A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus

被引：764

作者：

Prokunina-Olsson, Ludmila ^{[1
]}

Muchmore, Brian ^{[1
]}

Tang, Wei ^{[1
]}

Pfeiffer, Ruth M. ^{[2
]}

Park, Heiyoung ^{[3
]}

Dickensheets, Harold ^{[4
]}

Hergott, Dianna ^{[1
,5
]}

Porter-Gill, Patricia ^{[1
]}

Mumy, Adam ^{[1
]}

Kohaar, Indu ^{[1
]}

Chen, Sabrina ^{[6
]}

Brand, Nathan ^{[1
]}

Tarway, McAnthony ^{[1
]}

Liu, Luyang ^{[1
]}

Sheikh, Faruk ^{[4
]}

Astemborski, Jacquie ^{[7
]}

Bonkovsky, Herbert L. ^{[8
]}

Edlin, Brian R. ^{[9
,10
]}

Howell, Charles D. ^{[11
]}

Morgan, Timothy R. ^{[12
,13
]}

Thomas, David L. ^{[7
,14
]}

Rehermann, Barbara ^{[3
]}

Donnelly, Raymond P. ^{[4
]}

O'Brien, Thomas R. ^{[5
]}

机构：

[1] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, US NIH, Bethesda, MD 20892 USA

[2] NCI, Biostat Branch, Div Canc Epidemiol & Genet, US NIH, Bethesda, MD 20892 USA

[3] NIDDK, Immunol Sect, Liver Dis Branch, US NIH, Bethesda, MD 20892 USA

[4] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA

[5] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, US NIH, Bethesda, MD 20892 USA

[6] Informat Management Serv Inc, Silver Spring, MD USA

[7] Johns Hopkins Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[8] Carolinas Med Ctr, Dept Med, Charlotte, NC 28203 USA

[9] Natl Dev & Res Inst Inc, New York, NY USA

[10] Cornell Univ, Ctr Study Hepatitis C, Weill Med Coll, New York, NY 10021 USA

[11] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

[12] Vet Affairs VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA

[13] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA

[14] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 02期

基金：

美国国家卫生研究院;

关键词：

EARLY VIRAL KINETICS; INTERLEUKIN; 28B; MULTIETHNIC COHORT; STIMULATED GENES; LAMBDA; EXPRESSION; GENOTYPE; RIBAVIRIN; THERAPY; FOS;

D O I：

10.1038/ng.2521

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or Delta G), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[Delta G] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-lambda 4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.

引用

页码：164 / 171

页数：8

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