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.