Drug-gene interactions and the search for missing heritability: A cross-sectional pharmacogenomics study of the QT interval

C. L. Avery; C. M. Sitlani; D. E. Arking; D. K. Arnett; J. C. Bis; E. Boerwinkle; B. M. Buckley; Y. D. Ida Chen; A. J.M. De Craen; M. Eijgelsheim; D. Enquobahrie; D. S. Evans; I. Ford; M. E. Garcia; V. Gudnason; T. B. Harris; S. R. Heckbert; H. Hochner; A. Hofman; W. C. Hsueh; A. Isaacs; J. W. Jukema; P. Knekt; J. A. Kors; B. P. Krijthe; K. Kristiansson; M. Laaksonen; Y. Liu; X. Li; P. W. Macfarlane; C. Newton-Cheh; M. S. Nieminen; B. A. Oostra; G. M. Peloso; K. Porthan; K. Rice; F. F. Rivadeneira; J. I. Rotter; V. Salomaa; N. Sattar; D. S. Siscovick; P. E. Slagboom; A. V. Smith; N. Sotoodehnia; D. J. Stott; B. H. Stricker; T. Stürmer; S. Trompet; A. G. Uitterlinden; C. Van Duijn; R. G.J. Westendorp; J. C. Witteman; E. A. Whitsel; B. M. Psaty

doi:10.1038/tpj.2013.4

Drug-gene interactions and the search for missing heritability: A cross-sectional pharmacogenomics study of the QT interval

C. L. Avery, C. M. Sitlani, D. E. Arking, D. K. Arnett, J. C. Bis, E. Boerwinkle, B. M. Buckley, Y. D. Ida Chen, A. J.M. De Craen, M. Eijgelsheim, D. Enquobahrie, D. S. Evans, I. Ford, M. E. Garcia, V. Gudnason, T. B. Harris, S. R. Heckbert, H. Hochner, A. Hofman, W. C. HsuehA. Isaacs, J. W. Jukema, P. Knekt, J. A. Kors, B. P. Krijthe, K. Kristiansson, M. Laaksonen, Y. Liu, X. Li, P. W. Macfarlane, C. Newton-Cheh, M. S. Nieminen, B. A. Oostra, G. M. Peloso, K. Porthan, K. Rice, F. F. Rivadeneira, J. I. Rotter, V. Salomaa, N. Sattar, D. S. Siscovick, P. E. Slagboom, A. V. Smith, N. Sotoodehnia, D. J. Stott, B. H. Stricker, T. Stürmer, S. Trompet, A. G. Uitterlinden, C. Van Duijn, R. G.J. Westendorp, J. C. Witteman, E. A. Whitsel, B. M. Psaty

School of Medicine

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

15 Scopus citations

Abstract

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (P interaction >5.0 × 10 -8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Original language	English (US)
Pages (from-to)	6-13
Number of pages	8
Journal	Pharmacogenomics Journal
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/tpj.2013.4
State	Published - Feb 2014

Keywords

QT interval
gene-environment interaction
genetic epidemiology

ASJC Scopus subject areas

Molecular Medicine
Genetics
Pharmacology

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10.1038/tpj.2013.4

Cite this

Avery, C. L., Sitlani, C. M., Arking, D. E., Arnett, D. K., Bis, J. C., Boerwinkle, E., Buckley, B. M., Ida Chen, Y. D., De Craen, A. J. M., Eijgelsheim, M., Enquobahrie, D., Evans, D. S., Ford, I., Garcia, M. E., Gudnason, V., Harris, T. B., Heckbert, S. R., Hochner, H., Hofman, A., ... Psaty, B. M. (2014). Drug-gene interactions and the search for missing heritability: A cross-sectional pharmacogenomics study of the QT interval. Pharmacogenomics Journal, 14(1), 6-13. https://doi.org/10.1038/tpj.2013.4

Avery, CL, Sitlani, CM, Arking, DE, Arnett, DK, Bis, JC, Boerwinkle, E, Buckley, BM, Ida Chen, YD, De Craen, AJM, Eijgelsheim, M, Enquobahrie, D, Evans, DS, Ford, I, Garcia, ME, Gudnason, V, Harris, TB, Heckbert, SR, Hochner, H, Hofman, A, Hsueh, WC, Isaacs, A, Jukema, JW, Knekt, P, Kors, JA, Krijthe, BP, Kristiansson, K, Laaksonen, M, Liu, Y, Li, X, Macfarlane, PW, Newton-Cheh, C, Nieminen, MS, Oostra, BA, Peloso, GM, Porthan, K, Rice, K, Rivadeneira, FF, Rotter, JI, Salomaa, V, Sattar, N, Siscovick, DS, Slagboom, PE, Smith, AV, Sotoodehnia, N, Stott, DJ, Stricker, BH, Stürmer, T, Trompet, S, Uitterlinden, AG, Van Duijn, C, Westendorp, RGJ, Witteman, JC, Whitsel, EA & Psaty, BM 2014, 'Drug-gene interactions and the search for missing heritability: A cross-sectional pharmacogenomics study of the QT interval', Pharmacogenomics Journal, vol. 14, no. 1, pp. 6-13. https://doi.org/10.1038/tpj.2013.4

