Autoimmune renal disease and tumour necrosis factor beta gene polymorphism.

The genes encoding tumour necrosis factors (TNF) are located within the major histocompatibility complex. Since TNF may be involved in the pathogenesis of autoimmune disease the purpose of the present study was to investigate TNF beta gene polymorphism in two types of immune complex mediated glomerulonephritis, IgA nephropathy (IgAN) and idiopathic membranous glomerulonephritis (IMN) and to compare them with IDDM and healthy controls. DNA was studied by Southern-blot hybridisation methods using Nco I digestion and a TNF beta probe; two alleles were detected size 5.5 kb and 10.5 kb. In healthy controls (n = 107), 9% were 5.5 homozygotes, 47% heterozygotes and 44% 10.5 homozygotes. The corresponding figures in IMN (n = 51) were 21.5%, 61% and 17.5% (p = 0.002), in IDDM (n = 42) 24%, 50% and 26% (p = 0.027) and in IgAN (n = 77) 2.5%, 65% and 32.5% (p = 0.025). The increase in 5.5 homozygotes in both IMN and IDDM was found to be due to an increased frequency of the haplotype A1-B8-TNF beta 5.5-DR3 seen in both these diseases; whereas in IgAN the increased frequency of the 10.5 kb allele can be explained by an association of a Taq 1DQB1-T2 allele with the TNF beta 10.5 allele. These results demonstrate an association of TNF beta gene polymorphism with IMN and IgAN and confirm the associations found in IDDM. Although these disease associations can be explained by linkage disequilibrium with extended MHC haplotypes, a direct role of genetically determined TNF production in the etiology of these diseases remains to be excluded.