RESUMO
Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.
Assuntos
Anemia Hemolítica/induzido quimicamente , Anemia Hemolítica/genética , Variação Genética/genética , Hepatite C Crônica/tratamento farmacológico , Pirofosfatases/genética , Alelos , Anemia Hemolítica/complicações , Antivirais , Cromossomos Humanos Par 20 , Europa (Continente)/etnologia , Estudo de Associação Genômica Ampla , Hemoglobinas/deficiência , Hemoglobinas/metabolismo , Hepatite C Crônica/complicações , Humanos , Polimorfismo de Nucleotídeo Único/genética , Pirofosfatases/deficiência , Pirofosfatases/metabolismo , Grupos Raciais/genética , Ribavirina/uso terapêutico , Estados Unidos , Inosina TrifosfataseRESUMO
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.