigens; Haplotypes; Health; Histocompatibility Antigens Class II; Immune; Immune response; Immunosuppression; Incidence; Individual; Infection; Inflammation; Inflammatory; International; Joints; Laboratories; Lead; Light; Lymphoma; Lymphomagenesis; MHC Class II Genes; Major Histocompatibility Complex; Malignant Neoplasms; Modeling; Nature; Non-Hodgkin' s Lymphoma; Pathway interactions; Peptides; Predisposition; Prevention; Research; Risk; Risk Factors; Scanning; Therapeutic Intervention; Tumor Necrosis Factor-alpha; Variant; Woman; autoreactivity; base; case control; cytokine; cytotoxic; design; experience; gene environment interaction; genetic variant; genome wide association study; human leukocyte antigen gene; immune activation; insight; large cell Diffuse non-Hodgkin' s lymphoma; men; promoter; tumor

DESCRIPTION (provided by applicant): There are few established risk factors for non-Hodgkin lymphoma (NHL), a cancer of immune cells which has experienced one of the largest - and still unexplained - increases in incidence. Immune dysregulation has long been recognized as necessary for non-Hodgkin lymphoma etiology, but the nature of that dysregulation is still poorly understood. Opposite spectrums of immune dysregulation - immune suppression and immune activation - are implicated as NHL risk factors. Clinical and epidemiologic studies have established autoimmune disorders collectively as a risk factor for NHL. More recent consortial efforts among epidemiologic studies have further identified specific immune gene variations, including the tumor necrosis factor (TNF) and human leukocyte antigen (HLA) Class I and Class II genes, as NHL risk factors. We hypothesize that the chronic inflammation that results from autoimmune conditions, and the type of inflammation elicited, can be compounded by genetic susceptibility loci to increase NHL risk and influence which NHL subtype or cell lineage emerges. The overall objective of this application is to evaluate the contributions of genetic susceptibility loci to NHL risk jointly with chronic inflammation from autoimmune conditions on risk of NHL - and particularly B-cell NHLs and diffuse large B-cell lymphoma - among participating studies in the International Lymphoma Epidemiology (InterLymph) Consortium. In Aim 1, we will determine the joint associations of confirmed susceptibility loci from the InterLymph Consortium genome-wide association study (GWAS) and autoimmune conditions on risk of NHL. We will conduct a case-control analysis of GWAS- confirmed loci, which will be available on 8,188 cases and 7,084 controls of European ancestry. This aim will inform whether confirmed susceptibility loci act in concert with autoimmune conditions to alter NHL risk. No evidence of an interaction would suggest that alternative pathways might lead to the same disease entity, an important concept that would aid in therapeutic interventions aimed at the underlying disease biology. In Aim 2, we will conduct a case-only approach to identify new gene variants associated with NHL, in the context of autoimmune conditions, among the 6,068 NHL cases with GWAS data. The rationale for this aim is based on the hypothesis that there are genetic susceptibility loci that exert their influence on chronic inflammation and NHL risk only in the presence of the appropriate environmental trigger. In summary, we propose to determine whether genetic susceptibility loci act in concert with or independent from immune conditions by conducting a biologically-driven and rigorous application of complementary statistical approaches for assessing gene- environment interaction in NHL.

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）几乎没有既定的危险因素，这是一种免疫细胞癌，它经历了最大（但仍无法解释）的发病率之一。长期以来，免疫失调一直被认为是非霍奇金淋巴瘤病因所必需的，但是该失调的性质仍然很少了解。免疫失调 - 免疫抑制和免疫激活的相对光谱被视为NHL风险因素。临床和流行病学研究已将自身免疫性疾病统称为NHL的危险因素。流行病学研究之间的最新联盟努力进一步确定了特定的免疫基因变异，包括肿瘤坏死因子（TNF）和人类白细胞抗原（HLA）I类和II类基因，是NHL风险因素。我们假设，由于自身免疫性条件以及引起的炎症类型引起的慢性炎症，遗传易感性基因座可以增加NHL的风险和影响，而NHL亚型或细胞谱系出现了。该应用的总体目的是评估遗传易感性基因座对NHL风险的贡献，与自身免疫性条件的慢性炎症共同评估NHL风险（尤其是B细胞NHLS的风险）以及国际淋巴瘤流行病学（Interlymph）的参与研究中。在AIM 1中，我们将确定来自Interlymph全联盟全联盟协会研究（GWAS）和自身免疫性条件的NHL风险的确认易感基因座的联合关联。我们将对GWAS确认的基因座进行案例对照分析，该分析将在8,188例病例和7,084个对欧洲血统的控制下可用。该目标将告知确认的易感基因座法案是否与自身免疫性条件一起改变NHL风险。没有任何相互作用的证据表明，替代途径可能会导致相同的疾病实体，这是一个重要的概念，有助于采用针对潜在疾病生物学的治疗干预措施。在AIM 2中，我们将在具有GWAS数据的6,068例NHL病例中，在自身免疫性条件下，在自身免疫性条件下识别与NHL相关的新基因变体。该目标的理由是基于以下假设：遗传易感性基因座对慢性炎症和NHL风险发挥影响 适当的环境触发器的存在。总而言之，我们建议确定遗传敏感性基因座是通过对互补统计方法进行生物学驱动和严格应用来评估NHL中基因环境相互作用的互补统计方法来与免疫条件共同起作用。