Imbalance of the C4A and C4B genes dosage as a robust risk factor for premature cardiovascular disease morbidity and mortality

Abstract

The genes in the HLA class III region encoding the complement components C2, Factor B and C4 have been aligned by the isolation and characterisation of overlapping cloned fragments from a cosmid library of genomic DNA. The C2 and Factor B genes are less than 500 bp apart. They lie about 30 kb from the two C4 loci which are separated from each other by about 10 kb. This analysis has also established the presence of two cytochrome P450 21-hydroxylase genes that are located immediately 3′ to the C4A and the C4B genes.The gene encoding Factor B, a novel type of serine proteinase, has been further characterised by DNA sequence analysis. It is approx. 6 kb in length and is split into 18 exons. Comparison of the exon organisation of that part of the gene encoding the serine proteinase domain with that of other serine proteinases shows a close correlation between them, but also reveals the presence of an exon in Factor B with no homologous counterpart in other serine proteinases.