Immune/Inflammation Genomics and the Risk of SLE and CHD

6.项目总结/摘要 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患者发生冠心病的风险 妇女的死亡率比一般人口高50倍。传统的风险因素不足以 解释SLE患者的早发冠心病这表明SLE患者有一些独特之处， 使他们患冠心病的风险极高。很可能炎症和免疫因素起着重要的作用 在这方面的作用。SLE是一种复杂的多因素疾病，可能涉及多个 遗传和环境因素。遗传因素在SLE病因学中的重要作用， 家族风险估计值在20-40之间，遗传率高达66%。强大的生物 免疫和炎症反应参与SLE病因学的证据， SLE具有强遗传基础的证据为研究遗传变异的作用提供了强有力的理论基础 与SLE相关的免疫/炎症途径基因以及SLE中CHD的风险。在这 应用我们打算测试参与免疫/炎症的基因中的遗传变异的假设， 它们之间的相互作用与SLE风险和SLE中的CHD风险相关。我们将使用 Affyssin免疫和炎症9 K SNP试剂盒，其在约1，000个样本中含有约9，200个SNP， 基因，包括基于HapMap的tagSNP（频率>5%）和另外773个验证的非同义 SNPs。在确定显著的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。根据这些分析，我们应该能够确定 同时，在大量生物学相关的免疫/炎症中常见变异的作用 SLE中与SLE风险和CHD风险相关的基因。

6. Project Summary / Abstract Systemic lupus erythematosus (SLE) is the prototypic systemic inflammatory autoimmune disease that affects predominantly younger premenopausal women. The risk of coronary heat 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 ¿s 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.