A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough

J. D. Mosley; C. M. Shaffer; S. L. Van Driest; P. E. Weeke; Q. S. Wells; J. H. Karnes; D. R. Velez Edwards; W. Q. Wei; P. L. Teixeira; L. Bastarache; D. C. Crawford; R. Li; T. A. Manolio; E. P. Bottinger; C. A. McCarty; J. G. Linneman; M. H. Brilliant; J. A. Pacheco; W. Thompson; R. L. Chisholm; G. P. Jarvik; D. R. Crosslin; D. S. Carrell; E. Baldwin; J. Ralston; E. B. Larson; J. Grafton; A. Scrol; H. Jouni; I. J. Kullo; G. Tromp; K. M. Borthwick; H. Kuivaniemi; D. J. Carey; M. D. Ritchie; Y. Bradford; S. S. Verma; C. G. Chute; A. Veluchamy; M. K. Siddiqui; C. N.A. Palmer; A. Doney; S. H. MahmoudPour; A. H. Maitland-van der Zee; A. D. Morris; J. C. Denny; D. M. Roden

doi:10.1038/tpj.2015.51

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough

J. D. Mosley, C. M. Shaffer, S. L. Van Driest, P. E. Weeke, Q. S. Wells, J. H. Karnes, D. R. Velez Edwards, W. Q. Wei, P. L. Teixeira, L. Bastarache, D. C. Crawford, R. Li, T. A. Manolio, E. P. Bottinger, C. A. McCarty, J. G. Linneman, M. H. Brilliant, J. A. Pacheco, W. Thompson, R. L. ChisholmG. P. Jarvik, D. R. Crosslin, D. S. Carrell, E. Baldwin, J. Ralston, E. B. Larson, J. Grafton, A. Scrol, H. Jouni, I. J. Kullo, G. Tromp, K. M. Borthwick, H. Kuivaniemi, D. J. Carey, M. D. Ritchie, Y. Bradford, S. S. Verma, C. G. Chute, A. Veluchamy, M. K. Siddiqui, C. N.A. Palmer, A. Doney, S. H. MahmoudPour, A. H. Maitland-van der Zee, A. D. Morris, J. C. Denny, D. M. Roden

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Abstract

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10 -8). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10 -9). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Original language	English (US)
Pages (from-to)	231-237
Number of pages	7
Journal	Pharmacogenomics Journal
Volume	16
Issue number	3
DOIs	https://doi.org/10.1038/tpj.2015.51
State	Published - Jun 1 2016

Bibliographical note

Funding Information:
This work was supported by the VUMC Clinical Pharmacology Training grant (T32 GM07569), the electronic MEdical Records and GEnomics (eMERGE) Network U01- HG-04603 (Vanderbilt), 1U02HG004608-01, 1U01HG006389 and NCATS/NIH grant UL1TR000427 (Marshfield/EIRH/Penn State), U01HG006375 and U01AG06781 (Group Health and University of Washington), U01-HG04599 (Mayo Clinic), U01-HG004609 (Northwestern University), U01HG006382 (Geisinger), an ARRA grant RC2 GM092618, R01 LM 010685, a Vanderbilt PGRN grant U19 HL065962 and the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. At Geisinger, the sample collection was supported by NIH (P30DK072488, R01DK088231 and R01DK091601), Pennsylvania Commonwealth Universal Research Enhancement Program, the Ben Franklin Technology Development Fund of PA, the Geisinger Clinical Research Fund and a Grant-In-Aid from the American Heart Association. GoDARTS was funded by the Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program.

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© 2016 Macmillan Publishers Limited.

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Mosley, J. D., Shaffer, C. M., Van Driest, S. L., Weeke, P. E., Wells, Q. S., Karnes, J. H., Velez Edwards, D. R., Wei, W. Q., Teixeira, P. L., Bastarache, L., Crawford, D. C., Li, R., Manolio, T. A., Bottinger, E. P., McCarty, C. A., Linneman, J. G., Brilliant, M. H., Pacheco, J. A., Thompson, W., ... Roden, D. M. (2016). A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough. Pharmacogenomics Journal, 16(3), 231-237. https://doi.org/10.1038/tpj.2015.51

Mosley, JD, Shaffer, CM, Van Driest, SL, Weeke, PE, Wells, QS, Karnes, JH, Velez Edwards, DR, Wei, WQ, Teixeira, PL, Bastarache, L, Crawford, DC, Li, R, Manolio, TA, Bottinger, EP, McCarty, CA, Linneman, JG, Brilliant, MH, Pacheco, JA, Thompson, W, Chisholm, RL, Jarvik, GP, Crosslin, DR, Carrell, DS, Baldwin, E, Ralston, J, Larson, EB, Grafton, J, Scrol, A, Jouni, H, Kullo, IJ, Tromp, G, Borthwick, KM, Kuivaniemi, H, Carey, DJ, Ritchie, MD, Bradford, Y, Verma, SS, Chute, CG, Veluchamy, A, Siddiqui, MK, Palmer, CNA, Doney, A, MahmoudPour, SH, Maitland-van der Zee, AH, Morris, AD, Denny, JC & Roden, DM 2016, 'A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough', Pharmacogenomics Journal, vol. 16, no. 3, pp. 231-237. https://doi.org/10.1038/tpj.2015.51

