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Molecular analysis of C3 allotypes in patients with systemic vasculitis
Insights
The C3F allele of the third component of complement (C3) is linked to an increased risk of developing systemic vasculitis, with C3F homozygotes facing a particularly high risk.
Area of Science:
- Immunogenetics
- Molecular Biology
- Rheumatology
Background:
- The third component of complement (C3) has two main allotypes, C3S and C3F, differing by a single DNA base change.
- An increased frequency of the C3F allele is observed in autoimmune conditions like rheumatoid arthritis and IgA nephropathy.
- Genetic factors predisposing to systemic vasculitis are not well-established, with previous studies yielding conflicting results.
Purpose of the Study:
- To investigate the association between the C3S/F polymorphism and the predisposition to systemic vasculitis.
- To determine if the C3F allele represents a significant genetic risk factor for systemic vasculitis.
Main Methods:
- DNA allotyping using the amplification refractory mutation system (ARMS), a polymerase chain reaction (PCR) modification.
- Analysis of C3S/F allele frequencies in 63 patients with systemic vasculitis.
- Calculation of relative risk and gene dosage effects for C3F allele carriers.
Main Results:
- The allele frequency in patients was C3S 0.71 and C3F 0.29, differing from expected frequencies (C3S 0.8, C3F 0.19).
- A significant association was found between the C3F allele and systemic vasculitis (chi-squared = 5.1, P < 0.025), with an average relative risk of 2.6.
- C3FF homozygotes showed a marked excess (17.5% vs. 4% expected; chi-squared = 9.5, p < 0.01), indicating a gene dosage effect with an average relative risk of 5.1.
Conclusions:
- The C3F allele is associated with a predisposition to developing systemic vasculitis.
- Individuals homozygous for the C3F allele (C3FF) are at a particularly high risk.
- This finding represents the strongest genetic risk factor identified to date for 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: chi-squared = 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.