The effects of MDR-1 gene polymorphisms on the clinical course of chronic hepatitis B infection

Abstract

Aims: Chronic HBV infection is associated with high morbidity and mortality rate due to increased risk of hepatic cirrhosis and hepatocellular cancer. Treatment modilities and resistance is currently investigated. Several mechanisms were underlying in drug resistance. P-glycoprotein (P-gp), the product of multidrug resistance gene (MDR-1), is well-known mechanism of MDR phenotype. MDR gene C1236T polymorphism is associated with decreased p-gp function. The mutation of MDR gene can affect the clinical course of disease and response rate to treatment. It was aimed to investigate the relationship between MDR gene polymorphism and clinical course and treatment responses in chronic HBV infection in our study. Methods: A total of 90 (male/female:69/21) patients with chronic HBV infection under Lamivudine treatment was enrolled in this study. Mean ages were 49.8±12.6 (range:22-75) years. The patients were categorized as: Treatment responded (group 1: HBV-DNA is negative at 24th week) and treatment refractory (group 2: HBV-DNA is still positive after 24th week). Group 1 was consisted of 51 (M/F: 38/13) and group 2 was consisted of 39 (M/F: 31/9) patients. There was no significant difference between ages and genders of two groups. Histologic activity indexes (HAI), total bilirubin, AST and ALT levels, HBV-DNA titers were significantly higher in the patients in group 2 than group 1 (p<0.05). Results: Genotype distributions; homozygous CC genotype was in 8 (15.7%),heterozygous CT genotype was in 37 (%72.5), homozygous TT genotype wasin 6 (11.8%) in patients at group 1. Homozygous CC genotype was in 13 (33.3%), heterozygous CT genotype was in 21 (53.8%), homozygous TT genotype was in 5 (12.8%) in patients at group 2. CC genotype was more common in group 2 than group 1 (p=0.044). C and T alleles’ frequencies in the group 1 and 2 were 51.96% and 60.26%, 48.04% and 39.74%, respectively (p>0.05). The patients with YMDD mutation positive at group 2 (n:11), 5 (45%) had have CC genotype, 5 (45%) had have CT, 1 (9%) had have TT genotype.The patients with YMDD mutation negative at group 2 (n:8), 3 (37%) patients had have CC and 5 (63%) patients had have CT genotype. CC genotype was more common in the patients with YMDD mutation positive than group 1 (p=0.043). Moreover, CC genotype was more common in the patients with HBV-DNA positive at 12nd month of Lamivudine treatment than group 1 (p=0.042). Conclusion: Consequently; MDR-1 and p-gp polymorphisms are important factors in the clinical course of chronic HBV infection and may influence the treatment responses. In the current study, it was found that the CC genotype of MDR-1 gene C1236T was more common in the patients with lamivudine resistant HBV infection.