Genome-wide association study of epirubicin-induced leukopenia in Japanese patients

Yuvaraj Srinivasan, Mitsunori Sasa, Junko Honda, Atsushi Takahashi, Satoko Uno, Naoyuki Kamatani, Michiaki Kubo, Yusuke Nakamura, Hitoshi Zembutsu

Research output: Contribution to journalArticle

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Abstract

Objectives: Despite long-term clinical experience with epirubicin, unpredictable severe adverse reactions remain an important determinant to limit the drug use. To identify a genetic factor(s) affecting the risk of epirubicin-induced leukopenia/neutropenia, we performed a genome-wide association study. Methods: We studied 270 patients consisting of 67 patients with grade 3 or 4 leukopenia/neutropenia, and 203 patients showing no toxicity (patients with grade 1 or 2 were excluded from the study) for genome-wide association study. We further examined the single nucleotide polymorphisms (SNPs) showing P values of less than 0.0001 using an additional set of 48 patients with grade 3/4 leukopenia/neutropenia. Results: The combined analysis indicated that rs2916733 in microcephalin 1 [combined PFisher min=2.27×10 -9, odds ratio (OR)=2.74 with 95% confidence interval (CI)=1.96-3.83; the nonrisk genotype as reference] was significantly associated with epirubicin-induced leukopenia/neutropenia. A subgroup analysis of patients with only breast cancer showed a similar trend of association for the marker SNP rs2916733 (combined PFisher min=6.76×10 -7, OR=2.80 with 95% CI=1.86-4.21). We subsequently performed haplotype analysis and found that a haplotype constructed from rs2916733 and rs1031309, which was in linkage disequilibrium with rs2916733 (r 2=0.64), showed stronger association (P=2.20×10 -10, OR=2.88 with 95% CI=2.05-4.03) than a single landmark SNP (rs2916733; P=2.27×10 -9, OR=2.74 with 95% CI=1.96-3.83), suggesting that causative variant(s) that could influence the susceptibility of epirubicin-induced adverse drug reactions (ADRs) might exist in this haplotype. Conclusion: Our findings show that genetic variants in the microcephalin 1 locus are suggestively associated with the risk of epirubicin-induced ADRs and might be applicable in development of diagnostic system for predicting the risk of the ADRs, leading to better prognosis and quality of life for patients with cancer. However, these results should be considered preliminary until replicated in adequately larger powered and controlled samples.

Original languageEnglish
Pages (from-to)552-558
Number of pages7
JournalPharmacogenetics and Genomics
Volume21
Issue number9
DOIs
Publication statusPublished - 01-09-2011
Externally publishedYes

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Epirubicin
Genome-Wide Association Study
Leukopenia
Neutropenia
Drug-Related Side Effects and Adverse Reactions
Odds Ratio
Confidence Intervals
Haplotypes
Single Nucleotide Polymorphism
Linkage Disequilibrium
Genotype
Quality of Life
Breast Neoplasms
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Srinivasan, Y., Sasa, M., Honda, J., Takahashi, A., Uno, S., Kamatani, N., ... Zembutsu, H. (2011). Genome-wide association study of epirubicin-induced leukopenia in Japanese patients. Pharmacogenetics and Genomics, 21(9), 552-558. https://doi.org/10.1097/FPC.0b013e328348e48f
Srinivasan, Yuvaraj ; Sasa, Mitsunori ; Honda, Junko ; Takahashi, Atsushi ; Uno, Satoko ; Kamatani, Naoyuki ; Kubo, Michiaki ; Nakamura, Yusuke ; Zembutsu, Hitoshi. / Genome-wide association study of epirubicin-induced leukopenia in Japanese patients. In: Pharmacogenetics and Genomics. 2011 ; Vol. 21, No. 9. pp. 552-558.
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abstract = "Objectives: Despite long-term clinical experience with epirubicin, unpredictable severe adverse reactions remain an important determinant to limit the drug use. To identify a genetic factor(s) affecting the risk of epirubicin-induced leukopenia/neutropenia, we performed a genome-wide association study. Methods: We studied 270 patients consisting of 67 patients with grade 3 or 4 leukopenia/neutropenia, and 203 patients showing no toxicity (patients with grade 1 or 2 were excluded from the study) for genome-wide association study. We further examined the single nucleotide polymorphisms (SNPs) showing P values of less than 0.0001 using an additional set of 48 patients with grade 3/4 leukopenia/neutropenia. Results: The combined analysis indicated that rs2916733 in microcephalin 1 [combined PFisher min=2.27×10 -9, odds ratio (OR)=2.74 with 95{\%} confidence interval (CI)=1.96-3.83; the nonrisk genotype as reference] was significantly associated with epirubicin-induced leukopenia/neutropenia. A subgroup analysis of patients with only breast cancer showed a similar trend of association for the marker SNP rs2916733 (combined PFisher min=6.76×10 -7, OR=2.80 with 95{\%} CI=1.86-4.21). We subsequently performed haplotype analysis and found that a haplotype constructed from rs2916733 and rs1031309, which was in linkage disequilibrium with rs2916733 (r 2=0.64), showed stronger association (P=2.20×10 -10, OR=2.88 with 95{\%} CI=2.05-4.03) than a single landmark SNP (rs2916733; P=2.27×10 -9, OR=2.74 with 95{\%} CI=1.96-3.83), suggesting that causative variant(s) that could influence the susceptibility of epirubicin-induced adverse drug reactions (ADRs) might exist in this haplotype. Conclusion: Our findings show that genetic variants in the microcephalin 1 locus are suggestively associated with the risk of epirubicin-induced ADRs and might be applicable in development of diagnostic system for predicting the risk of the ADRs, leading to better prognosis and quality of life for patients with cancer. However, these results should be considered preliminary until replicated in adequately larger powered and controlled samples.",
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Srinivasan, Y, Sasa, M, Honda, J, Takahashi, A, Uno, S, Kamatani, N, Kubo, M, Nakamura, Y & Zembutsu, H 2011, 'Genome-wide association study of epirubicin-induced leukopenia in Japanese patients', Pharmacogenetics and Genomics, vol. 21, no. 9, pp. 552-558. https://doi.org/10.1097/FPC.0b013e328348e48f

