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

• DOI: 10.1093/hmg/ddr249
• Publication Date: 2011-06-10T04:24:51Z
• 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
• Keywords: 0303 health sciences; Genotype; Hepatitis C, Chronic; Antiviral Agents; Polymorphism, Single Nucleotide; Thrombocytopenia; Linkage Disequilibrium; 3. Good health; 03 medical and health sciences; Ribavirin; Humans; Interferons; Pyrophosphatases; Genome-Wide Association Study

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.