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Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort
Katherine R Smith, Vijayaprakash Suppiah, Kate O'Connor, Thomas Berg, Martin Weltman, Maria Lorena Abate, Ulrich Spengler, Margaret Bassendine, Gail Mathews, William L Irving, Elizabeth Powell, Stephen Riordan, Golo Ahlenstiel, Graeme J Stewart, Melanie Bahlo, Jacob George, David R Booth and the International Hepatitis C Genetics Consortium (ihcgc)
Genome Medicine 2011, 3:57 doi:10.1186/gm273Published: 31 August 2011
The hepatitis C virus (HCV) infects nearly 3% of the World's population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B single nucleotide polymorphisms (SNPs), rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of HCV infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (more than 1%) haplotypes for IL28B, one tagged by rs8099917 minor allele, four tagged by rs12979860.
We used massively parallel sequencing of the IL28B and IL28A gene regions generated by polymerase chain reaction (PCR) from pooled DNA samples from 100 responders and 99 non-responders to therapy, to identify common variants. Variants that had high odds ratios and were validated were then genotyped in a cohort of 905 responders and non-responders. Their predictive power was assessed, alone and in combination with HLA-C.
Only SNPs in the IL28B linkage disequilibrium block predicted drug response. Eighteen SNPs were identified with evidence for association with drug response, and with a high degree of confidence in the sequence call. We found that two SNPs, rs4803221 (homozygote minor allele positive predictive value (PPV) of 77%) and rs7248668 (PPV 78%), predicted failure to respond better than the current best, rs8099917 (PPV 73%) and rs12979860 (PPV 68%) in this cross-sectional cohort. The best SNPs tagged a single common haplotype, haplotype 2. Genotypes predicted lack of response better than alleles. However, combination of IL28B haplotype 2 carrier status with the HLA-C C2C2 genotype, which has previously been reported to improve prediction in combination with IL28B, provides the highest PPV (80%). The haplotypes present alternative putative transcription factor binding and methylation sites.
Massively parallel sequencing allowed identification and comparison of the best common SNPs for identifying treatment failure in therapy for HCV. SNPs tagging a single haplotype have the highest PPV, especially in combination with HLA-C. The functional basis for the association may be due to altered regulation of the gene. These approaches have utility in improving diagnostic testing and identifying causal haplotypes or SNPs.
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Genome-wide association studies have identified 8q24 region variants as risk factors for prostate cancer. In the Agricultural Health Study, a prospective study of licensed pesticide applicators, we observed increased prostate cancer risk with specific pesticide use among those with a family history of prostate cancer. Thus, we evaluated the interaction among pesticide use, 8q24 variants, and prostate cancer risk. The authors estimated odds ratios (OR) and 95% confidence intervals (95% CI) for interactions among 211 8q24 variants, 49 pesticides, and prostate cancer risk in 776 cases and 1,444 controls. The ORs for a previously identified variant, rs4242382, and prostate cancer increased significantly (P < 0.05) with exposure to the organophosphate insecticide fonofos, after correction for multiple testing, with per allele ORnonexposed of 1.17 (95% CI, 0.93–1.48), per allele ORlow of 1.30 (95% CI, 0.75–2.27), and per allele ORhigh of 4.46 (95% CI, 2.17–9.17; P-interaction = 0.002, adjusted P-interaction = 0.02). A similar effect modification was observed for three other organophosphate insecticides (coumaphos, terbufos, and phorate) and one pyrethroid insecticide (permethrin). Among ever users of fonofos, subjects with three or four risk alleles at rs7837328 and rs4242382 had approximately three times the risk of prostate cancer (OR, 3.14; 95% CI, 1.41–7.00) compared with subjects who had zero risk alleles and never used fonofos. We observed a significant interaction among variants on chromosome 8q24, pesticide use, and risk of prostate cancer. Insecticides, particularly organophosphates, were the strongest modifiers of risk, although the biological mechanism is unclear. This is the first report of effect modification between 8q24 and an environmental exposure on prostate cancer risk. Cancer Res; 70(22); 9224–33. ©2010 AACR.cancerres.aacrjournals.org
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