Genome-wide association study of epirubicin-induced leukopenia in Japanese patients. / Srinivasan, Yuvaraj; Sasa, Mitsunori; Honda, Junko; Takahashi, Atsushi; Uno, Satoko; Kamatani, Naoyuki; Kubo, Michiaki; Nakamura, Yusuke; Zembutsu, Hitoshi.

In: Pharmacogenetics and Genomics, Vol. 21, No. 9, 01.09.2011, p. 552-558.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study of epirubicin-induced leukopenia in Japanese patients

AU - Srinivasan, Yuvaraj

AU - Sasa, Mitsunori

AU - Honda, Junko

AU - Takahashi, Atsushi

AU - Uno, Satoko

AU - Kamatani, Naoyuki

AU - Kubo, Michiaki

AU - Nakamura, Yusuke

AU - Zembutsu, Hitoshi

PY - 2011/9/1

Y1 - 2011/9/1

N2 - Objectives: Despite long-term clinical experience with epirubicin, unpredictable severe adverse reactions remain an important determinant to limit the drug use. To identify a genetic factor(s) affecting the risk of epirubicin-induced leukopenia/neutropenia, we performed a genome-wide association study. Methods: We studied 270 patients consisting of 67 patients with grade 3 or 4 leukopenia/neutropenia, and 203 patients showing no toxicity (patients with grade 1 or 2 were excluded from the study) for genome-wide association study. We further examined the single nucleotide polymorphisms (SNPs) showing P values of less than 0.0001 using an additional set of 48 patients with grade 3/4 leukopenia/neutropenia. Results: The combined analysis indicated that rs2916733 in microcephalin 1 [combined PFisher min=2.27×10 -9, odds ratio (OR)=2.74 with 95% confidence interval (CI)=1.96-3.83; the nonrisk genotype as reference] was significantly associated with epirubicin-induced leukopenia/neutropenia. A subgroup analysis of patients with only breast cancer showed a similar trend of association for the marker SNP rs2916733 (combined PFisher min=6.76×10 -7, OR=2.80 with 95% CI=1.86-4.21). We subsequently performed haplotype analysis and found that a haplotype constructed from rs2916733 and rs1031309, which was in linkage disequilibrium with rs2916733 (r 2=0.64), showed stronger association (P=2.20×10 -10, OR=2.88 with 95% CI=2.05-4.03) than a single landmark SNP (rs2916733; P=2.27×10 -9, OR=2.74 with 95% CI=1.96-3.83), suggesting that causative variant(s) that could influence the susceptibility of epirubicin-induced adverse drug reactions (ADRs) might exist in this haplotype. Conclusion: Our findings show that genetic variants in the microcephalin 1 locus are suggestively associated with the risk of epirubicin-induced ADRs and might be applicable in development of diagnostic system for predicting the risk of the ADRs, leading to better prognosis and quality of life for patients with cancer. However, these results should be considered preliminary until replicated in adequately larger powered and controlled samples.

AB - Objectives: Despite long-term clinical experience with epirubicin, unpredictable severe adverse reactions remain an important determinant to limit the drug use. To identify a genetic factor(s) affecting the risk of epirubicin-induced leukopenia/neutropenia, we performed a genome-wide association study. Methods: We studied 270 patients consisting of 67 patients with grade 3 or 4 leukopenia/neutropenia, and 203 patients showing no toxicity (patients with grade 1 or 2 were excluded from the study) for genome-wide association study. We further examined the single nucleotide polymorphisms (SNPs) showing P values of less than 0.0001 using an additional set of 48 patients with grade 3/4 leukopenia/neutropenia. Results: The combined analysis indicated that rs2916733 in microcephalin 1 [combined PFisher min=2.27×10 -9, odds ratio (OR)=2.74 with 95% confidence interval (CI)=1.96-3.83; the nonrisk genotype as reference] was significantly associated with epirubicin-induced leukopenia/neutropenia. A subgroup analysis of patients with only breast cancer showed a similar trend of association for the marker SNP rs2916733 (combined PFisher min=6.76×10 -7, OR=2.80 with 95% CI=1.86-4.21). We subsequently performed haplotype analysis and found that a haplotype constructed from rs2916733 and rs1031309, which was in linkage disequilibrium with rs2916733 (r 2=0.64), showed stronger association (P=2.20×10 -10, OR=2.88 with 95% CI=2.05-4.03) than a single landmark SNP (rs2916733; P=2.27×10 -9, OR=2.74 with 95% CI=1.96-3.83), suggesting that causative variant(s) that could influence the susceptibility of epirubicin-induced adverse drug reactions (ADRs) might exist in this haplotype. Conclusion: Our findings show that genetic variants in the microcephalin 1 locus are suggestively associated with the risk of epirubicin-induced ADRs and might be applicable in development of diagnostic system for predicting the risk of the ADRs, leading to better prognosis and quality of life for patients with cancer. However, these results should be considered preliminary until replicated in adequately larger powered and controlled samples.

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