We have found a powerful genetic association with systemic lupus erythematosus in African American families. Our data to this point show an odds ration of 9.0, chi square of 9.55 and p=0.002. At the same locus there is no genetic association with lupus in American white families who are multiplex for lupus (odds ratio = 1.8, chi square = 0.04, and p = 0.4). The genetic marker for these data, D1S117, was chosen for its proximity to the Fcgamma receptor IIIPMN gene, the product of which is the most abundant receptor for immune complexes on the surface of normal neutrophils. Uncommon deletions in this gene have been identified in two lupus patients. Preliminary genetic modelling has revealed a lod score of 2.17 at a recombination fraction of zero for a homozygous recessive effect at D1S117 in African American families. At this locus in seven white families the lod score under this model is less than -2.0 for any recombination frequency lower than 0.07. The proposed study is designed to evaluate this genetic association in African Americans families. We plan to collect additional African American pedigrees who are multiplex for systemic lupus erythematosus. Then the optimal model for the mode of inheritance will be determined by applying the maximum likelihood algorithms of analysis. By evaluating the other polymorphic loci on chromosome 1 we will localize the linkage interval. Alleles of the Fcgamma RIIIPMN gene from affected African lupus patients will be characterized, first by Southern blot, then by their single stranded conformational polymorphisms and finally be sequencing. If a gene linked to D1S117 is responsible, but not Fcgamma RIIIPMN itself, then we will apply selection cloning in a quest to identify this locus. Whether at Fcgamma RIIIPMN or not, our goal during this project is to identify the gene and its allelic differences responsible for the observed genetic association with lupus in our growing collection of African American pedigrees multiplex for lupus.
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