title: VDR gene polymorphisms impact on anemia at 2 weeks of anti-HCV therapy: a possible mechanism for early RBV-induced anemia.
abstract: OBJECTIVE
  Vitamin 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.
  
  
  METHODS
  Two hundred and twenty-five patients treated with ribavirin and pegylated interferon-α were genotyped by real-time PCR.
  
  
  RESULTS
  BMI at baseline more than 30 kg/m² [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.
  
  
  CONCLUSIONS
  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 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.
authors.affiliation: Laboratory of Clinical Pharmacology and Pharmacogenetics, Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy UNI EN ISO 9001: 2008 Certified Laboratory; Certificate No. IT-64386; Certification for: 'Design, Development and Application of Determination Methods for Anti-Infective Drugs. Pharmacogenetic Analyses.'
authors.forename: Jessica
authors.initials: J
authors.lastname: Cusato
authors.forename: Sarah
authors.initials: S
authors.lastname: Allegra
authors.forename: Lucio
authors.initials: L
authors.lastname: Boglione
authors.forename: Amedeo
authors.initials: A
authors.lastname: De Nicolò
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cariti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000328:Adult; D000740:Anemia / Q000139:chemically induced* / Q000235:genetics; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics*; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects*; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics; D000097630:Inosine Triphosphatase
chemical_list: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D000998:Antiviral Agents; D016898:Interferon-alpha; D011755:Pyrophosphatases; D018167:Receptors, Calcitriol; D012254:Ribavirin; D065668:Vitamin D3 24-Hydroxylase; C579457:VDR protein, human; C585549:CYP24A1 protein, human; C000600378:CYP27B1 protein, human; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase