Application of a Combination of a Knowledge-Based Algorithm and 2-Stage Screening to Hypothesis-Free Genomic Data on Irinotecan-Treated Patients for Identification of a Candidate Single Nucleotide Polymorphism Related to an Adverse Effect
| Autor: | Hiromi Sakamoto, Tetsuya Hamaguchi, Yoshiro Saito, Risa Ichinohe, Haruhiro Okuda, Atsushi Ohtsu, Hiro Takahashi, Kimie Sai, Nahoko Kaniwa, Jun-ichi Sawada, Yasuhiro Matsumura, Yasuhiro Shimada, Anna Takahashi, Toshihiko Doi, Teruhiko Yoshida, Takayuki Yoshino, Yoko Odaka, Ayano Doi, Misuzu Okuyama, Nagahiro Saijo |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Diarrhea Male Epidemiology Bioinformatics Knowledge Bases lcsh:Medicine Health Informatics Single-nucleotide polymorphism Genome-wide association study Research and Analysis Methods Irinotecan Polymorphism Single Nucleotide Disease Informatics Database and Informatics Methods Neoplasms Medicine and Health Sciences Humans SNP Medicine lcsh:Science Multidisciplinary KCNQ Potassium Channels Genome Human business.industry lcsh:R Cancer Genomics medicine.disease Antineoplastic Agents Phytogenic Exact test ROC Curve Pharmacogenomics Multiple comparisons problem lcsh:Q Camptothecin Female business Algorithm Algorithms Research Article Genome-Wide Association Study medicine.drug |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 8, p e105160 (2014) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0105160 |
| Popis: | Interindividual variation in a drug response among patients is known to cause serious problems in medicine. Genomic information has been proposed as the basis for "personalized" health care. The genome-wide association study (GWAS) is a powerful technique for examining single nucleotide polymorphisms (SNPs) and their relationship with drug response variation; however, when using only GWAS, it often happens that no useful SNPs are identified due to multiple testing problems. Therefore, in a previous study, we proposed a combined method consisting of a knowledge-based algorithm, 2 stages of screening, and a permutation test for identifying SNPs. In the present study, we applied this method to a pharmacogenomics study where 109,365 SNPs were genotyped using Illumina Human-1 BeadChip in 168 cancer patients treated with irinotecan chemotherapy. We identified the SNP rs9351963 in potassium voltage-gated channel subfamily KQT member 5 (KCNQ5) as a candidate factor related to incidence of irinotecan-induced diarrhea. The p value for rs9351963 was 3.31×10-5 in Fisher's exact test and 0.0289 in the permutation test (when multiple testing problems were corrected). Additionally, rs9351963 was clearly superior to the clinical parameters and the model involving rs9351963 showed sensitivity of 77.8% and specificity of 57.6% in the evaluation by means of logistic regression. Recent studies showed that KCNQ4 and KCNQ5 genes encode members of the M channel expressed in gastrointestinal smooth muscle and suggested that these genes are associated with irritable bowel syndrome and similar peristalsis diseases. These results suggest that rs9351963 in KCNQ5 is a possible predictive factor of incidence of diarrhea in cancer patients treated with irinotecan chemotherapy and for selecting chemotherapy regimens, such as irinotecan alone or a combination of irinotecan with a KCNQ5 opener. Nonetheless, clinical importance of rs9351963 should be further elucidated. |
| Databáze: | OpenAIRE |
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