MOLECULAR ANALYSIS OF C3 ALLOTYPES IN PATIENTS WITH SYSTEMIC VASCULITIS

The third component of complement (C3) exists in two main allotypic fo rms, C3S and C3F, distinguished at the DNA level by a single base chan ge. An increased frequency of the rarer C3F allele has been reported i n patients with the autoantibody nephritic factor and in several other autoimmune conditions such as rheumatoid arthritis and IgA nephropath y. Studies of the immunogenetic factors predisposing to the developmen t of systemic vasculitis have produced conflicting results and no majo r genetic predisposing factors have been identified. We have studied t he C3S/F polymorphism in 63 patients with systemic vasculitis using DN A allotyping by the amplification refractory mutation system, a modifi cation of the polymerase chain reaction. The allele frequency in these patients was C3S 0.71, C3F 0.29 (expected C3S 0.8, C3F 0.19; chi-squa red = 5.1, P < 0.025), with the average relative risk for the developm ent of systemic vasculitis associated with the presence of a C3F allel e being 2.6. Moreover, there was a marked excess of C3FF homozygotes ( 11/63, [17.5%], versus 4% expected: chisquared = 9.5, p < 0.01). The a verage relative risk for the development of systemic vasculitis in C3F homozygotes was 5.1, indicating a gene dosage effect. These data indi cate that the C3F allele is associated with a predisposition to the de velopment of systemic vasculitis and that C3F homozygotes are at parti cularly high risk. This association is the strongest genetic factor re ported so far for this group of diseases.