@article{db1b3b57542b4a2b801d1a23b8928690,

title = "Drug-gene interactions and the search for missing heritability: A cross-sectional pharmacogenomics study of the QT interval",

abstract = "Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (P interaction >5.0 × 10 -8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.",

keywords = "QT interval, gene-environment interaction, genetic epidemiology",

author = "Avery, {C. L.} and Sitlani, {C. M.} and Arking, {D. E.} and Arnett, {D. K.} and Bis, {J. C.} and E. Boerwinkle and Buckley, {B. M.} and {Ida Chen}, {Y. D.} and {De Craen}, {A. J.M.} and M. Eijgelsheim and D. Enquobahrie and Evans, {D. S.} and I. Ford and Garcia, {M. E.} and V. Gudnason and Harris, {T. B.} and Heckbert, {S. R.} and H. Hochner and A. Hofman and Hsueh, {W. C.} and A. Isaacs and Jukema, {J. W.} and P. Knekt and Kors, {J. A.} and Krijthe, {B. P.} and K. Kristiansson and M. Laaksonen and Y. Liu and X. Li and Macfarlane, {P. W.} and C. Newton-Cheh and Nieminen, {M. S.} and Oostra, {B. A.} and Peloso, {G. M.} and K. Porthan and K. Rice and Rivadeneira, {F. F.} and Rotter, {J. I.} and V. Salomaa and N. Sattar and Siscovick, {D. S.} and Slagboom, {P. E.} and Smith, {A. V.} and N. Sotoodehnia and Stott, {D. J.} and Stricker, {B. H.} and T. St{\"u}rmer and S. Trompet and Uitterlinden, {A. G.} and {Van Duijn}, C. and Westendorp, {R. G.J.} and Witteman, {J. C.} and Whitsel, {E. A.} and Psaty, {B. M.}",

note = "Funding Information: Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute Contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant No. UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Cardiovascular Health Study (CHS): This CHS research was supported by National Heart, Lung and Blood Institute (NHLBI) Contracts N01-HC-85239, N01-HC-85079–N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI Grants HL080295, HL075366, HL087652 and HL105756, with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098 and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources CTSI Grant UL 1RR033176, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK063491 to the Southern California Diabetes Endocrinology Research Center and the Cedars-Sinai Board of Governors{\textquoteright} Chair in Medical Genetics (JIR). Framingham Heart Study (FHS): FHS work was supported by the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (Contract No. N01-HC-25195), its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278), based on analyses by FHS investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II), funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Measurement of the Gen 3 ECGs was supported by grants from the Doris Duke Charitable Foundation and the Burroughs Wellcome Fund (Newton-Cheh) and the NIH (HL080025, Newton-Cheh). Health 2000: Supported by the Orion-Farmos Research Foundation (KK and KP), the Finnish Foundation for Cardiovascular Research (KK, KP) and the Academy of Finland (Grant Nos. 129494 and 139635 to VS). Health Aging, Body and Composition (Health ABC): This research was supported by NIA Contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA Grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract No. HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Multi-Ethnic Study of Atherosclerosis (MESA): MESA and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by Grants and Contracts N01 HC-95159–N01-HC-95169 and RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. Additional funding was supported in part by the Clinical Translational Science Institute Grant UL1RR033176 and the Cedars-Sinai General Clinical Research Center Grant RR00425. We also thank the other investigators, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Professor Dr J W Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (Grant No. 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (Grant No. 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging Grant 050-060-810). Rotterdam Study (RS): The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research; The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by The Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was supported by The Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Project No. 050-060-810. This collaborative effort was supported by an award from the National Heart, Lung and Blood Institute (R01-HL-103612, PI BMP). CLA was supported in part by Grant R00-HL-098458 from the National Heart, Lung, and Blood Institute.",

year = "2014",

month = feb,

doi = "10.1038/tpj.2013.4",

language = "English (US)",

volume = "14",

pages = "6--13",

journal = "Pharmacogenomics Journal",

issn = "1470-269X",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Drug-gene interactions and the search for missing heritability

T2 - A cross-sectional pharmacogenomics study of the QT interval

AU - Avery, C. L.

