Immune/Inflammation Genomics and the Risk of SLE and CHD

描述（由申请人提供）：系统性红斑狼疮（SLE）是典型的系统性炎症性自身免疫性疾病，主要影响年轻的绝经前妇女。SLE女性患冠心病（CHD）的风险比一般人群高50倍。常规的危险因素不足以解释SLE患者的早期冠心病。这表明SLE患者有一些独特之处，使他们患冠心病的风险极高。炎症和免疫因素可能在这一病因中起重要作用。SLE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病因学中的重要作用。免疫和炎症反应参与SLE病因学的强有力的生物学证据，以及SLE具有强大的遗传基础的证据，为研究与SLE和SLE中冠心病风险相关的免疫/炎症通路基因的遗传变异的作用提供了强有力的理论依据。在本应用中，我们打算验证参与免疫/炎症途径的基因的遗传变异及其相互作用与SLE患者SLE风险和CHD风险相关的假设。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个基因的约9,200个SNP，包括基于hapmap的标签SNP（频率>5%）和额外的773个经过验证的非同义SNP。在确定显著snp后，我们将在相关基因/区域筛选其他snp，以定位假定的功能变异。作为这些分析的结果，我们应该能够同时确定大量生物学相关的免疫/炎症基因的共同变异在SLE和CHD风险中所起的作用。公共卫生相关性：本研究的目的是使用Affymetrix基因芯片人类免疫和炎症9K SNP面板，对与系统性红斑狼疮（SLE）风险和SLE患者冠心病（CHD）风险相关的免疫和炎症途径中约1000个基因中的约9200个单核苷酸多态性（SNP）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.