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

Severe iron overload usually develops in patients with hereditary hemochromatosis (HHC), but variability in the phenotypic expression of the disease has been reported. This study assessed whether tumor necrosis factor α (TNF-α) plays a role in phenotypic expression of HHC. Sixty-four patients with HHC and 172 healthy volunteers (controls) were studied. Release of TNF-α from stimulated peripheral blood monocytes was measured by enzyme-linked immunosorbent assay, and 308 and 238 TNF-α polymorphisms were detected with polymerase chain reaction and restriction fragmentlength polymorphism analysis. The relation between TNF-α polymorphisms and clinical expression of HHC was evaluated. Patients with HHC released less TNF-α than controls, but the difference was significant only in homozygotes for the C282Y mutation. The prevalence of the 308 TNF-α polymorphism was similar in patients and controls, whereas the prevalence of the 238 polymorphic allele was significantly lower in patients (3% versus 16%; P=.002). A lower prevalence of cirrhosis was observed in patients with TNF-α polymorphism than in those without it (4 of 15 [27%] versus 28 of 49 [57%]), but the difference was not significant (P = .07). In nonhomozygotes for the C282Y mutation, severe liver siderosis was less prevalent in patients with the 308 polymorphism than in those without it (P = .05). Alanine aminotransferase (ALT) values were significantly lower in patients with TNF-α polymorphism (P = .006), even when patients with other hepatotoxic factors were excluded. Multivariate analysis showed that TNF-α polymorphism was independently associated with ALT values (P = .0008 and P = .045, respectively, in homozygotes and nonhomozygotes for the C282Y mutation) and siderosis in nonhomozygotes (P = .047). Thus, TNF-α appears to play a role in HHC by modulating the severity of liver damage.