Tumor necrosis factor or promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis

Severe iron overload usually develops in patients with hereditary hemochrom atosis (HHC), but variability in the phenotypic expression of the disease h as been reported. This study assessed whether tumor necrosis factor alpha ( TNF-alpha) plays a role in phenotypic expression of HHC, Sixty-four patient s with HHC and 172 healthy volunteers (controls) were studied. Release of T NF-alpha from stimulated peripheral blood monocytes was measured by enzyme- linked immunosorbent assay, and 308 and 238 TNF-alpha polymorphisms were de tected with polymerase chain reaction and restriction fragment-length polym orphism analysis. The relation between TNF-alpha polymorphisms and clinical expression of HHC was evaluated. Patients with HHC released less TNF-alpha than controls, but the difference was significant only in homozygotes for the C282Y mutation. The prevalence of the 308 TNF-alpha polymorphism was si milar in patients and controls, whereas the prevalence of the 238 polymorph ic allele was significantly lower in patients (3% versus 16%; P=.002), A lo wer prevalence of cirrhosis was observed in patients with TNF-alpha polymor phism than in those without it (4 of 15 [27%] versus 28 of 49 [57%]), but t he difference was not significant (P = .07), In nonhomozygotes for the C282 Y mutation, severe liver siderosis was less prevalent in patients with the 308 polymorphism than in those without it (P = .05). Alanine aminotransfera se (ALT) values were significantly lower in patients with TNF-alpha polymor phism (P = .006), even when patients with other hepatotoxic factors were ex cluded. Multivariate analysis showed that TNF-alpha polymorphism was indepe ndently associated with ALT values (P = .0008 and P = .045, respectively, i n homozygotes and nonhomozygotes for the C282Y mutation) and siderosis in n onhomozygotes (P = .047). Thus, TNF-a appears to play a role in HHC by modu lating the severity of liver damage. (C) 2001 by The American Society of He matology.