POLYMORPHISM IN THE HUMAN-COMPLEMENT C4 GENES AND GENETIC SUSCEPTIBILITY TO AUTOIMMUNE HEPATITIS

Susceptibility to autoimmune hepatitis is associated with the HLA-DR3 and DR4 haplotypes, but which genes are directly involved in the patho genesis, has not been established. Low levels of complement component C4 and elevated frequencies of C4 null allotypes have been described i n patients, suggesting that the C4 genes, which are closely linked wit h the HLA loci, may play a role. We therefore examined restriction fra gment length polymorphisms in the C4 and 21-hydroxylase genes, and det ermined HLA-A and B phenotypes, and HLA-DR, DQ and DP genotypes in a l arge series of Caucasoid patients with autoimmune hepatitis and matche d controls. A DNA deletion of the C4A gene and the 21-hydroxylase A ps eudogene was found to be present in 50% of patients compared to 23% of controls (P-c < 0.005, relative risk = 3.3). This increase, however, appears to be due to linkage disequilibrium with HLA-DR52a which was m ost strongly associated with the disease. Complete C4A deficiency, det ermined by homozygosity for the deletion increased the risk to 18.1 (1 6% versus 1%, P-c < 0.005), suggesting an additional role for C4 in di sease susceptibility. C4 deletions were associated with an increased m ortality and tendency to relapse whilst on treatment but did not corre late with age of onset of disease. Our data suggest that MHC-encoded s usceptibility to autoimmune hepatitis is polygenic, involving the HLA- DR genes plus other loci, and C4 deficiency may be a marker of disease susceptibility and/or severity.