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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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Association of APE1 and hOGG1 polymorphisms with colorectal cancer risk in a Turkish population.
Curr Med Res Opin. 2011 May 12;
Authors: Canbay E, Cakmakoglu B, Zeybek U, Sozen S, Cacina C, Gulluoglu M, Balik E, Bulut T, Yamaner S, Bugra D
Abstract Background: There is growing evidence describing DNA repair genes polymorphisms are related to increased cancer risk including colorectal cancer (CRC). The aim of this study was to investigate the associations between the APE1 Asp148Glu, hOGG1 Ser326Cys, XRCC1 Arg399Gln, XRCC3 Thr241Met, XPD Lys751Gln, XPG Asp1104His polymorphisms and CRC risk in Turkish population. Patients and methods: Polymorphisms of APE1 Asp148Glu (rs3136820), hOGG1 Ser326Cys (rs1052133), XRCC1 Arg399Gln(rs25487), XRCC3 Thr241Met (rs861539), XPD Lys751Gln (rs13181), and XPG Asp1104His (rs17655) were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods in blood samples of 79 CRC patients at their initial staging and 247 healthy controls. Of the CRC patients, 26 out of 40 were diagnosed with rectal cancer and received neoadjuvant chemoradiotherapy following diagnosis; 39 others were diagnosed as colon cancer. Results: Our preliminary results showed that frequencies of Glu allele of APE1 Asp148Glu and Cys allele of hOGG1 Ser326Cys were higher in CRC patients than in controls (p?=?0.006, OR: 3.43; 95% CI: 1.76-6.70; p?=?0.000, OR: 2.77; 95% CI: 1.40-5.48, respectively). Higher frequency of Met allele of XRCC3 Thr241Met was detected in patients treated with neoadjuvant chemoradiotherapy (p?=?0.024, OR: 5.25; 95% CI: 1.23-23.39) and with proximal colon tumors (p?=?0.04, OR: 2; 95% CI: 1.18-3.34). Increased frequency of Ser/Ser genotype of hOGG1 Ser326Cys was found to be associated both with higher grade (p?=?0.001, OR: 6.4; 95% CI: 2.69-62.69) and liver metastasis (p?=?0.005, OR: 7.5; 95% CI: 0.7-68.36). Conclusion: APE1 Asp148Glu and hOGG1 Ser326Cys polymorphisms might be associated with increasing risk of CRC in a Turkish population. Future studies with larger-sized samples, as well as detecting the association of DNA repair genes with other confounding factors will help elucidate the exact roles of DNA repair genes polymorphisms in development and progression of CRC.
PMID: 21561390 [PubMed - as supplied by publisher]www.ncbi.nlm.nih.gov
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