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


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Inproceedings: an article in a conference proceedings.
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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
Title of the conference
61st Annual Meeting of the American Association for the Study of Liver Diseases
Thompson A.J., Clark P.J., Singh A., Ge D., Fellay J., Sulkowski M.S., Muir A.J., Tillman H.L., Patel K., Naggie S., Shianna K., Afdhal N.H., Jacobson I.M., Esteban R., Poordad F., Lawitz E., McCone J., Shiffman M.L., Galler G.W., King J.W., Kwo P.Y., Nyberg L., Noviello S., Boparai N., Koury K.J., Pedicone L., Brass C.A., Albrecht J.K., Goldstein D.B., McHutchison J.G.
Boston, United-States, October 29-November 2, 2010
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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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01/03/2012 15:14
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20/08/2019 14:23
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