Immune/Inflammation Genomics and the Risk of SLE and CHD

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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.