Allotypes of the fourth component of complement in healthy and disease families

Abstract

1857 serum samples from healthy individuals, patients, and their families were characterized with respect to C4 polymorphic variants, the relationship between genotype and C4 concentration, associations between C4 haplotypes and other MHC variants, and the inheritance of C4 and other MHC allotypes in multiple sclerosis (MS) and insulin-dependent diabetes (IDDM) families. -- Patterns obtained were consistent with (i) two gene products, C4A (Rg+) and C4B (Ch+), (ii) two loci, A and B, per chromosome, (iii) at least five alleles at each locus, A3 and B1 being the most common, and (iv) moderately frequent null alleles, AQO and BQO. Some individuals with the rare patterns A3A2 and B2B1 appeared to have two A or two B genes per chromosome. For two rare products, B3 and B4, the appropriate Chido antigen could not always be demonstrated. -- Null alleles could not be excluded from many A3B1 phenotypes. Measurement of relative amounts of C4A and C4B products per individual and of total serum C4 is of limited value in predicting the number of genes an individual possesses. Factors other than MHC-linked genes are likely to be important in determining serum C4 levels. -- Frequencies of C4 haplotypes and of C4*A and C4*B genes were estimated from 1048 founder haplotypes. Five A-B combinations had frequencies > 2% and were non-randomly associated. -- Many MHC alleles, C4-C2-BF complotypes, and extended MHC supratypes showed high positive linkage disequilibria. The associations suggest that the C4 loci are between HLA-B and HLA-DR, closer to HLA-DR. The frequent clustering of rare C4, BF, and C2 alleles in the same supratype indicates that some may be hypermutable. -- Supratypes of patients were compared with non—disease supratypes from the same families. HLA-B7 C4*A3B1 BF*S C2*1 HLA-DR2 was increased in MS-patient supratypes. This is likely to reflect strong associations among these alleles and between MS and HLA-DR2 suggesting that an MS susceptibility gene is very closely linked to HLA-DR. C4*AQ0B1 and C4*B3 occurred more frequently in IDDM supratypes. These associations may also be secondary to strong associations reported for IDDM and HLA-DR or, because other rare complement variants are associated with IDDM, may indicate a direct role for particular complement variants in this disease.