Genome-wide association study identifies an association between ITPA gene variants and IFN-induced thrombocytopenia in chronic hepatitis C patients from the ideal study


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Inproceedings: an article in a conference proceedings.
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Abstract (Abstract): shot summary in a article that contain essentials elements presented during a scientific conference, lecture or from a poster.
Genome-wide association study identifies an association between ITPA gene variants and IFN-induced thrombocytopenia in chronic hepatitis C patients from the ideal study
Title of the conference
61st Annual Meeting of the American Association for the Study of Liver Diseases
Thompson A.J., Singh A., Fellay J., Ge D., Sulkowski M.S., Muir A.J., Tillmann 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.M., 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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Issued date
Publication type : Meeting Abstract
Background/Aims: Interferon-α(IFN)-related thrombocytopenia
is common and may be dose-limiting. We performed a genome
wide association study on a well-characterized genotype 1
HCV treatment cohort to identify genetic determinants of IFNrelated
thrombocytopenia. Methods: 1604/3070 patients in
the IDEAL study consented to DNA testing. Inclusion criteria for
the parent study included a platelet (Pl) count ≥ 80,000/mm3.
Samples were 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 primary analyses focused on genetic determinants
of quantitative change in Pl count at wk4 of treatment in
compliant (≥ 80%) patients (wk4 chosen to minimize confounding
by dose modification). 3 separate populations (Caucasians,
African Americans, Hispanics) were analyzed using
linear regression, adjusting for age, gender, weight, liver fibrosis,
baseline Hb level, RBV dose, type/dose of pegIFN. A modified
Eigenstrat method controlled for population stratification,
and Bonferroni adjustment corrected for multiple testing.
Results: The final analysis included 1286 patients. 6 SNPs on
chromosome 20 were significantly and positively associated
with Pl reduction at week 4 (top SNP rs965469,overall P=10-
10). No other loci were associated. These tag SNPs have previously
been shown to be in high linkage disequilibrium with 2
functional variants in the ITPA gene, rs1127354 and
rs7270101, that cause ITPase deficiency and protect against
RBV-induced hemolytic anemia (HA). These 2 SNPs showed
strong independent associations with Pl reduction (rs1127354
P=10-12, rs7270101 P=10-7, combined variable =10-20) and
entirely explained the genome-wide significant association
(rs965469, P=0.8 in a model containing the 2 functional variants).
Hb decline was strongly inversely correlated with Pl
reduction at wk4 (P=10-18). We tested whether the association
between Pl reduction and ITPA variants might indirectly reflect
an association between anemia and relative reactive thrombocytosis,
which was attenuating the IFN-effect on Pl counts. Inclusion
of Hb decline into the regression model with the 2 ITPA
variants significantly attenuated the strength of the association
between the ITPA variants and Pl reduction (from 10-20 to 10-
7). Conclusions: In CHC patients, two functional variants in the
ITPA gene that are strongly associated with protection from RBVinduced
HA are also associated with greater thrombocytopenia.
This association is largely explained by a relative reactive
thrombocytosis in response to RBV-induced HA, which attenuates
IFN-related thrombocytopenia.
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01/03/2012 16:14
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