Molecular analysis of C3 allotypes in patients with systemic vasculitis

Abstract

The third component of complement (C3) exists in two main allotypic forms, C3S and C3F, distinguished at the DNA level by a single base change. An increased frequency of the rarer C3F allele has been reported in patients with the autoantibody nephritic factor and in several other autoimmune conditions such as rheumatoid arthritis and IgA nephropathy. Studies of the immunogenetic factors predisposing to the development of systemic vasculitis have produced conflicting results and no major genetic predisposing factors have been identified. We have studied the C3S/F polymorphism in 63 patients with systemic vasculitis using DNA allotyping by the amplification refractory mutation system, a modification 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-squared=5.1, P<0.025), with the average relative risk for the development of systemic vasculitis associated with the presence of a C3F allele 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 average relative risk for the development of systemic vasculitis in C3F homozygotes was 5.1, indicating a gene dosage effect. These data indicate that the C3F allele is associated with a predisposition to the development of systemic vasculitis and that C3F homozygotes are at particularly high risk. This association is the strongest genetic factor reported so far for this group of diseases.