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Common genetic variants do not associate with IFN-induced neutropenia in a genome-wide association study of chronic hepatitis C patients in the ideal study
Titre de la conférence
61st Annual Meeting of the American Association for the Study of Liver Diseases
Boston, United-States, October 29-November 2, 2010
Date de publication
Publication type : Meeting Abstract
Background/Aims: Interferonα-related neutropenia is a commonand frequently dose-limiting toxicity of treatment forchronic HCV infection. We performed a genome wide associationstudy (GWAS) on a large, well characterized genotype 1HCV treatment cohort to identify genetic determinants of IFNrelatedneutropenia and leukopenia. Methods: 1604/3070patients treated with peginterferonα (pegIFN) and RBV in theIDEAL study consented to DNA testing. Inclusion criteria for theparent study included an absolute neutrophil count(ANC)≥1500/mm3. Samples were genotyped using the IlluminaHuman610-quad BeadChip. After quality control, 97.5%of the single nucleotide polymorphisms (SNPs) included on thechip were used in the analyses. The primary analysis focusedon the genetic determinants of quantitative change in ANCfrom baseline to week 4 of treatment, in 3 separate populations(Caucasians (Cauc), African Americans (AA), Hispanics (His))using linear regression, adjusting for: age, gender, weight, liverfibrosis, baseline Hb level, RBV dose, type/dose of pegIFN,and treatment compliance. Wk4 was chosen to minimize confoundingby dose modification. Separate GWAS analyses ofwk4 reduction in lymphocyte (Lφ) and total white cell counts(WCC) were performed. A modified Eigenstrat method controlledfor population stratification, and Bonferroni adjustmentcorrected for multiple testing. Results: The final analysis of ANCincluded 1286 patients (Cauc=988, AA=198, His=100). Baselinemedian ANC: Cauc=3.7 (3.0-4.7), AA=3.1 (2.2-4.1),His=3.4 (2.8-4.3), P=10-10. Median ANC reduction at wk4:Cauc=2.0 (1.4-2.7), AA=1.3 (0.6-2.0), His=1.7 (0.9-2.4),P=10-16. In the genome-wide analysis, no common geneticvariants were significantly associated with treatment-relatedreduction in ANC at wk4 (threshold for significance, P<8x10-8). In particular, IL28B genotype was not associated with IFNrelatedneutropenia. A genome-wide analysis of baseline ANCwas also negative. In AA, we noted associations between baselineANC and DARC gene polymorphism but these did not meetgenome-wide significance criteria (top SNP rs3027041, P=10-6; DARC variants have been associated with low ANC in AA).Separate GWAS did not identify any SNPs to be significantlyassociated with either baseline or wk4 reductions of Lφ or totalWCC. Conclusions: No common genetic variants were associatedwith pegIFN-induced neutropenia or leucopenia. This suggeststhe mechanism of pegIFN-induced bone marrowsuppression is not related to the biology of the IL28B-pegIFNHCV treatment response association
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