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

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.

• Authors: Yasuhito Tanaka, Masayuki Kurosaki, Nao Nishida, Masaya Sugiyama, Kentaro Matsuura, Naoya Sakamoto, Nobuyuki Enomoto, Hiroshi Yatsuhashi, Shuhei Nishiguchi, Keisuke Hino, Shuhei Hige, Yoshito Itoh, Eiji Tanaka, Satoshi Mochida, Masao Honda, Yoichi Hiasa, Asako Koike, Fuminaka Sugauchi, Shuichi Kaneko, Namiki Izumi, Katsushi Tokunaga, Masashi Mizokami
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 20 Issue 17 Pg. 3507-16 (Sep 01 2011) ISSN: 1460-2083 [Electronic] England
• PMID: 21659334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Ribavirin
• Interferons
• Pyrophosphatases
• ITPA protein, human

Topics

• Antiviral Agents (adverse effects, therapeutic use)
• Genome-Wide Association Study (methods)
• Genotype
• Hepatitis C, Chronic (drug therapy)
• Humans
• Interferons (adverse effects, therapeutic use)
• Linkage Disequilibrium (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Pyrophosphatases (genetics)
• Ribavirin (adverse effects, therapeutic use)
• Thrombocytopenia (chemically induced, genetics)