TNFalpha genotype affects TNFalpha release, insulin sensitivity and the severity of liver disease in HCV chronic hepatitis.
OBJECTIVE
TNFalpha induces insulin resistance and promoter polymorphisms of TNFalpha gene affect the release of this cytokine, implicated in the pathogenesis of HCV-related diabetes and fatty liver. The aim was to define whether in patients with HCV chronic hepatitis TNFalpha genotype influences TNFalpha activity, insulin resistance, and the severity of the disease.


METHODS
186 patients, 65% with steatosis, 17% with diabetes. TNFalpha and sTNFR2 were determined by ELISA, insulin resistance by HOMA-R index and TNFalpha -238, -308, and -863 polymorphisms by restriction analysis.


RESULTS
TNFalpha, sTNFR2, and insulin resistance were higher in patients than in 89 controls. TNFalpha pathway activity was correlated with LDL cholesterol, steatosis, and insulin resistance, which, in turn, was correlated with the severity of liver damage. Patients subdivided according to TNFalpha genotype significantly differed for TNFalpha release, insulin sensitivity and the prevalence of cirrhosis. The -308 and -238 TNFalpha polymorphisms, characterized by increased promoter activity, were associated with higher TNFalpha activity, insulin resistance and severity of the disease, whereas the -863 polymorphism, characterized by reduced promoter activity, with lower TNFalpha activity, and higher insulin sensitivity.


CONCLUSIONS
TNFalpha genotype modulates the activity of the TNFalpha pathway, influences insulin sensitivity and the severity of HCV chronic hepatitis.
Valenti
Luca
L
Dipartimento di Medicina Interna, Ospedale Maggiore IRCCS, Università degli Studi, Pad Granelli, Via F Sforza 35, 20122 Milano, Italy.
Pulixi
Edoardo
E
Fracanzani
Anna Ludovica
AL
Dongiovanni
Paola
P
Maggioni
Marco
M
Orsatti
Alessandra
A
Gianni
Cristina
C
Fargion
Silvia
S
D000328:Adult; D000368:Aged; D003920:Diabetes Mellitus / Q000503:physiopathology; D005234:Fatty Liver / Q000150:complications / Q000235:genetics; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D007328:Insulin / Q000096:biosynthesis; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D007328:Insulin; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha