COMPARATIVE-ANALYSIS OF THE DISEASE-ASSOCIATED COMPLEMENT C4 GENE FROM THE HLA-A1, B8, DR3 HAPLOTYPE

Complement component C4 is an important protein of the classical, or a ntibody-mediated pathway of complement activation. Human C4 is located within the central region of the major histocompatibility complex on chromosome 6. Partial C4 deficiency has been associated with an increa sed susceptibility to immune complex disease. The strongest associatio n with partial C4 deficiency is with systemic lupus erythematosus (SLE ) and has been shown in most racial groups studied. Interestingly, Cau casian population studies have demonstrated an increased prevalence of C4A null alleles in SLE patients, in particular in association with t he haplotype HLA-A1, B8, BfS, C4AQ0, C4B1, DR3. To investigate whether the C4 gene on this haplotype had any structural irregularities which may explain disease association, we sequenced the entire C4B gene fro m this haplotype. The results revealed that the gene encoded on the di sease-associated haplotype carried major structural differences (when compared to C4A3) at the exonic level only in the C4d region. A high d egreee of conservation in both the 5' and 3' untranslated regions impl y that disease associations will not be due to differential C4 express ion as a result of regulatory differences between C4 genes. It appears likely that protein clearance mechanisms may account for the altered levels of C4 seen between different isotypes.