SNPMiner Trials by Shray Alag


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Report for Mutation G143E

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 3 clinical trials

Clinical Trials


1 Characterisation of the Human Carboxylesterase 1 (CES1) Mutation(s) Which May be Responsible for Markedly Reduced Conversion of Oseltamivir Phosphate to Oseltamivir Carboxylate

The aim of this study is to evaluate the conversion of OP to OC in individual X and the family member of individual X. The investigators hypothesize that one or more of the single nucleoprotein polymorphisms (SNPs) of the CES1 gene represent a clinically important functional polymorphism.

NCT01443806 Metabolic Disease Drug: Oseltamivir
MeSH: Metabolic Diseases

A study from Zhu HJ et al presented potentially 2 functional polymorphisms locating in exon 4 (Gly143Glu) and 6 (Asp260fs) that can impair the CES1 hydrolytic activity to methylphenidate in vitro. --- Gly143Glu ---

Primary Outcomes

Description: Conversion of Oseltamivir at 2 and 4 hours post dose

Measure: Tmax

Time: 2 and 4 hours

Secondary Outcomes

Description: Document the sequence of all 14 exons of CES1 from individual X and the family members of individual X.

Measure: Conversion of oseltamivir phosphate to oseltamivir carboxylate

Time: one year (anticipate)

2 Genetic Determinants of ACEI Prodrug Activation

Angiotensin-converting enzyme inhibitors (ACEIs) are among the most frequently prescribed medications worldwide for the treatment of essential hypertension, left ventricular systolic dysfunction, acute myocardial infarction, and prevention of the progression of diabetic nephropathy. However, the outcome of ACEI treatment varies significantly between individuals and selected populations. Suboptimal response, therapeutic failure, and significant side effects are commonly documented in patients receiving ACEI therapy. Approximately 80% of the ACEIs available for use in the US are synthesized as esterified prodrugs in order to improve otherwise poor oral bioavailability of the active molecule. The activation of ACEI prodrugs primarily occurs in the liver via metabolic de-esterification of the parent drug. The critical activation step is essential in delivering a successful therapeutic outcome since the active metabolites are approximately 10-1000 times more potent relative to their respective parent compounds. Carboxylesterase 1 (CES1), the most abundant hydrolase in the liver, is responsible for the activation of ACEI prodrugs in humans. Marked interindividual variability in CES1 expression and activity has been documented, which results in varied therapeutic efficacy and tolerability of many drugs serving as substrates of CES1. Genetic variation of CES1 is considered to be a major factor contributing to variability in CES1 function. The study team proposes to conduct a multiple-dose healthy volunteer study to evaluate the impact of CES1 genetic variation on the activation, pharmacokinetics, and pharmacodynamics of enalapril, a model ACEI prodrug activated by CES1. The completion of this study will represent a major step towards the establishment of an evidence base from which a more individualized use of ACEI prodrugs can emerge.

NCT03051282 Healthy Volunteers Drug: Enalapril

To compare the mean AUC of enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groups. --- G143E ---

To compare the maximum enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groupsG143E carriers groups. --- G143E ---

To compare the plasma ACE activity between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment. --- G143E ---

To compare the changes of BPs between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment. --- G143E ---

- A positive urine pregnancy test in the MCRU prior to the study - No subjects weighing under 50 kg will be selected - The lack of use of acceptable methods of birth control unless abstinent - Subjects who regularly take medications, vitamins, herbal supplements - The use of any illicit drugs or habitual consumption of large quantities of ethanol (>3 drinks/day) - The consumption of grapefruit or grapefruit juice a week prior to, and during the study - Asians will not be included in the study as the CES1 SNP G143E is absent in this population - Subjects hypersensitive to enalapril - Subject with a history of angioedema - Smokers Inclusion Criteria: - Subjects must be male and female (50:50) between the ages of 18-55 years - Females must have a negative urine pregnancy test prior to the study - All subjects must have no clinically significant diseases or clinically significant abnormal laboratory values as assessed during the screening medical history, nursing assessment, and laboratory evaluations - Informed consent must be signed by the eligible subject prior to the initiation of any study procedures Exclusion Criteria: - The presence of a known medical condition that would preclude the use of enalapril - The presence of any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion. --- G143E ---

- A positive urine pregnancy test in the MCRU prior to the study - No subjects weighing under 50 kg will be selected - The lack of use of acceptable methods of birth control unless abstinent - Subjects who regularly take medications, vitamins, herbal supplements - The use of any illicit drugs or habitual consumption of large quantities of ethanol (>3 drinks/day) - The consumption of grapefruit or grapefruit juice a week prior to, and during the study - Asians will not be included in the study as the CES1 SNP G143E is absent in this population - Subjects hypersensitive to enalapril - Subject with a history of angioedema - Smokers Healthy Volunteers null --- G143E ---

Primary Outcomes

Description: To compare the mean AUC of enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groups

Measure: The measurements of the mean area under the curve (AUC) of enalaprilat plasma concentrations

Time: 72 hours

Secondary Outcomes

Description: To compare the maximum enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groupsG143E carriers groups

Measure: The measurements of the maximum enalaprilat plasma concentrations

Time: 72 hours

Description: To compare the plasma ACE activity between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment

Measure: The measurements of angiotensin converting enzyme (ACE) activity in plasma

Time: 72 hours

Description: To compare the changes of BPs between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment

Measure: The measurements of blood pressures (BPs) following enalapril treatment

Time: 72 hours

3 Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD

The study team will determine the association between d,l-methylphenidate (MPH) therapeutic outcomes in ADHD patients and genetic variants of CES1 and reveal key associations between CES1 genotypes and the PK and PD of MPH.

