HLA Region Genetics and SLE in U.S. Black Women

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DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects African-American women. Numerous studies have shown that HLA-region genes play a key role in genetic susceptibility to SLE, but studies so far have not established which factors in the HLA region are important and how much of overall risk is explained by HLA. We propose to address these questions with a large and uniformly collected group of samples from the Black Women's Health Study (BWHS), the largest follow-up study of African-American women yet conducted. We will use cheek cell samples collected from 400 BWHS participants with SLE and 800 matched controls. Since the collection of cheek cell samples is already funded, the present grant will focus on (a) DNA extraction from the samples, (b) DNA amplification, (c) SNP haplotyping of the HLA region, (d) PCR-based genotyping for the C4A deletion allele for which there is particular evidence of association to SLE in order to control for its effect, and (e) genotyping a panel of SNPs to control for European admixture in African-Americans. We will exhaustively survey the HLA region for genetic associations with SLE; this will involve typing a high-density panel of SNPs over the region, which will provide excellent power to detect variants that confer 2-fold or greater increased risk for SLE. Among the specific genes that we will assess are TNF, IKBL, MICA, and HLA-DRB1, with adjustment for C4A gene deletion status. In addition, we will genotype a panel of SNPs across the genome to ensure that any associations with HLA alleles that we detect are real rather than due to population stratification (systematic differences in allele frequency between cases and controls due to differences in their population ancestry). This will also allow us to assess whether specific regions of the genome show unusually high or low levels of European ancestry in African-American SLE patients, thus allowing us to use an 'admixture mapping' approach to find sections of the genome containing genes that modify HLA-induced risk for SLE. The proposed study is population-based and not only uses an innovative and statistically high-powered design-which will exhaustively survey the HLA region for SLE risk, as well as search the rest of the genome for modifiers of that risk-but also focuses on African-American women, a population that is high-risk for SLE but medically and scientifically underserved.