AU - Sitlani, C. M.

AU - Arking, D. E.

AU - Arnett, D. K.

AU - Bis, J. C.

AU - Boerwinkle, E.

AU - Buckley, B. M.

AU - Ida Chen, Y. D.

AU - De Craen, A. J.M.

AU - Eijgelsheim, M.

AU - Enquobahrie, D.

AU - Evans, D. S.

AU - Ford, I.

AU - Garcia, M. E.

AU - Gudnason, V.

AU - Harris, T. B.

AU - Heckbert, S. R.

AU - Hochner, H.

AU - Hofman, A.

AU - Hsueh, W. C.

AU - Isaacs, A.

AU - Jukema, J. W.

AU - Knekt, P.

AU - Kors, J. A.

AU - Krijthe, B. P.

AU - Kristiansson, K.

AU - Laaksonen, M.

AU - Liu, Y.

AU - Li, X.

AU - Macfarlane, P. W.

AU - Newton-Cheh, C.

AU - Nieminen, M. S.

AU - Oostra, B. A.

AU - Peloso, G. M.

AU - Porthan, K.

AU - Rice, K.

AU - Rivadeneira, F. F.

AU - Rotter, J. I.

AU - Salomaa, V.

AU - Sattar, N.

AU - Siscovick, D. S.

AU - Slagboom, P. E.

AU - Smith, A. V.

AU - Sotoodehnia, N.

AU - Stott, D. J.

AU - Stricker, B. H.

AU - Stürmer, T.

AU - Trompet, S.

AU - Uitterlinden, A. G.

AU - Van Duijn, C.

AU - Westendorp, R. G.J.

AU - Witteman, J. C.

AU - Whitsel, E. A.

AU - Psaty, B. M.

N1 - Funding Information: Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute Contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant No. UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Cardiovascular Health Study (CHS): This CHS research was supported by National Heart, Lung and Blood Institute (NHLBI) Contracts N01-HC-85239, N01-HC-85079–N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI Grants HL080295, HL075366, HL087652 and HL105756, with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098 and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources CTSI Grant UL 1RR033176, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK063491 to the Southern California Diabetes Endocrinology Research Center and the Cedars-Sinai Board of Governors’ Chair in Medical Genetics (JIR). Framingham Heart Study (FHS): FHS work was supported by the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (Contract No. N01-HC-25195), its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278), based on analyses by FHS investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II), funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Measurement of the Gen 3 ECGs was supported by grants from the Doris Duke Charitable Foundation and the Burroughs Wellcome Fund (Newton-Cheh) and the NIH (HL080025, Newton-Cheh). Health 2000: Supported by the Orion-Farmos Research Foundation (KK and KP), the Finnish Foundation for Cardiovascular Research (KK, KP) and the Academy of Finland (Grant Nos. 129494 and 139635 to VS). Health Aging, Body and Composition (Health ABC): This research was supported by NIA Contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA Grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract No. HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Multi-Ethnic Study of Atherosclerosis (MESA): MESA and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by Grants and Contracts N01 HC-95159–N01-HC-95169 and RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. Additional funding was supported in part by the Clinical Translational Science Institute Grant UL1RR033176 and the Cedars-Sinai General Clinical Research Center Grant RR00425. We also thank the other investigators, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Professor Dr J W Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (Grant No. 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (Grant No. 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging Grant 050-060-810). Rotterdam Study (RS): The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research; The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by The Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was supported by The Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Project No. 050-060-810. This collaborative effort was supported by an award from the National Heart, Lung and Blood Institute (R01-HL-103612, PI BMP). CLA was supported in part by Grant R00-HL-098458 from the National Heart, Lung, and Blood Institute.

PY - 2014/2

Y1 - 2014/2

N2 - Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (P interaction >5.0 × 10 -8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

AB - Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (P interaction >5.0 × 10 -8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

KW - QT interval

KW - gene-environment interaction

KW - genetic epidemiology

UR - http://www.scopus.com/inward/record.url?scp=84893705905&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893705905&partnerID=8YFLogxK

U2 - 10.1038/tpj.2013.4

DO - 10.1038/tpj.2013.4

M3 - Article

C2 - 23459443

AN - SCOPUS:84893705905

SN - 1470-269X

VL - 14

SP - 6

EP - 13

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

IS - 1

ER -

Drug-gene interactions and the search for missing heritability: A cross-sectional pharmacogenomics study of the QT interval

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