Background: Chronic hepatitis C (CHC) is a significant cause of liver related morbidity and mortality worldwide. The role of genetics in the host response to hepatitis C virus is not elucidated. Genetic variations in UGT1A1 gene are the most common cause of hereditary unconjugated hyperbilirubinemia-Gilbert syndrome. This is the first study investigating the association of UGT1A1 TA repeats promoter genotypes with the degree of liver injury, viremia and biochemical markers in CHC patients with advanced liver injury and late virological relapse.
Methods: Genetic testing of UGT1A1 TA repeats promoter genotypes was performed in 42 CHC patients with advanced fibrosis and cirrhosis who achieved sustained virological response and 42 healthy blood donors. CHC patients were evaluated for clinical findings, laboratory tests and imaging.
Results: UGT1A1*28 genotype (7/7 TA repeats) was observed in 23.8% CHC patients and 16.7% healthy controls with no significant difference in genotype frequencies (p=0.49). Pretreatment levels of ferritin and bilirubin were associated with the presence of UGT1A1*28 genotype, indicating its potential as a predictive marker. However, in our study, there was no correlation of UGT1A1*28 genotype with the degree of fibrosis or viremia. During antiviral treatment, dose reductions and treatment interruptions, as well as treatment success and occurrence of late virological relapse were not related to the presence of UGT1A1*28 genotype in CHC patients with severe liver injury.
Conclusions: Frequencies of UGT1A1*28 genotype are high in both Serbian CHC patients and healthy subjects. The presence of UGT1A1*28 genotype was not associated with ribavirin-related adverse effects and had no effect on long term outcome in CHC patients.
Uvod: Hronični hepatitis C (HHC) je značajan uzročnik morbiditeta i mortaliteta u svetu. Značaj genetskih faktora u patogenezi HHC još uvek nije u potpunosti razjašnjen. Varijacije UGT1A1 gena su najčešći uzrok nasledne nekonjugovane hiperbilirubinemije – Žilberovog sindroma. Ovo je prva studija koja se bavi ispitivanjem učesta losti TA ponavljanja u promotorskoj regiji UGT1A1 gena i analizom povezanosti UGT1A1*28 genotipa sa stepenom fibroze, viremijom i biohemijskim markerima kod pacijenata sa teš kim oštećenjem jetre izazvanim HHC i virusološkim relapsom.
Metode: Analizirana su TA ponavljanja u promotorskoj regiji UGT1A1 gena, kod 42 pacijenta sa teškom fibrozom i cirozom izazvanom HHC, koji postigli stabilan virusološki odgovor i 42 ispitanika u kontrolnoj grupi zdravih dobrovoljnih davalaca krvi. Pacijenti sa HHC su dodatno analizirani kliničkim pregledima, laboratorijskim analizama (hematološki, biohemijski i virusološki) i fibroskenom jetre.
Rezultati: UGT1A1*28 genotip (7/7 TA ponavljanja) je bio prisutan kod 23.8% pacijenata sa HHC i 16,7% zdravih ispitanika, ali bez statistički značajne razlike (p=0,49). Nivoi feritina i ukupnog bilirubina su bili u korelaciji sa prisustvom UGT1A1*28 pre primene antivirusne terapije, što sugeriše prediktivnu ulogu ovog genotipa. U ovoj studiji nije bilo korelacije UGT1A1*28 genotipa sa stepenom fibroze i viremijom. Prisustvo UGT1A1*28 genotipa nije uticalo na terapijske prekide i redukcije doze antivirusnih lekova, ishod lečenja niti pojavu kasnog virusološkog relapsa kod pacijenata sa HHC i teškim oštećenjem jetre.
Zaključak: Učestalost UGT1A1*28 genotipa je visoka među srpskim zdravim ispitanicima i pacijentima sa HHC infekcijom. Ispitivani genotip se ne dovodi u vezu sa neželjenim efektima ribavirina niti ima uticaj na ishod lečenja i dugoročnu prognozu pacijenata sa HHC.
Keywords: Gilbert syndrome; UGT1A1; hepatitis C; hyperbilirubinemia; late relapse.