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, Iftikhar Jan 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

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)231-237
Number of pages7
JournalPharmacogenomics Journal
Volume16
Issue number3
DOIs
StatePublished - Jun 1 2016

Fingerprint

Genome-Wide Association Study
Angiotensin-Converting Enzyme Inhibitors
Cough
Electronic Health Records
Odds Ratio
Scotland
Genomics
Single Nucleotide Polymorphism
Metagenomics
Chromosomes, Human, Pair 4
Research
Gene Frequency
Introns
Confidence Intervals
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Genetics

Cite this

Mosley, J. D., Shaffer, C. M., Van Driest, S. L., Weeke, P. E., Wells, Q. S., Karnes, J. H., ... 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

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough. / 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.; Chisholm, R. L.; Jarvik, G. P.; Crosslin, D. R.; Carrell, D. S.; Baldwin, E.; Ralston, J.; Larson, E. B.; Grafton, J.; Scrol, A.; Jouni, H.; Kullo, Iftikhar Jan; Tromp, G.; Borthwick, K. M.; Kuivaniemi, H.; Carey, D. J.; Ritchie, M. D.; Bradford, Y.; Verma, S. S.; Chute, C. G.; Veluchamy, A.; Siddiqui, M. K.; Palmer, C. N A; Doney, A.; MahmoudPour, S. H.; Maitland-van der Zee, A. H.; Morris, A. D.; Denny, J. C.; Roden, D. M.

In: Pharmacogenomics Journal, Vol. 16, No. 3, 01.06.2016, p. 231-237.

Research output: Contribution to journalArticle

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
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. ; Chisholm, R. L. ; Jarvik, G. P. ; Crosslin, D. R. ; Carrell, D. S. ; Baldwin, E. ; Ralston, J. ; Larson, E. B. ; Grafton, J. ; Scrol, A. ; Jouni, H. ; Kullo, Iftikhar Jan ; Tromp, G. ; Borthwick, K. M. ; Kuivaniemi, H. ; Carey, D. J. ; Ritchie, M. D. ; Bradford, Y. ; Verma, S. S. ; Chute, C. G. ; Veluchamy, A. ; Siddiqui, M. K. ; Palmer, C. N A ; Doney, A. ; MahmoudPour, S. H. ; Maitland-van der Zee, A. H. ; Morris, A. D. ; Denny, J. C. ; Roden, D. M. / A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough. In: Pharmacogenomics Journal. 2016 ; Vol. 16, No. 3. pp. 231-237.
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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, Iftikhar Jan

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.

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.

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