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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3707-3712
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Tumor necrosis factor  promoter polymorphisms influence the
phenotypic expression of hereditary hemochromatosis
Silvia Fargion,
Luca Valenti,
Paola Dongiovanni,
Anna Scaccabarozzi,
Anna Ludovica Fracanzani,
Emanuela Taioli,
Michela Mattioli,
Maurizio Sampietro, and
Gemino Fiorelli
From Dipartimento di Medicina Interna, Università
di Milano, Ospedale Maggiore IRCCS, Milan, Italy; and Unità di
Epidemiologia, Ospedale Maggiore IRCCS, Milan, Italy.
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  (TNF-) plays a role in phenotypic expression of
HHC. Sixty-four patients with HHC and 172 healthy volunteers (controls)
were studied. Release of TNF- from stimulated peripheral blood
monocytes was measured by enzyme-linked immunosorbent assay, and 308 and 238 TNF- polymorphisms were detected with polymerase chain
reaction and restriction fragment-length polymorphism analysis. The
relation between TNF- polymorphisms and clinical expression of HHC
was evaluated. Patients with HHC released less TNF- than controls,
but the difference was significant only in homozygotes for the C282Y
mutation. The prevalence of the 308 TNF- 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- 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- polymorphism (P = .006), even when patients with other hepatotoxic factors were excluded. Multivariate analysis showed that TNF- 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-
appears to play a role in HHC by modulating the severity of liver damage.
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