title: 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.affiliation: Department of Virology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kurosaki
authors.forename: Nao
authors.initials: N
authors.lastname: Nishida
authors.forename: Masaya
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Kentaro
authors.initials: K
authors.lastname: Matsuura
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yatsuhashi
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nishiguchi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hino
authors.forename: Shuhei
authors.initials: S
authors.lastname: Hige
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Itoh
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mochida
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.forename: Asako
authors.initials: A
authors.lastname: Koike
authors.forename: Fuminaka
authors.initials: F
authors.lastname: Sugauchi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Namiki
authors.initials: N
authors.lastname: Izumi
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007372:Interferons / Q000009:adverse effects / Q000627:therapeutic use*; D015810:Linkage Disequilibrium / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics*; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics*; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D011755:Pyrophosphatases; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase