CES1 SNPs and their impacts on the PK and PD of CES1 substrate medications

AA/Nucleotide Change (db SNP ID)CitationTreatmentPopulationDesign/OutcomeResultConclusion
G143E (rs71647871)Patrick et al., 2007; Zhu et al., 2008Methylphenidaten = 20 (with one carrier)Prospective studyThe study unexpectedly found one volunteer with elevated PK parameters of methylphenidate; Cmax of l-methylphenidate was 100-fold higher (62 ng/ml) compared with the rest of participantsThe later analysis found this volunteer had G143E and D260fs SNPs, which resulted in elevated plasma concentration of methylphenidate
Single dose of 0.3 mg/kgHealthy volunteersAim: to examine the interaction between methylphenidate and alcohol
Nemoda et al., 2009Methylphenidaten = 122 (with seven carriers)Retrospective studyG143E carriers needed lower doses of methylphenidate for symptom reduction compared with noncarriers (0.410 vs. 0.572 mg/kg, P = 0.022)G143E impaired methylphenidate metabolism in vivo
Dose adjusted based on symptom reduction × 1 moHungarian patients with ADHDOutcome: methylphenidate dose reduction
Stage et al., 2017aMethylphenidaten = 22 (with six carriers)Open labeled, prospective, PK studyG143E carriers showed 152.4% higher AUC (53.3 ng × ml−1 × h−1) compared with the noncarrier group (21.4 ng × ml−1 × h−1) (P < 0.0001)G143E carriers had higher exposure to methylphenidate compared with noncarriers
Single dose 10 mgHealthy Danish Volunteers
Lewis et al., 2013Clopidogreln = 506 (with seven carriers)Retrospective subanalysis of two clinical studies: 1) PAPI Study1) A 50% higher active metabolite concentration was observed in G143E carriers (n = 7, 30.3 ng/ml) compared with noncarriers (n = 499, 19.0 ng/ml) (P = 0.001)G143E carriers had higher plasma concentrations of clopidogrel active metabolites and consequently had a higher antiplatelet effect
1) Patients in PAPI received 300 mg loading dose (LD) with 75 mg maintenance dose (MD)n = 350 (with six carriers)2) Patients who were clopidogrel-treated at Sinai Hospital
2) Patients from Sinai Hospital received either 300 or 600 mg LD (n = 204) with MD, or just received 75 mg MDPatient going through percutaneous coronary intervention (PCI)Outcome: 1) PK parameter: Clopidogrel and its active metabolite concentration 2) PD parameter: ADP-stimulated platelet aggregation2) The inhibition of ADP-induced platelet aggregation effect was 24% higher in G143E carriers (reduced to 71% from baseline) compared with noncarriers (reduced to 57% from baseline) (P = 0.003)
Tarkiainen et al., 2015aClopidogreln = 22 (with 10 carriers)Prospective, PK/PD study1) AUC0–∞ ratios of the clopidogrel carboxylic acid to clopidogrel was 53% less in G143E carriers (P = 0.009)G143E carriers had higher exposure to clopidogrel active metabolite, and consequently had a higher antiplatelet aggregation effect
Single dose 600 mgHealthy volunteersPD outcome: inhibition of P2Y12-mediated platelet aggregation2) Average inhibition of P2Y12-mediated platelet aggregation in the carriers was 19 percentage points higher in noncarriers (P = 0.036)
Tarkiainen et al., 2015bEnalapril, Quinapriln = 22 (with 10 carriers)Prospective PK study1) AUC0–∞ of the enalapril active metabolite enalaprilat was 20% lower in the G143E carriers (n = 10) compared with noncarriers (n = 12) (P = 0.049)G143E carriers had a lower enalaprilat exposure compared with noncarriers
Single dose 10 mg Enalapril or QuinaprilHealthy volunteers2) AUCs0-∞ of the quinapril and its active metabolite (i.e., quinaprilat) were not significantly different between the noncarriers and carriers (P = 0.114)
Tarkiainen et al., 2012Oseltamivirn = 22 (with nine G143E heterozygotes, 1 G143E homozygote)Prospective PK Study1) The AUC0–∞ ratio of oseltamivir carboxylate (active metabolite) to oseltamivir (parent molecule) was 23% lower in G143E heterozygotes compared with noncarriers (P = 0.006)G143E carriers had less exposure to oseltamivir active metabolite compared with noncarriers
Single dose 75 mgHealthy volunteers2) The one G143E homozygous individual had an AUC0–∞ of oseltamivir that was approximately 360% greater than the noncarriers
Shi et al., 2016cDabigatrann = 102 human liver samplesIn vitro study with human liver samplesThe activation rates of DABE, M1, and M2 in G143E carriers were 53% (P = 0.018), 43% (P = 0.004), and 37% (P = 0.001) of normal carriers (after normalized by CES1 expression)G143E carriers had a lower dabigatran activation rate, potentially resulting in a lower dabigatran active metabolite concentration in the carriers
Shi et al., 2016bSacubitriln = 53 (with five carrier) human liver samplesIn vitro study with human liver samplesThe activation rates of sacubitril were lower in the carriers compared with the noncarriers (4.2 vs. 7.2 nmol/mg protein/min, P = 0.025)G143E carriers had a lower sacubitril activation rate, potentially resulting in a lower sacubitril active metabolite plasma concentration in the carriers
