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

PLoS One. 2014 Aug 15;9(8):e105160. doi: 10.1371/journal.pone.0105160. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Algorithms
  • Antineoplastic Agents, Phytogenic / adverse effects*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use
  • Diarrhea / chemically induced*
  • Diarrhea / genetics
  • Female
  • Genome, Human
  • Genome-Wide Association Study
  • Genomics
  • Humans
  • Irinotecan
  • KCNQ Potassium Channels / genetics*
  • Knowledge Bases
  • Male
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Polymorphism, Single Nucleotide
  • ROC Curve

Substances

  • Antineoplastic Agents, Phytogenic
  • KCNQ Potassium Channels
  • KCNQ5 protein, human
  • Irinotecan
  • Camptothecin

Grant support

This work was supported in part by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT): Grants-in-Aid for Scientific Research for Young Scientists (B) (nos. 21710211 and 24710222 to H.T.) and Grant-in-Aid for Scientific Research on Innovative Areas (no. 26114703 to H.T.). This work was also supported by the Advanced Research for Medical Products Mining Program of the National Institute of Biomedical Innovation (NIBIO ID10-41), the Futaba Electronics Memorial Foundation, the Research Foundation for the Electrotechnology of Chubu, and the Nakajima Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.