Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.
The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).
Tanaka
Yasuhito
Y
Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Nishida
Nao
N
Sugiyama
Masaya
M
Kurosaki
Masayuki
M
Matsuura
Kentaro
K
Sakamoto
Naoya
N
Nakagawa
Mina
M
Korenaga
Masaaki
M
Hino
Keisuke
K
Hige
Shuhei
S
Ito
Yoshito
Y
Mita
Eiji
E
Tanaka
Eiji
E
Mochida
Satoshi
S
Murawaki
Yoshikazu
Y
Honda
Masao
M
Sakai
Akito
A
Hiasa
Yoichi
Y
Nishiguchi
Shuhei
S
Koike
Asako
A
Sakaida
Isao
I
Imamura
Masatoshi
M
Ito
Kiyoaki
K
Yano
Koji
K
Masaki
Naohiko
N
Sugauchi
Fuminaka
F
Izumi
Namiki
N
Tokunaga
Katsushi
K
Mizokami
Masashi
M
D000483:Alleles; D000998:Antiviral Agents / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D002888:Chromosomes, Human, Pair 19; D004338:Drug Combinations; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006239:Haplotypes; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012254:Ribavirin / Q000627:therapeutic use*; D016896:Treatment Outcome; D000095022:Interferon Lambda
D000998:Antiviral Agents; D004338:Drug Combinations; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda