VDR gene polymorphisms impact on anemia at 2 weeks of anti-HCV therapy: a possible mechanism for early RBV-induced anemia

摘要

ObjectivesVitamin D receptors (VDR) bind calcitriol and modulate several physiological systems through genomic and nongenomic pathways. Calcitriol stimulates store-operated channels Ca2+ influx by translocation of the caveolar VDR to the plasma membrane. Intracellular Ca2+ levels in erythrocytes control biophysical properties and an increase in its concentration can deregulate membrane composition, cell volume, glycolytic enzymes regulation, redox state, and cell clearance.We evaluated the role of single nucleotide polymorphisms in ITPA, CYP27B1, CYP24A1, and VDR genes in the prediction of ribavirin-induced anemia in HCV-1/2/3/4 patients at 2 and 4 weeks of treatment.Patients and methodsTwo hundred and twenty-five patients treated with ribavirin and pegylated interferon- were genotyped by real-time PCR.ResultsBMI at baseline more than 30kg/m(2) [P=0.013, odds ratio (OR): 10.95, 95% confidence interval (CI): 1.66-74.21], alanine aminotransferase at baseline more than 37IU/l (P=0.020, OR: 0.26, 95% CI: 0.09-0.81), and the VDR BsmI AA profile (P=0.003, OR: 5.09, 95% CI: 1.72-15.05) were anemia-predictive factors at 2 weeks of therapy. At week 4, the ITPA rs6051702 AC/CC profile (P=0.001, OR: 0.19, 95% CI: 0.07-0.51) was the only factor that could predict this side effect.ConclusionThe BsmI AA genotype is a predictive factor of 2-week anemia and it could be related to a VDR-enhanced activity, and thus an increased calcium influx, resulting in the deregulation of the Ca2+-dependent signaling, which can lead to erythrocytes hemolysis. This rapid mechanism could be responsible for the development of early anemia.These results indicate for the first time the strong, significant, and independent role of VDR in the early development of ribavirin-induced anemia and confirm the ITPA function in the prediction of anemia at week 4.