title: Relationship between ITPA polymorphisms and hemolytic anemia in HCV-infected patients after ribavirin-based therapy: a meta-analysis.
abstract: BACKGROUND
  There is growing evidence that variations in the gene encoding inosine triphosphate pyrophosphohydrolase (ITPase), known as inosine triphosphatase (ITPA), are related to hemolytic anemia, which is frequently observed among hepatitis C virus (HCV)-infected patients receiving ribavirin (RBV)-based therapy. We performed a meta-analysis of all eligible studies assessing ITPA gene polymorphisms related to RBV-induced hemolytic anemia in HCV-infected patients published in PubMed, Embase and the Cochrane library prior to the end of 2014.
  
  
  METHODS
  Three outcomes were evaluated: (1) hemoglobin decline, (2) severe anemia, and (3) RBV dose reduction or treatment discontinuation. Pooled odds ratio (OR) and 95 % confidence interval (95 % CI) were estimated by either fixed or random effects models.
  
  
  RESULTS
  Twenty-nine studies were selected from the literature search: 20 references involving 6533 individuals for hemoglobin decline, 13 references on 3764 patients for severe anemia, and 16 references on 3918 patients for RBV dose reduction or discontinuation. Significant associations with hemoglobin decline were found for rs1127354 CC [OR = 12.84 (95 % CI 7.44; 22.17)], rs7270101 AA [OR = 3.41 (95 % CI 2.08; 5.59)] and rs6051702 AA [OR = 4.43 (95 % CI 2.80; 7.00)] genotypes. Moreover, significant associations with hemoglobin decline were also found for absent [OR = 6.01 (95 % CI 4.84; 7.46)] and mild [OR = 4.68 (95 % CI 2.83; 7.74)] ITPase deficiency haplotypes. The ITPA rs1127354 CC genotype and absent ITPase deficiency haplotype were also associated with severe anemia {[OR = 7.77 (95 % CI 5.03; 12.00)] and [OR = 4.79 (95 % CI 1.69; 13.56)], respectively}. Additionally, the rs1127354 CC genotype showed significant association with RBV dose reduction or stopping treatment (OR = 2.24; 95 % CI 1.79; 2.81).
  
  
  CONCLUSIONS
  ITPA polymorphisms increase the likelihood of developing hemolytic anemia for HCV-infected patients on RBV-based therapy, particularly rs1127354 CC and rs7270101 AA genotypes, suggesting the utility of screening for ITPA polymorphisms to avoid hematological toxicity and increase adherence to RBV-based therapy.
authors.affiliation: Servicio de Laboratorio Clínico, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain. dpinedatenor@gmail.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pineda-Tenor
authors.affiliation: Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain. monica_gap@yahoo.es.
authors.forename: Mónica
authors.initials: M
authors.lastname: García-Álvarez
authors.affiliation: Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain. majimenezsousa@yahoo.es.
authors.forename: María A
authors.initials: MA
authors.lastname: Jiménez-Sousa
authors.affiliation: Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain. svazquez@isciii.es.
authors.forename: Sonia
authors.initials: S
authors.lastname: Vázquez-Morón
authors.affiliation: Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain. sresino@isciii.es.
authors.forename: Salvador
authors.initials: S
authors.lastname: Resino
mesh_terms: D000368:Aged; D000743:Anemia, Hemolytic / Q000139:chemically induced / Q000235:genetics*; D000998:Antiviral Agents / Q000009:adverse effects; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006454:Hemoglobins / Q000032:analysis; D016174:Hepacivirus; D006526:Hepatitis C; D019698:Hepatitis C, Chronic / Q000235:genetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics; D008875:Middle Aged; D016017:Odds Ratio; D011092:Polyethylene Glycols / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000172:deficiency / Q000235:genetics*; D011994:Recombinant Proteins / Q000009:adverse effects; D012044:Regression Analysis; D012254:Ribavirin / Q000009:adverse effects*; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D006454:Hemoglobins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a