Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.
Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.
Ge
Dongliang
D
Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina 27708, USA.
Fellay
Jacques
J
Thompson
Alexander J
AJ
Simon
Jason S
JS
Shianna
Kevin V
KV
Urban
Thomas J
TJ
Heinzen
Erin L
EL
Qiu
Ping
P
Bertelsen
Arthur H
AH
Muir
Andrew J
AJ
Sulkowski
Mark
M
McHutchison
John G
JG
Goldstein
David B
DB
D001741:Black or African American / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D002986:Clinical Trials as Topic; D005060:Europe / Q000208:ethnology; D005202:Asia, Eastern / Q000208:ethnology; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics* / Q000821:virology; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D010597:Pharmacogenetics; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011994:Recombinant Proteins; D019562:Viral Load; D000095022:Interferon Lambda
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C417083:peginterferon alfa-2b
J Virol. 2005 Mar;79(6):3851-4
15731279
Genome Res. 2008 Apr;18(4):640-3
18256235
N Engl J Med. 2009 Apr 30;360(18):1827-38
19403902
Hepatology. 2009 Apr;49(4):1335-74
19330875
Proc Natl Acad Sci U S A. 2008 May 13;105(19):7034-9
18467494
Hepatology. 1994 Jul;20(1 Pt 1):15-20
8020885
Nat Immunol. 2003 Jan;4(1):63-8
12469119
Nat Immunol. 2003 Jan;4(1):69-77
12483210
Gastroenterology. 2004 Apr;126(4):1015-23; discussion 947
15057741
N Engl J Med. 2004 May 27;350(22):2265-71
15163776
Nat Genet. 2001 Nov;29(3):265-9
11685208
Clin Infect Dis. 2008 Nov 15;47(10):1260-9
18834319
N Engl J Med. 2009 Aug 6;361(6):580-93
19625712
Am J Hum Genet. 2007 Sep;81(3):559-75
17701901
J Evol Biol. 2005 Sep;18(5):1368-73
16135132
World J Gastroenterol. 2008 Jun 7;14(21):3416-20
18528940
Nat Genet. 2006 Aug;38(8):904-9
16862161