Pharmacodynamic Impact of Carboxylesterase 1 Gene Variants in Patients with Congestive Heart Failure Treated with Angiotensin-Converting Enzyme Inhibitors.
BACKGROUND
Variation in the carboxylesterase 1 gene (CES1) may contribute to the efficacy of ACEIs. Accordingly, we examined the impact of CES1 variants on plasma angiotensin II (ATII)/angiotensin I (ATI) ratio in patients with congestive heart failure (CHF) that underwent ACEI dose titrations. Five of these variants have previously been associated with drug response or increased CES1 expression, i.e., CES1 copy number variation, the variant of the duplicated CES1 gene with high transcriptional activity, rs71647871, rs2244613, and rs3815583. Additionally, nine variants, representatives of CES1Var, and three other CES1 variants were examined.


METHODS
Patients with CHF, and clinical indication for ACEIs were categorized according to their CES1 genotype. Differences in mean plasma ATII/ATI ratios between genotype groups after ACEI dose titration, expressed as the least square mean (LSM) with 95% confidence intervals (CIs), were assessed by analysis of variance.


RESULTS
A total of 200 patients were recruited and 127 patients (63.5%) completed the study. The mean duration of the CHF drug dose titration was 6.2 (SD 3.6) months. After ACEI dose titration, there was no difference in mean plasma ATII/ATI ratios between subjects with the investigated CES1 variants, and only one previously unexplored variation (rs2302722) qualified for further assessment. In the fully adjusted analysis of effects of rs2302722 on plasma ATII/ATI ratios, the difference in mean ATII/ATI ratio between the GG genotype and the minor allele carriers (GT and TT) was not significant, with a relative difference in LSMs of 0.67 (95% CI 0.43-1.07; P = 0.10). Results of analyses that only included enalapril-treated patients remained non-significant after Bonferroni correction for multiple parallel comparisons (difference in LSM 0.60 [95% CI 0.37-0.98], P = 0.045).


CONCLUSIONS
These findings indicate that the included single variants of CES1 do not significantly influence plasma ATII/ATI ratios in CHF patients treated with ACEIs and are unlikely to be primary determinants of ACEI efficacy.
Department of Cardiology, Gentofte University Hospital, Gentofte, Denmark.
Karl Emil
http://orcid.org/0000-0002-2967-4848
KE
Nelveg-Kristensen
Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Peter
P
Bie
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.
Laura
L
Ferrero
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.
Ditte
D
Bjerre
Department of Cardiology, Gentofte University Hospital, Gentofte, Denmark.|Clinical Institute, Aalborg University, Aalborg, Denmark.
Niels E
NE
Bruun
Department of Nephrology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Martin
M
Egfjord
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.
Henrik B
HB
Rasmussen
Department of Cardiology, Gentofte University Hospital, Gentofte, Denmark.
Peter R
PR
Hansen
J Card Fail. 1996 Mar;2(1):47-54
8798105
J Am Coll Cardiol. 2001 Apr;37(5):1456-60
11300461
J Pharmacol Exp Ther. 2013 Mar;344(3):665-72
23275066
Int J Cardiol. 2015 Mar 1;182:90-6
25576729
Br J Clin Pharmacol. 2015 Oct;80(4):662-9
25980448
J Biol Chem. 2010 Aug 13;285(33):25602-12
20530478
Drug Metab Dispos. 2014 Feb;42(2):201-6
24212379
J Cardiovasc Pharmacol. 1994 Sep;24(3):479-85
7528305
Drug Metabol Drug Interact. 2014;29(3):143-51
24988246
Pharmacogenet Genomics. 2008 Oct;18(10):911-20
18794728
Curr Heart Fail Rep. 2012 Mar;9(1):23-32
22135185
Pharmacogenomics J. 2013 Oct;13(5):476-80
22688218
Annu Rev Pharmacol Toxicol. 2015;55:333-52
25251994
Pharmacogenomics J. 2010 Dec;10 (6):524-36
20195289
Clin Pharmacokinet. 2014 Dec;53(12):1083-114
25248847
Lancet. 2010 Mar 13;375(9718):906-15
20226989
Hypertens Res. 2005 Sep;28(9):719-25
16419644
Biol Pharm Bull. 2015;38(2):292-7
25747989
Clin Pharmacol Ther. 1996 Nov;60(5):582-8
8941032
J Clin Invest. 1994 Jul;94(1):301-10
8040271
Pharmacogenomics. 2015;16(6):649-65
25896426
Am J Physiol Regul Integr Comp Physiol. 2003 Nov;285(5):R981-91
12869368
Cell Mol Life Sci. 2004 Jul;61(13):1633-51
15224187
J Clin Invest. 1972 Jul;51(7):1731-42
4338121
J Mol Biol. 2006 Oct 13;363(1):201-14
16962139
J Physiol. 1996 Aug 1;494 ( Pt 3):809-18
8865076
Pharmacogenomics J. 2016 Jun;16(3):220-30
26076923
Circulation. 2013 Apr 2;127(13):1404-12
23467860
Biochim Biophys Acta. 2008 Oct;1781(10):643-54
18762277
N Engl J Med. 1995 Dec 21;333(25):1670-6
7477219
Clin Pharmacol Ther. 2014 Dec;96(6):713-22
25222620
Bioinformatics. 2005 Jan 15;21(2):263-5
15297300
Circulation. 2001 Feb 6;103(5):630-3
11156871
Eur J Heart Fail. 2012 Aug;14(8):803-69
22828712
J Am Coll Cardiol. 2013 Jan 15;61(2):131-42
23219304
Diabetes. 2006 Jul;55(7):2091-7
16804080
J Mol Cell Cardiol. 1996 Sep;28(9):2027-32
8899561
Clin Cardiol. 2005 Dec;28(12):551-5
16405197
Hypertension. 1990 Nov;16(5):564-72
2172161
Toxicology. 2010 Apr 11;270(2-3):59-65
20097249
Br J Clin Pharmacol. 1982 Sep;14(3):363-8
6289859
Biol Pharm Bull. 1997 Aug;20(8):869-73
9300133
Drugs. 2004;64(16):1801-16
15301563
Arch Mal Coeur Vaiss. 1989 May;82 Spec No 1:35-41
2549899
Physiol Genomics. 2000 Jan 24;2(1):1-8
11015575
Am J Hypertens. 1992 Jun;5(6 Pt 1):393-8
1326287
Drug Metab Dispos. 2014 Jan;42(1):126-33
24141856
Drug Metab Dispos. 2012 Jul;40(7):1389-96
22504157
Circ Res. 1991 Aug;69(2):475-82
1650297
Am J Med. 2007 Apr;120(4 Suppl 1):S10-20
17403377
Biochem Pharmacol. 2009 Apr 1;77(7):1266-72
19185566
Br J Clin Pharmacol. 2015 Nov;80(5):1131-8
25919042
Diabetologia. 2007 Oct;50(10):2061-6
17676311
BMJ. 2003 Jun 28;326(7404):1423
12829554
Clin Pharmacokinet. 2004;43(15):1127-56
15568891
Biochem Biophys Res Commun. 2008 May 9;369(3):939-42
18328811
Pharmacotherapy. 2013 Feb;33(2):210-22
23386599
Drug Metab Dispos. 2009 May;37(5):956-61
19225040
Peptides. 2011 Jul;32(7):1551-65
21699940
Br J Clin Pharmacol. 2010 Aug;70(2):222-33
20653675
Eur Heart J. 2012 Aug;33(16):2088-97
22511654