Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.
Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.
Thomas
David L
DL
Johns Hopkins University, Division of Infectious Diseases, Baltimore, Maryland 21205, USA.
Thio
Chloe L
CL
Martin
Maureen P
MP
Qi
Ying
Y
Ge
Dongliang
D
O'Huigin
Colm
C
Kidd
Judith
J
Kidd
Kenneth
K
Khakoo
Salim I
SI
Alexander
Graeme
G
Goedert
James J
JJ
Kirk
Gregory D
GD
Donfield
Sharyne M
SM
Rosen
Hugo R
HR
Tobler
Leslie H
LH
Busch
Michael P
MP
McHutchison
John G
JG
Goldstein
David B
DB
Carrington
Mary
M
D000328:Adult; D000349:Africa / Q000208:ethnology; D005060:Europe / Q000208:ethnology; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000276:immunology*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000095022:Interferon Lambda
D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda