Systemic lupus erythematosus (SLE) is a serious disease among African-Americans affecting up to 1 in every 250 women, and often causing severe organ injury (nephritis, ulcers, arthritis, pericarditis, pleuritis, rashes, strokes, heart attacks, vasculitis, nervous dysfunction, cytopenias, Raynaud's disease, and immune dysfunction). Lupus is familial, but like other diseases with no obvious pattern of inheritance, the data suggest many different genes are contributing to the phenotype. Our results from AR42460 show the profound differences dominating lupus genetics of African- Americans relative to European-derived populations. Among other findings, this project has produced four established (LOD equal to or greater than approximately 3.2 or p equal to or less than 0.00002) and independently confirmed (LOD equal to or greater than approximately 1.2 or p equal to or p less than or equal too 0.01) linkages in African-American pedigrees multiplex for lupus at 1q23, 2q34, 11p13, and 11q14. Association has been found at Fc gamma RIIIA making this a strong candidate for explaining the linkage at 1q23. The most robust of these linkages is at 2q34 with strong aggregate evidence for linkage (p=0.0000006). The 2q34 linkage is found in the African-American pedigrees multiplex for lupus with renal involvement in at least one of the affecteds. We enthusiastically embrace the reviewers' recommendation to focus the available resources on a single linkage. We will concentrate on the 2q34 linkage for the competitive renewal. We will fine map to reduce the support interval for linkage and then will search for the responsible gene by linkage disequilibrium. There are 7991 dbSNPs available in the current 2q34 linkage interval from 205 mb to 227 mb on chromosome 2. We will exploit the HapMap project to choose the single nucleotide polymorphisms (SNPs) that appear to be the most informative for a search for linkage disequilibrium in cases from linked pedigrees and unrelated controls, beginning with the candidate genes in the 2q34 linkage interval. Tentative associations will be further explored by family based association methods to help eliminate false positives. Then, the surviving association(s) will be explored in a separate set of African-American isolated SLE nephritis cases and controls. Association(s) convincingly replicated will then be explored across individual genes, and their polymorphisms, using DNA sequencing and functional gene studies. We anticipate that the proposed translational work under AR42460 will culminate in the identification of a gene important in the cause of nephritis in African-Americans with lupus, as well as a more complete explanation of the pathophysiologic mechanisms, improved prognostic assessment in lupus nephritis, and the introduction of new molecular targets for therapeutic development.
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