Hepatology Xagena

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Early Ribavirin-induced anemia: VDR gene polymorphisms impact on anemia at 2 weeks of anti-HCV therapy

Vitamin D receptors ( VDR ) bind calcitriol and modulate several physiological systems through genomic and nongenomic pathways. Calcitriol stimulates store-operated channels Ca influx by translocation of the caveolar VDR to the plasma membrane.
Intracellular Ca 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.
Researchers have 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.

Two hundred and twenty-five patients treated with Ribavirin and Pegylated Interferon-alpha were genotyped by real-time PCR.

BMI ( body mass index ) at baseline more than 30  kg/m [ P=0.013, odds ratio, OR=10.95, 95% confidence interval (CI): 1.66-74.21 ], alanine aminotransferase at baseline more than 37  IU/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.

In conclusion, the 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 Ca-dependent signaling, which can lead to erythrocytes hemolysis.
This rapid mechanism could be responsible for the development of early anemia.
These results have indicated 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. ( Xagena )

Cusato J et al, Pharmacogenet Genomics 2015; Epub ahead of print