NCT03781752 ADHD Attention Deficit Hyperactivity Disorder Drug: Methylphenidate
MeSH: Attention Deficit Disorder with Hyperactivity
HPO: Attention deficit hyperactivity disorder

The first clinically significant CES1 variant G143E (rs71647871), discovered in the study team's lab during the course of a healthy volunteer MPH PK study, led to gross impairments in MPH metabolism. --- G143E ---

The study team has established the minor allele frequency (MAF) of the G143E variant as 3-4% in the general population. --- G143E ---

G143E carrier's frequency 6-8%) with a genetically impaired ability to metabolize/deactivate the drug will receive it - exposing them to high systemic concentrations of MPH and any attendant risks or toxicities. --- G143E ---

The study team's hypothesis is that the CES1 variants, such as the G143E and D203E, can significantly alter the expression and/or activity of CES1, thereby influencing the metabolism and disposition of MPH. --- G143E ---

Primary Outcomes

Description: The maximum plasma concentration achieved after dosing.

Measure: Maximum methylphenidate plasma concentration (Cmax),

Time: up to 8 Hours

Secondary Outcomes

Description: The time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination.

Measure: Time to maximum concentration (Tmax)

Time: up 8 hours

Description: Area under the plasma concentration-time curve from time zero to the last measurable concentration.

Measure: Area under the plasma concentration curve (AUClast)

Time: up to 8 hours

Description: Area under the plasma concentration-time curve from time zero to infinity.

Measure: Area under the plasma concentration curve (AUCinf)

Time: up to 8 hours


HPO Nodes


Attention deficit hyperactivity disorder
Genes 271
TIMM8A ALG13 SNORD116-1 IL1RAPL1 DHDDS CSNK2A1 BAZ1B ALKBH8 GRIN2A UPF3B SCN8A ZNF41 BCORL1 KCNA2 FGFR3 MED12 RAI1 PARS2 GLUD1 ND4 CLTC IQSEC2 RFC2 TKT OPHN1 PRKCG HDC CPLX1 GABRA1 MKRN3 GABRA2 DLG3 PCNT YWHAG FAN1 HOXA2 TRNQ TBX1 DPP6 GTF2IRD1 UBA5 NECAP1 MECP2 USP9X TLK2 IGF1 ARX TRIO SMC3 PHIP SCN3A SATB2 AUTS2 AGTR2 TBC1D24 PWRN1 IFNG GABRG2 SCN8A SPG7 SOX5 ARF1 SETD5 PPM1D TBX1 GRIA4 CYFIP2 GRIN2D HIRA MAP11 STAG2 DNM1 MLXIPL DEAF1 MCTP2 CLIP2 PANK2 GNB5 JRK TRNF KIF11 PAH POLA1 TMCO1 UBE3A UPF3B ELN SH2B1 PAK3 GABRG2 SMPD1 DYM NDP IQSEC2 RSRC1 TSC1 YWHAG SLC1A2 TBL2 PTCHD1 SH3KBP1 BMPR1A LIG4 SNORD115-1 RAI1 STXBP1 HDAC8 ELN ARVCF SEC24C MLH3 DYNC1I2 ARID2 ND6 CLCN4 SLC9A7 SH2B1 FLI1 MED12 JMJD1C GNE ARHGEF6 ND5 USP27X MED12 FMR1 COMT UFD1 ZNF81 PMS1 HERC2 PRNP NBN SNRPN PTCHD1 TSC2 GTF2I SLC13A5 MID2 SPRED1 SRPX2 DHTKD1 AARS1 SIM1 MLH1 TRNH PMS2 C12ORF4 PIEZO2 IPW GDI1 AP3B2 NPAP1 GNAQ TRNL1 SYP TAF1 GATA4 MSH6 ABCD1 HDAC4 ARV1 STS CRKL KMT2A CACNA1H GRIN2A GP1BB VPS13A CACNA1B DMD ZDHHC9 KRAS NSUN2 TRNS2 MSH2 ASPM SLC2A1 KIF14 PIK3CA FTSJ1 STS CHRNA7 TRNS1 SIN3A DNAJC12 LIMK1 RAI1 TRAK1 RPS20 SLITRK1 SYNGAP1 HCN1 CACNA1A DHCR7 NIPBL LHCGR ADNP SMC1A TRIO WAC PAH WWOX MED12 HSPG2 NDN COX1 GABRB2 MAGEL2 KCNA2 MKRN3-AS1 RERE PCGF2 RAD21 ND1 TBX1 ZNF711 MAPK1 PWAR1 GABRA5 PPP3CA SETBP1 OCRL TRNW COX3 RREB1 EPCAM GABRG2 SIN3A CNKSR2 SLC6A8 DRD5 NUS1 SZT2 FGF12 TGFBR2 SEMA4A COX2 FLII FGD1 EEF1A2 NOP56 FRMPD4 ACTL6B SEMA3E CNKSR2 NTRK2 BCR CXORF56 CHD7 CRBN SETD5 TSPAN7 DRD4 KCNB1 ATP6V1A RAB39B RPS6KA3 CLTC GABRB3 ACSL4 TBX1 CIC TUBB2B GNE THRB IKBKG FGD1 SYNJ1 CNKSR2 HCFC1