Immune/Inflammation Genomics and the Risk of SLE and CHD

描述(申请人提供)：系统性红斑狼疮(SLE)是一种典型的全身性炎症性自身免疫性疾病，主要影响年轻的绝经前妇女。系统性红斑狼疮女性患冠心病的风险是普通人群的50倍。传统的危险因素不足以解释SLE患者的早发冠心病。这表明，SLE患者有一些独特的地方，使他们面临着极高的冠心病风险。炎症和免疫因素可能在此病因中起重要作用。系统性红斑狼疮是一种复杂的多因素疾病，可能涉及多种遗传和环境因素。家族性风险估计在20-40之间，遗传率高达66%，这证明了遗传因素在SLE病因中的强烈参与。免疫和炎症反应参与SLE病因的强有力的生物学证据，以及SLE具有强大的遗传学基础的证据，为研究参与免疫/炎症通路的基因变异在SLE和SLE中的CHD风险中的作用提供了强有力的理论基础。在这一应用中，我们打算检验这一假设，即参与免疫/炎症途径的基因的遗传变异以及它们之间的相互作用与SLE风险和CHD风险都有关。我们将使用Affymetrix免疫和炎症9K SNP试剂盒，该试剂盒包含约1,000个基因中的约9,200个SNP，包括基于HapMap的标签SNP(频率和>5%)和另外773个已验证的非同义SNP。在确定了重要的SNPs后，我们将在相关基因/区域中筛选更多的SNPs，以定位可能的功能变异。作为这些分析的结果，我们应该能够同时确定大量生物相关的免疫/炎症基因的共同变异在SLE风险和CHD风险中的作用。公共卫生相关性：这项研究的目标是使用Affymetrix GeneChip人类免疫和炎症9K SNP小组对参与免疫和炎症途径的大约1,000个基因中的约9,200个单核苷酸多态(SNPs)与系统性红斑狼疮(SLE)和冠心病(CHD)风险进行关联分析。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is the prototypic systemic inflammatory autoimmune disease that affects predominantly younger premenopausal women. The risk of coronary heart disease (CHD) in SLE women is up to 50 times higher than in the general population. The conventional risk factors are insufficient to explain premature CHD in SLE patients. This indicates that there is something unique about SLE patients that render them at extremely high risk for CHD. It is likely that inflammatory and immune factors play an important role in this etiology. SLE is a complex and multifactorial disease with the possible involvement of several genetic and environmental factors. The strong involvement of genetic factors in the etiology of SLE is evidenced by familial risk estimates of between 20-40 and heritability of up to 66%. The strong biological evidence of the involvement of immune and inflammatory responses in the etiology of SLE couple with the evidence that SLE has a strong genetic basis provide strong rationale to examine the role of genetic variation in genes involved in immune/inflammation pathways in relation to SLE and the risk of CHD in SLE. In this application we intend to test the hypothesis that genetic variation in genes involved in immune/inflammation pathways and interactions among them are associated with both SLE risk and CHD risk in SLE. We will use the Affymetrix Immune and Inflammatory 9K SNP kit that contains about 9,200 SNPs in approximately 1,000 genes, including HapMap-based tagSNPs (frequency >5%) and additional 773 validated non-synonymous SNPs. After identifying significant SNPs, we will screen additional SNPs in relevant genes/ regions in order to locate putative functional variants. As a result of these analyses, we should be able to determine simultaneously the role of common variation in a large number of biologically relevant immune/inflammation genes that contribute to SLE risk and CHD risk in SLE. PUBLIC HEALTH RELEVANCE: The objective of this study is to perform an association analysis of about 9,200 single nucleotide polymorphisms (SNPs) in approximately 1,000 genes involved in immune and inflammatory pathways in relation to the risk of systemic lupus erythematosus (SLE) and the risk of coronary heart disease (CHD) in SLE patients using the Affymetrix GeneChip Human Immune and Inflammation 9K SNP panel.