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A single nucleotide polymorphism: variation between individuals in the nucleotide at a particular genetic locus that leads to alternative forms of the genotype being present in a population.
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The region around the IL28B gene on chromosome 19 and the SNPs associated with SVR in the four independent GWAS [13-16]. SNP: Single nucleotide polymorphism.
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Background
Worldwide, 130-170 million people are infected with the hepatitis C virus (HCV) [1]. Between 60 and 80% of patients fail to clear the virus acutely and develop chronic infection, with the long-term risks of cirrhosis, liver failure and hepatocellular carcinoma [1]. Chronic HCV infection (CHC) is the leading indication for liver transplantation around the world [1].
Combination therapy with pegylated-IFN-α(Peg-IFN) and ribavirin (RBV) is the current standard-of-care (SOC) therapy for CHC. Unfortunately, treatment is expensive and response rates are poor [2-6]. Only 42-52% of HCV genotype 1 (HCV-1) patients achieve a sustained virological response (SVR), defined as undetectable HCV RNA 6 months post-therapy. Treatment success is higher in HCV genotypes 2 and 3 (HCV-2/3), with SVR rates of approximately 75-80%. Therapy is often poorly tolerated owing to the significant side effects, and, in the major registration studies, 10-14% of patients required premature cessation of treatment [2-4].
Several host and viral factors have previously been reported to be associated with SVR, including HCV genotype, baseline serum HCV RNA level, age, gender, hepatic fibrosis stage, hepatic steatosis, insulin resistance and body mass index [5-8]. Ethnicity has also been demonstrated to affect treatment outcome with African-Americans having the lowest response rates to therapy [6-10]; approximately half that observed in Caucasians. This difference in response rates between ethnic groups strongly suggests the existence of a genetic determinant of treatment response.
Unfortunately, in the pretreatment setting, none of these factors predicts treatment outcome with sufficient accuracy to be used as a reliable tool in determining which patients will ultimately achieve an SVR. Taking into consideration the toxicities and cost of treatment together with the overall poor response to therapy, identification of biomarkers of SVR prior to initiation of treatment is critical.
Genome-wide association studies & pharmacogenetics
A single nucleotide polymorphism (SNP) is defined as a variation in a single nucleotide (adenine, thymine, guanosine or cytosine)...