Genome wide analysis of patients from the ideal study identifies a causal role for ITPA genetic variation in ribavirin-induced hemolytic anemia

Détails

ID Serval
serval:BIB_1E6FE0601CAC
Type
Actes de conférence (partie): contribution originale à la littérature scientifique, publiée à l'occasion de conférences scientifiques, dans un ouvrage de compte-rendu (proceedings), ou dans l'édition spéciale d'un journal reconnu (conference proceedings).
Sous-type
Abstract (résumé de présentation): article court qui reprend les éléments essentiels présentés à l'occasion d'une conférence scientifique dans un poster ou lors d'une intervention orale.
Collection
Publications
Titre
Genome wide analysis of patients from the ideal study identifies a causal role for ITPA genetic variation in ribavirin-induced hemolytic anemia
Titre de la conférence
5th Annual Meeting of the European Association for the Study of the Liver
Auteur(s)
Thompson A.J., Fellay J., Ge D., Urban T., Shianna K., Sulkowski M., Muir A., Afdhal N., Jacobson I., Esteban R., Poordad F., Lawitz E., Mc Cone J., Shiffman M., Galler G., Lee W., Reindollar R., King J., Kwo P., Ghalib R., Freilich B., Nyberg L., Patel K., Tillmann H., Noviello S., Bopari N., Koury K., Pedicone L., Brass C., Albrecht J.K., Goldstein D., Mc Hutchison J.G.
Adresse
Vienna, Austria, April 14-18, 2010
ISBN
0168-8278
Statut éditorial
Publié
Date de publication
2010
Peer-reviewed
Oui
Volume
52
Série
Journal of Hepatology
Pages
S470
Langue
anglais
Notes
Publication type : Meeting Abstract
Résumé
Background and Aims: We performed a genome wide associationstudy on a well characterized genotype 1 HCV treatment cohort toidentify genetic determinants of ribavirin (RBV)-induced hemolyticanemia (HA).Methods: 1604/3070 patients treated with peginterferona (pegIFN)and RBV in the IDEAL study consented to DNA testing. Sampleswere genotyped using the Illumina Human610-quad BeadChip.After quality control, 97.5% of the single nucleotide polymorphisms(SNPs) included on the chip were used in the analyses. The primaryanalysis focused on the genetic determinants of quantitative changein hemoglobin (Hb) levels from baseline to week 4 of treatment(to minimize confounding by erythropoietin use), in 3 separatepopulations (Caucasians, African Americans, Hispanics) by logisticregression, adjusting for: age, gender, weight, liver fibrosis, baselineHb level, RBV dose, and type/dose of pegIFN. A modified Eigenstratmethod controlled for population stratification, and Bonferroniadjustment corrected for multiple testing.Results: 1,286 patients were included in the final analysis. TheSNP rs6051702 on chromosome 20 was strongly associated withHb reduction at week 4 in the 3 separate populations (overallP < 10−46). Genotyping of known functional variants demonstratedthat the association signal was entirely explained by SNPs inthe adjacent ITPA gene (encoding inosine triphosphatase, ITPase):rs1127354 and rs7270101; the minor alleles cause ITPase deficiencyand were protective against anemia. A composite ITPase deficiencyallele showed an association of P = 10−91. Predicted ITPase deficiency,defined according to functional studies of these variants, stronglyprotected patients against Hb falling >3g/dL by week 4 (P < 0.0001)(Figure 1). The causal ITPA variants were not associated with SVR.Figure 1. ITPase deficiency protects against week 4 anemia.Conclusions: We have identified two functional variants in theITPA gene that are strongly associated with the risk of RBV-inducedHA. ITPA genotyping could help guide clinical decision-making,especially in patients at high risk for anemia or related morbidity.
Mots-clé
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Web of science
Création de la notice
01/03/2012 16:14
Dernière modification de la notice
03/03/2018 14:35
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