Autoimmune Conditions, Genetic Variations, and Lymphoma Etiology

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）是一种免疫细胞癌症，其发病率增加最多，但仍无法解释。免疫失调长期以来被认为是非霍奇金淋巴瘤病因学所必需的，但这种失调的性质仍然知之甚少。免疫失调的相反谱-免疫抑制和免疫激活-被认为是NHL的风险因素。临床和流行病学研究已经确定自身免疫性疾病作为NHL的危险因素。流行病学研究中最近的联合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，作为NHL的风险因素。我们假设，慢性炎症，导致自身免疫性疾病，和炎症引起的类型，可以通过遗传易感性基因座复合，以增加NHL的风险和影响NHL亚型或细胞谱系出现。本申请的总体目标是在国际淋巴瘤流行病学（InterLymph）联盟的参与研究中，评价遗传易感性基因座对NHL风险的贡献，以及自身免疫性疾病引起的慢性炎症对NHL风险的贡献，特别是B细胞NHL和弥漫性大B细胞淋巴瘤。在目标1中，我们将确定来自国际淋巴结联盟全基因组关联研究（GWAS）的已确认易感基因位点与自身免疫性疾病对NHL风险的联合关联。我们将对GWAS确认的基因座进行病例对照分析，这些基因座将在欧洲血统的8，188例病例和7，084例对照中获得。这一目标将告知确认的易感基因座是否与自身免疫性疾病一起改变NHL风险。没有相互作用的证据表明替代途径可能导致相同的疾病实体，这是一个重要的概念，有助于针对潜在疾病生物学的治疗干预。在目标2中，我们将进行一种仅病例的方法，以确定在自身免疫性疾病的背景下，在6,068例具有GWAS数据的NHL病例中与NHL相关的新基因变异。这一目标的基本原理是基于这样的假设，即存在遗传易感性基因座，其仅对慢性炎症和NHL风险产生影响， 适当的环境触发因素的存在。总之，我们建议通过进行生物驱动和严格应用互补统计方法来评估NHL中的基因-环境相互作用，以确定遗传易感性基因座是否与免疫状况一致或独立。

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.