The long term aim of this project is the identification of inherited factors predisposing to the disease, membranoproliferative glomerulonephritis Types I and III (MPGN I and III), forms of chronic glomerulonephritis which lead to end-stage renal disease, on the average, 9 years after diagnosis. Work from this laboratory has already identified partial complement component deficiency as a risk factor for this disease.
The specific aim of the present application is to gain evidence for one or more susceptibility genes, predisposing to the disease, located on the short arm of the 6th chromosome. The impetus for this research rises from the observation that 64% of 11 patients with MPGN I and III have the C4 haplotype, C4A*QOC4B*1, a haplotype present in about 10% of normal subjects (p = 0.0001). The loci for C4A and C4B variants are in strong linkage disequilibrium with the loci for C2 and factor B. These genes comprise a complotype, in turn in linkage disequilibrium with HLA-DR. Recent work has shown that certain combinations of HLA antigens and complotypes are more frequent in normal subjects than would be expected by chance association. These combinations, known as extended haplotypes, are inherited as a unit because of crossover suppression. Disease susceptibility genes on this extended haplotype will therefore be inherited in association with HLA alleles and complotypes present on that haplotype. The frequent presence of a single C4 haplotype in patients with MPGN I and III suggests a diease susceptibility gene in linkage disequilibrium with a specific complotype, in turn a part of an extended haplotype. Observations from another center strongly suggest that white patients with systemic lupus erythematosus (SLE) have a susceptibility gene on an extended haplotype which also includes C4A*QOC4B*1. This application proposes family studies of HLA, complotype and glyoxalase markers in patients with MPGN, SLE, and normal subjects as a means of identifying the extended haplotypes which may bear susceptibility genes for these diseases. Recent studies in this laboratory have shown that inherited deficiency of a complement component is a predisposing factor in the pathogenesis of MPGN I and III. Determining the distribution of such deficiencies together with susceptibility genes in propositi and family members may indicate that these factors are additive in causing the disease to be expressed.
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