Letters to the Editor

COMPLEMENT C4 IS A MARKER FOR ADULT RHEUMATOID ARTHRITIS

The association between allotypes of properdin factor B (Bf), the fourth component of complement (C4A and C4B), and rheumatoid arthritis (RA), was investigated in a well-characterized cohort of RA patients who were followed from an early phase of the disease for a mean duration of 6 years. The frequencies of probable heterozygous C4AQ0 and of C4A3 were lower in RA patients compared to controls, irrespective of the presence of DR4 [relative risk (RR): 0.52 and 0.49, respectively, 95% confidence intervals (95% CI): 0.34–0.80 and 0.29–0.82]. The frequency of C4A4 was higher in RA patients compared to control (RR: 1.86, 95% CI: 1.03–3.35), especially in DR4 positive RA patients compared to DR4 positive controls (RR: 2.58, 95% CI: 1.07–6.25), indicating a positive association of this allotype with RA additional to DR4. Bf and C4B allotypes were comparable in RA patients and controls. We did not find significant differences in Bf and C4 allotype frequencies in RA patients subdivided according to severity of the disease into a mild group and a progressive group. Because of inconsistent results in all studies on Bf and C4 allotypes, we conclude that C4 and Bf allotypes do not seem to have an important independent effect on determining disease susceptibility.

The class III complement proteins (C2, BF, C4A, and C4B) were studied in 57 multicase rheumatoid arthritis (RA) families. When the gene frequencies for RA probans were compared to a normal control panel (162 haplotypes), a significantly higher frequency of the rare variant C4B^∗3 was observed (p < 0.05). No significant differences were seen for the other C2, BF, C4A, or C4B alleles. The most common haplotype found in the probands was HLA-Cw5, B44, C2^∗C, BF^∗S, C4A^∗3, C4B^∗3, DR4, occurring with a frequency of 0.088. Haplotypes containing HLA-DR4 and Bw62 were found to carry either C4A^∗3, C4B^∗3; C4A^∗3, C4B^∗1; or C4A^∗4,C4B^∗2. When only haplotypes containing DR4 were compared between probands and controls, the frequency of the C4B^∗3-bearing haplotype remained higher in the probands. It is concluded that Bw62, C4A^∗3, C4B^∗3DR4 is a haplotype which is especially associated with RA. The low frequency in the RA population of this haplotype indicates that C4B^∗3 has a minor role in overall RA susceptibility.

Gold salt therapy-induced pneumonitis is a rare complication in patients with rheumatoid arthritis (RA). We studied HLA-A, B, C, D/DR, and complement factor B (Bf) and C4 alleles in 17 patients with RA and gold-induced pneumonitis and found that these patients had strikingly homogeneous major histocompatibility complex (MHC) markers. Eight of them (47 percent) had the alleles HLA-A3 B35 Dw1 BfF C4A3,2 (BO) which were shown by family studies of some patients to be inherited as an extended MHC-haplotype with an apparent gene duplication in the C4A locus. The other high-risk phenotype, HLA-B40 with a C4 null allele, was found in eight patients (47 percent.) All but three of the 17 patients had at least one of the two high-risk markers, the frequency of these combinations being clearly higher than in the two control groups: patients with RA but with no gold-induced side effects and healthy individuals. Our study shows that use of several MHC markers together results in a strong association between the markers and the disease.

C4 is encoded at two polymorphic genetic loci (C4A and B), and “null” or unex-pressed alleles are relatively common. An increased frequency of nulls has been reported in a variety of diseases. In the present study, C4 allotypes and C4 hemolytic efficiencies (the ratios of functional to antigenic levels) were determined for a population of 75 normal unrelated individuals. Of these, 28 had three gene products (single null at C4A or B) while three had no expressed C4A products and three had no C4B products (homozygous null). Mean antigenic C4 levels correlated with the number of expressed gene products but there was a wide spread of individual values. Those homozygous null for C4A had greater, and for C4B less, hemolytic efficiency than those with four gene products. However, there was no difference in the in vitro kinetics of C3 convertase formation between homozygous null C4A or C4B individuals. Therefore, the presence of null genes for C4 does not appear to compromise complement function sufficiently to account for the reported disease associations. Some of the associations may result from the fact that null genes for C4, as part of an extended HLA haplotype, may be genetically linked to disease susceptibility.

59 unselected patients with primary glomerulonephritis were phenotyped for alleles of the MHC-linked complement genes, C4A, C4B, and BF. A rare variant of the C4B locus, C4B*2·9, was found in 25% of these patients compared with only 2% of the normal population—a relative risk of 22·1 for glomerulonephritis in individuals with this variant. Subdivision of patients by histological classification of glomerulonephritis revealed a significant association of C4B*2·9 with the membranoproliferative form. There were no significant associations between primary glomerulonephritis or its subtypes and the other HLA markers tested.