title: Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C.
abstract: Cytopenia during interferon-based (IFN-based) therapy for chronic hepatitis C (CHC) often necessitates reduction of doses of drugs and premature withdrawal from therapy resulting in poor response to treatment. To identify genetic variants associated with IFN-induced neutropenia, we conducted a genome-wide association study (GWAS) in 416 Japanese CHC patients receiving IFN-based therapy. Based on the results, we selected 192 candidate single nucleotide polymorphisms (SNPs) to carry out a replication analysis in an independent set of 404 subjects. The SNP rs2305482, located in the intron region of the PSMD3 gene on chromosome 17, showed a strong association when the results of GWAS and the replication stage were combined (OR = 2.18, P = 3.05 × 10(-7) in the allele frequency model). Logistic regression analysis showed that rs2305482 CC and neutrophil count at baseline were independent predictive factors for IFN-induced neutropenia (OR = 2.497, P = 0.0072 and OR = 0.998, P < 0.0001, respectively). Furthermore, rs2305482 genotype was associated with the doses of pegylated interferon (PEG-IFN) that could be tolerated in hepatitis C virus genotype 1-infected patients treated with PEG-IFN plus ribavirin, but not with treatment efficacy. Our results suggest that genetic testing for this variant might be useful for establishing personalized drug dosing in order to minimize drug-induced adverse events.
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, 467-8601, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Iio
authors.forename: Kentaro
authors.initials: K
authors.lastname: Matsuura
authors.forename: Nao
authors.initials: N
authors.lastname: Nishida
authors.forename: Shinya
authors.initials: S
authors.lastname: Maekawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.forename: Mina
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yatsuhashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kurosaki
authors.forename: Namiki
authors.initials: N
authors.lastname: Izumi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.forename: Naohiko
authors.initials: N
authors.lastname: Masaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ide
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hino
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tamori
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mochida
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nomura
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nishiguchi
authors.forename: Chiaki
authors.initials: C
authors.lastname: Okuse
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Itoh
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Isao
authors.initials: I
authors.lastname: Sakaida
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Shuhei
authors.initials: S
authors.lastname: Hige
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects* / Q000627:therapeutic use; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics*; D011092:Polyethylene Glycols / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D046988:Proteasome Endopeptidase Complex; C548045:proteasome activator PA700 subunit p58, human; C100416:peginterferon alfa-2a