Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C

• DOI: 10.1038/ng.449
• Publication Date: 2009-09-13T17:54:21Z
• Authors: Yasuhito Tanaka; Nao Nishida; Masaya Sugiyama; Masayuki Kurosaki; Kentaro Matsuura; Naoya Sakamoto; Mina Nakagawa; Masaaki Korenaga; Keisuke Hino; Shuhei Hige; Yoshito Ito; Eiji Mita; Eiji Tanaka; Satoshi Mochida; Yoshikazu Murawaki; Masao Honda; Akito Sakai; Yoichi Hiasa; Shuhei Nishiguchi; Asako Koike; Isao Sakaida; Masatoshi Imamura; Kiyoaki Ito; Koji Yano; Naohiko Masaki; Fuminaka Sugauchi; Namiki Izumi; Katsushi Tokunaga; Masashi Mizokami
• Keywords: Male; 0303 health sciences; Genome, Human; Interleukins; Interferon-alpha; Hepatitis C, Chronic; Antiviral Agents; Polymorphism, Single Nucleotide; 3. Good health; Drug Combinations; 03 medical and health sciences; Treatment Outcome; Asian People; Haplotypes; Ribavirin; Humans; Female; Interferons; Chromosomes, Human, Pair 19; Alleles; Genome-Wide Association Study

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).