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）是典型的全身性炎症性自身免疫性疾病，主要影响绝经前的年轻女性。SLE女性患冠心病（CHD）的风险比一般人群高50倍。传统的危险因素不足以解释SLE患者早发冠心病的原因。这表明SLE患者有一些独特之处，使他们患CHD的风险极高。炎症和免疫因素可能在这种病因学中起重要作用。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。遗传因素在SLE病因学中的强烈参与通过20-40之间的家族风险估计和高达66%的遗传性来证明。免疫和炎症反应参与SLE病因学的强有力的生物学证据与SLE具有强有力的遗传基础的证据相结合，为研究免疫/炎症途径相关基因的遗传变异在SLE中的作用和SLE中CHD的风险提供了强有力的理论基础。在本申请中，我们打算检验这样的假设，即参与免疫/炎症途径的基因的遗传变异及其相互作用与SLE风险和CHD风险相关。我们将使用Affyssin Immune and Inflammatory 9 K 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tagSNP（频率>5%）和另外773个经验证的非同义SNP。在识别出显著的SNP后，我们将在相关基因/区域中筛选额外的SNP，以定位推定的功能变体。作为这些分析的结果，我们应该能够同时确定在大量的生物学相关的免疫/炎症基因，有助于SLE的风险和CHD的风险在SLE的共同变异的作用。公共卫生相关性：本研究的目的是使用Affyssin GeneChip Human Immune and Inflammation 9 K SNP panel对涉及免疫和炎症通路的约1，000个基因中约9，200个单核苷酸多态性（SNP）与SLE患者中系统性红斑狼疮（SLE）风险和冠心病（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.