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title = "A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough",

abstract = "The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10 -8). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10 -9). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.",

author = "Mosley, {J. D.} and Shaffer, {C. M.} and {Van Driest}, {S. L.} and Weeke, {P. E.} and Wells, {Q. S.} and Karnes, {J. H.} and {Velez Edwards}, {D. R.} and Wei, {W. Q.} and Teixeira, {P. L.} and L. Bastarache and Crawford, {D. C.} and R. Li and Manolio, {T. A.} and Bottinger, {E. P.} and McCarty, {C. A.} and Linneman, {J. G.} and Brilliant, {M. H.} and Pacheco, {J. A.} and W. Thompson and Chisholm, {R. L.} and Jarvik, {G. P.} and Crosslin, {D. R.} and Carrell, {D. S.} and E. Baldwin and J. Ralston and Larson, {E. B.} and J. Grafton and A. Scrol and H. Jouni and Kullo, {I. J.} and G. Tromp and Borthwick, {K. M.} and H. Kuivaniemi and Carey, {D. J.} and Ritchie, {M. D.} and Y. Bradford and Verma, {S. S.} and Chute, {C. G.} and A. Veluchamy and Siddiqui, {M. K.} and Palmer, {C. N.A.} and A. Doney and MahmoudPour, {S. H.} and {Maitland-van der Zee}, {A. H.} and Morris, {A. D.} and Denny, {J. C.} and Roden, {D. M.}",

note = "Funding Information: This work was supported by the VUMC Clinical Pharmacology Training grant (T32 GM07569), the electronic MEdical Records and GEnomics (eMERGE) Network U01- HG-04603 (Vanderbilt), 1U02HG004608-01, 1U01HG006389 and NCATS/NIH grant UL1TR000427 (Marshfield/EIRH/Penn State), U01HG006375 and U01AG06781 (Group Health and University of Washington), U01-HG04599 (Mayo Clinic), U01-HG004609 (Northwestern University), U01HG006382 (Geisinger), an ARRA grant RC2 GM092618, R01 LM 010685, a Vanderbilt PGRN grant U19 HL065962 and the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. At Geisinger, the sample collection was supported by NIH (P30DK072488, R01DK088231 and R01DK091601), Pennsylvania Commonwealth Universal Research Enhancement Program, the Ben Franklin Technology Development Fund of PA, the Geisinger Clinical Research Fund and a Grant-In-Aid from the American Heart Association. GoDARTS was funded by the Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program. Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited.",

year = "2016",

month = jun,

day = "1",

doi = "10.1038/tpj.2015.51",

language = "English (US)",

volume = "16",

pages = "231--237",

journal = "Pharmacogenomics Journal",

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T1 - A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough

AU - Mosley, J. D.

AU - Shaffer, C. M.

AU - Van Driest, S. L.

AU - Weeke, P. E.

AU - Wells, Q. S.

AU - Karnes, J. H.

AU - Velez Edwards, D. R.

AU - Wei, W. Q.

AU - Teixeira, P. L.

AU - Bastarache, L.

AU - Crawford, D. C.

AU - Li, R.

AU - Manolio, T. A.

AU - Bottinger, E. P.

AU - McCarty, C. A.

AU - Linneman, J. G.

AU - Brilliant, M. H.

AU - Pacheco, J. A.

AU - Thompson, W.

AU - Chisholm, R. L.

AU - Jarvik, G. P.

AU - Crosslin, D. R.

AU - Carrell, D. S.

AU - Baldwin, E.

AU - Ralston, J.

AU - Larson, E. B.

AU - Grafton, J.

AU - Scrol, A.

AU - Jouni, H.

AU - Kullo, I. J.

AU - Tromp, G.

AU - Borthwick, K. M.

AU - Kuivaniemi, H.

AU - Carey, D. J.

AU - Ritchie, M. D.

AU - Bradford, Y.

AU - Verma, S. S.

AU - Chute, C. G.

AU - Veluchamy, A.

AU - Siddiqui, M. K.

AU - Palmer, C. N.A.

AU - Doney, A.

AU - MahmoudPour, S. H.

AU - Maitland-van der Zee, A. H.

AU - Morris, A. D.

AU - Denny, J. C.

AU - Roden, D. M.

N1 - Funding Information: This work was supported by the VUMC Clinical Pharmacology Training grant (T32 GM07569), the electronic MEdical Records and GEnomics (eMERGE) Network U01- HG-04603 (Vanderbilt), 1U02HG004608-01, 1U01HG006389 and NCATS/NIH grant UL1TR000427 (Marshfield/EIRH/Penn State), U01HG006375 and U01AG06781 (Group Health and University of Washington), U01-HG04599 (Mayo Clinic), U01-HG004609 (Northwestern University), U01HG006382 (Geisinger), an ARRA grant RC2 GM092618, R01 LM 010685, a Vanderbilt PGRN grant U19 HL065962 and the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. At Geisinger, the sample collection was supported by NIH (P30DK072488, R01DK088231 and R01DK091601), Pennsylvania Commonwealth Universal Research Enhancement Program, the Ben Franklin Technology Development Fund of PA, the Geisinger Clinical Research Fund and a Grant-In-Aid from the American Heart Association. GoDARTS was funded by the Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program. Publisher Copyright: © 2016 Macmillan Publishers Limited.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10 -8). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10 -9). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

AB - The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10 -8). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10 -9). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

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A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough

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