E220G (rs200707504)Oh et al., 2017Oseltamivir 75 mg single dosen = 20 (with eight carriers)Prospective, PK studyAUC0–48 h of oseltamivir was increased by 10% (P = 0.334) and AUC0–48 h of oseltamivir carboxylate was decreased by 5% (P = 0.513) in carriersE220G appears to have no significant impact on oseltamivir activation in humans
S75N (rs2307240)Xiao et al., 2017Clopidogreln = 851 (with 372 carriers)Retrospective PD analysisCES1 S75N carriers (n = 372) had more cerebrovascular events (P < 0.001), acute myocardial infarction (P < 0.001), and unstable angina (P < 0.001) compared with noncarriersS75N appears to increase the function of CES1, resulting in the decreased efficacy of clopidogrel
75 mg × 1 yOutcome: cerebrovascular events, acute myocardial infarction, and unstable angina
Johnson et al., 2013Methylphenidaten = 44 (with 2 carriers)Naturalistic, prospective studyNo significant differences in methylphenidate side effect were found between carriers and noncarriers (P = 1)S75N does not appear to affect the function of CES1
Weight based dosing × 6 wkChildren with ADHDOutcome: side effect reported via behavioral questionnaires
Wang et al., 2017Enalapriln = 36 (with three carriers)In vitro study with human liver samplesNo statistical difference in enalapril activation rate or CES1 protein expression level between carriers and noncarriersS75N does not appear to affect the function of CES1
−816A>C (rs3785161)Geshi et al., 2005Imidapriln = 105 (with 47 carriers)Prospective clinical studyGreater systolic blood pressure reduction (24.1 mm Hg) was observed compared with noncarriers (17.6 mm Hg) after 8 wk of imidapril therapy (P = 0.0184)−816A>C appears to up-regulate the CES1P1 VAR expression
5–10 mg × 8 wkPatients with hypertension
Xie et al., 2014Clopidogreln = 162 (with 75 carriers)Retrospective PD analysisThe carriers had decreased VASP-PRI (45.93 vs. 53.18%) (P = 0.014)−816A>C appears to up-regulate the CES1P1 VAR expression
300 or 600 mg (LD) or 75 mg (MD) for minimum 5 daysPatient on dual antiplatelet therapy (i.e., aspirin and clopidogrel) with coronary heart diseasesOutcome: VASP-PRI to measure platelet reactivity
Zou et al., 2014Clopidogreln = 249 (with 108 heterozygous carrier, 17 homozygous carrier)Retrospective PD analysisA lower ADP-induced maximum platelet aggregation (21.5%, n = 125) was observed compared with noncarriers (31.7%, n = 124) (P = 0.001)−816A>C appears to down-regulate the CES1P1 VAR expression
300 mg LD + 75 mg MD × 3 dayPatient going throught PCIOutcome: maximum platelet aggregation (MPA)
Zhu et al., 2016Trandolapril1) n = 486 (with 109 heterozygous carriers, 10 homozygous carriers)1) Retrospective analysis of the INternational VErapamil SR Trandolapril Study1) No association between the -816A>C and the blood pressure–lowering effect of trandolapril−816A>C does not appears to be associated with overall CES1 function
2–4 mg × 104 wk2) n = 100 (in vitro study) (26 heterozygous carriers, three homozygous carriers)2) In vitro study with human liver samples2) Not associated with CES1 protein expression and trandolapril activation in human liver samples
Outcome: blood pressure
−75G>T (rs3815583)Bruxel et al., 2013Methylphenidaten = 205 (with 129 carriers)Retrospective PD analysisThe carriers had worse appetite reduction compared with noncarriers (41% vs. 77%, P = 0.01)−75G>T appears to be associated with decreased CES1 function
Dose titrated up × 3 mo as tolerableOutcome: appetite reduction - the side effect of methylphenidate
Sai et al., 2010Irinotecann = 177Retrospective PK analysisThe carriers had higher plasma (SN-38 + SN-38G)/irinotecan AUC ratios relative to noncarriers (P = 0.027)−75G>T appears to be associated with higher CES1 function
100 mg m−2 weekly or 150 mg m−2 biweekly177 Patients who were Japanese with cancer
Nelveg-Kristensen et al., 2016ACEIn = 200 Patients with congestive heart failureRetrospective PD analysisThe -75G>T genotypes did not significantly impact the plasma ATII/ATI ratios in the study subjects or fatal outcomes (i.e., cardiovascular death and all-cause death)−75G>T was not associated with CES1 function
1168-33C>A (rs2244613)Paré et al., 2013Dabigatrann = 2944 (with 587 carriers)Retrospective Genome-Wide Association Study (GWAS) of Randomized Evaluation of Long-term Anticoagulation Therapy clinical trialThe carriers had lower trough concentrations of the active metabolite (15% decrease per allele; P = 1.2 × 10−8) and a lower risk of any bleeding (odds ratio, 0.67; P = 7 × 10−5) compared with noncarriers1168-33C>A appears to be associated with lower CES1 function
110 or 150 mg twice dailyPatients with atrial fibrillation (within 6 mo) and additional risk factors for strokeOutcome: trough concentrations of dabigatran, bleeding risk
Shi et al., 2016bDabigatrann = 102 (with 29 heterozygous carriers and five homozygous carriers)In vitro study with human liver samplesNo association between 1168-33C>A and dabigatran activation1168-33C>A appears to be not associated with CES1 function