Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults

Quinn S. Wells; Olivia J. Veatch; Joshua P. Fessel; Aron Y. Joon; Rebecca T. Levinson; Jonathan D. Mosley; Elizabeth P. Held; Chase S. Lindsay; Christian M. Shaffer; Peter E. Weeke; Andrew M. Glazer; Kevin R. Bersell; Sara L. Van Driest; Jason H. Karnes; Marcia A. Blair; Lore W. Lagrone; Yan R. Su; Erica A. Bowton; Ziding Feng; Bonnie Ky; Daniel J. Lenihan; Michael J. Fisch; Joshua C. Denny; Dan M. Roden

doi:10.1097/FPC.0000000000000284

Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults

Quinn S. Wells, Olivia J. Veatch, Joshua P. Fessel, Aron Y. Joon, Rebecca T. Levinson, Jonathan D. Mosley, Elizabeth P. Held, Chase S. Lindsay, Christian M. Shaffer, Peter E. Weeke, Andrew M. Glazer, Kevin R. Bersell, Sara L. Van Driest, Jason H. Karnes, Marcia A. Blair, Lore W. Lagrone, Yan R. Su, Erica A. Bowton, Ziding Feng, Bonnie KyDaniel J. Lenihan, Michael J. Fisch, Joshua C. Denny, Dan M. Roden

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

Background Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy. Methods We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10_-5 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants. Results Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10_-7 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling. Conclusion Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.

Original language	English (US)
Pages (from-to)	247-254
Number of pages	8
Journal	Pharmacogenetics and Genomics
Volume	27
Issue number	7
DOIs	https://doi.org/10.1097/FPC.0000000000000284
State	Published - 2017
Externally published	Yes

Keywords

Anthracycline
Cardiotoxicity
Genome-wide association study
Pathway analysis

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
General Pharmacology, Toxicology and Pharmaceutics
Genetics(clinical)

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10.1097/FPC.0000000000000284

Cite this

Wells, Q. S., Veatch, O. J., Fessel, J. P., Joon, A. Y., Levinson, R. T., Mosley, J. D., Held, E. P., Lindsay, C. S., Shaffer, C. M., Weeke, P. E., Glazer, A. M., Bersell, K. R., Van Driest, S. L., Karnes, J. H., Blair, M. A., Lagrone, L. W., Su, Y. R., Bowton, E. A., Feng, Z., ... Roden, D. M. (2017). Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults. Pharmacogenetics and Genomics, 27(7), 247-254. https://doi.org/10.1097/FPC.0000000000000284

Wells, QS, Veatch, OJ, Fessel, JP, Joon, AY, Levinson, RT, Mosley, JD, Held, EP, Lindsay, CS, Shaffer, CM, Weeke, PE, Glazer, AM, Bersell, KR, Van Driest, SL, Karnes, JH, Blair, MA, Lagrone, LW, Su, YR, Bowton, EA, Feng, Z, Ky, B, Lenihan, DJ, Fisch, MJ, Denny, JC & Roden, DM 2017, 'Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults', Pharmacogenetics and Genomics, vol. 27, no. 7, pp. 247-254. https://doi.org/10.1097/FPC.0000000000000284

@article{e2487476b36e48c6a0df257af4c85d79,

title = "Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults",

abstract = "Background Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy. Methods We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10-5 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants. Results Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10-7 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling. Conclusion Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.",

keywords = "Anthracycline, Cardiotoxicity, Genome-wide association study, Pathway analysis",

author = "Wells, {Quinn S.} and Veatch, {Olivia J.} and Fessel, {Joshua P.} and Joon, {Aron Y.} and Levinson, {Rebecca T.} and Mosley, {Jonathan D.} and Held, {Elizabeth P.} and Lindsay, {Chase S.} and Shaffer, {Christian M.} and Weeke, {Peter E.} and Glazer, {Andrew M.} and Bersell, {Kevin R.} and {Van Driest}, {Sara L.} and Karnes, {Jason H.} and Blair, {Marcia A.} and Lagrone, {Lore W.} and Su, {Yan R.} and Bowton, {Erica A.} and Ziding Feng and Bonnie Ky and Lenihan, {Daniel J.} and Fisch, {Michael J.} and Denny, {Joshua C.} and Roden, {Dan M.}",

year = "2017",

doi = "10.1097/FPC.0000000000000284",

language = "English (US)",

volume = "27",

pages = "247--254",

journal = "Pharmacogenetics and Genomics",

issn = "1744-6872",

publisher = "Lippincott Williams and Wilkins",

number = "7",

}

TY - JOUR

T1 - Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults

AU - Wells, Quinn S.

AU - Veatch, Olivia J.

AU - Fessel, Joshua P.

AU - Joon, Aron Y.

AU - Levinson, Rebecca T.

AU - Mosley, Jonathan D.

AU - Held, Elizabeth P.

AU - Lindsay, Chase S.

AU - Shaffer, Christian M.

AU - Weeke, Peter E.

AU - Glazer, Andrew M.

AU - Bersell, Kevin R.

AU - Van Driest, Sara L.

AU - Karnes, Jason H.

AU - Blair, Marcia A.

AU - Lagrone, Lore W.

AU - Su, Yan R.

AU - Bowton, Erica A.

AU - Feng, Ziding

AU - Ky, Bonnie

AU - Lenihan, Daniel J.

AU - Fisch, Michael J.

AU - Denny, Joshua C.

AU - Roden, Dan M.

PY - 2017

Y1 - 2017

N2 - Background Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy. Methods We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10-5 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants. Results Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10-7 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling. Conclusion Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.

AB - Background Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy. Methods We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10-5 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants. Results Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10-7 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling. Conclusion Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.

KW - Anthracycline

KW - Cardiotoxicity

KW - Genome-wide association study

KW - Pathway analysis

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U2 - 10.1097/FPC.0000000000000284

DO - 10.1097/FPC.0000000000000284

M3 - Article

C2 - 28542097

AN - SCOPUS:85019665792

SN - 1744-6872

VL - 27

SP - 247

EP - 254

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

IS - 7

ER -

Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults

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