DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Response to hepatitis C treatment. The EFO term Chronic Hepatitis C infection was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: Chronic Hepatitis C infection

SCORE TYPE:

P-Value

THRESHOLD:

<= 0.05

GENES IN THRESHOLD:

2

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-10-22

SPECIES:

AUTHORS:

Y Tanaka, M Kurosaki, N Nishida, M Sugiyama, K Matsuura, N Sakamoto, N Enomoto, H Yatsuhashi, S Nishiguchi, K Hino, S Hige, Y Itoh, E Tanaka, S Mochida, M Honda, Y Hiasa, A Koike, F Sugauchi, S Kaneko, N Izumi, K Tokunaga, M Mizokami

TITLE:

Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C.

JOURNAL:

Human molecular genetics Sep 2011, Vol 20, pp. 3507-16

ABSTRACT:

Hematologic abnormalities during current therapy with pegylated interferon and ribavirin (PEG-IFN/RBV) for chronic hepatitis C (CHC) often necessitate dose reduction and premature withdrawal from therapy. The aim of this study was to identify host factors associated with IFN-induced thrombocytopenia by genome-wide association study (GWAS). In the GWAS stage using 900K single-nucleotide polymorphism (SNP) microarrays, 303 Japanese CHC patients treated with PEG-IFN/RBV therapy were genotyped. One SNP (rs11697186) located on DDRGK1 gene on chromosome 20 showed strong associations in the minor-allele-dominant model with the decrease of platelet counts in response to PEG-IFN/RBV therapy [P = 8.17 × 10(-9); odds ratio (OR) = 4.6]. These associations were replicated in another sample set (n = 391) and the combined P-values reached 5.29 × 10(-17) (OR = 4.5). Fine mapping with 22 SNPs around DDRGK1 and ITPA genes showed that rs11697186 at the GWAS stage had a strong linkage disequilibrium with rs1127354, known as a functional variant in the ITPA gene. The ITPA-AA/CA genotype was independently associated with a higher degree of reduction in platelet counts at week 4 (P < 0.0001), as well as protection against the reduction in hemoglobin, whereas the CC genotype had significantly less reduction in the mean platelet counts compared with the AA/CA genotype (P < 0.0001 for weeks 2, 4, 8, 12), due to a reactive increase of the platelet count through weeks 1-4. Our present results may provide a valuable pharmacogenetic diagnostic tool for tailoring PEG-IFN/RBV dosing to minimize drug-induced adverse events. PUBMED: 21659334
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