Titre
Genome wide analysis of patients from the ideal study identifies a causal role for ITPA genetic variation in ribavirin-induced hemolytic anemia
Type
abstract de conférence/colloque
Institution
Externe
Série
Journal of Hepatology
Auteur(s)
Thompson, A.J.
Auteure/Auteur
Fellay, J.
Auteure/Auteur
Ge, D.
Auteure/Auteur
Urban, T.
Auteure/Auteur
Shianna, K.
Auteure/Auteur
Sulkowski, M.
Auteure/Auteur
Muir, A.
Auteure/Auteur
Afdhal, N.
Auteure/Auteur
Jacobson, I.
Auteure/Auteur
Esteban, R.
Auteure/Auteur
Poordad, F.
Auteure/Auteur
Lawitz, E.
Auteure/Auteur
Mc Cone, J.
Auteure/Auteur
Shiffman, M.
Auteure/Auteur
Galler, G.
Auteure/Auteur
Lee, W.
Auteure/Auteur
Reindollar, R.
Auteure/Auteur
King, J.
Auteure/Auteur
Kwo, P.
Auteure/Auteur
Ghalib, R.
Auteure/Auteur
Freilich, B.
Auteure/Auteur
Nyberg, L.
Auteure/Auteur
Patel, K.
Auteure/Auteur
Tillmann, H.
Auteure/Auteur
Noviello, S.
Auteure/Auteur
Bopari, N.
Auteure/Auteur
Koury, K.
Auteure/Auteur
Pedicone, L.
Auteure/Auteur
Brass, C.
Auteure/Auteur
Albrecht, J.K.
Auteure/Auteur
Goldstein, D.
Auteure/Auteur
Mc Hutchison, J.G.
Auteure/Auteur
Liens vers les personnes
Titre du livre ou conférence/colloque
5th Annual Meeting of the European Association for the Study of the Liver
Adresse
Vienna, Austria, April 14-18, 2010
ISBN
0168-8278
Statut éditorial
Publié
Date de publication
2010
Volume
52
Première page
S470
Peer-reviewed
Oui
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.
PID Serval
serval:BIB_1E6FE0601CAC
Date de création
2012-03-01T14:14:31.981Z
Date de création dans IRIS
2025-05-20T16:46:15Z