SNPMiner Trials by Shray Alag


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Report for Mutation E23K

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 4 clinical trials

Clinical Trials


1 Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans

The SUGAR-MGH investigators are studying the influence of inherited gene variants on the response to two commonly prescribed type 2 diabetes medications, metformin and glipizide. They hypothesize that variants in genes that are associated with type 2 diabetes or related traits may impact the effect of anti-diabetic medications. In addition, physiological responses to an insulin secretagogue or an insulin sensitizer may shed light on the mechanism of action of reported genetic associations.

NCT01762046 Diabetes Mellitus, Type 2 Drug: Glipizide Drug: Metformin Other: Oral Glucose Tolerance Test
MeSH:Diabetes Mellitus Diabetes Mellitus, Type 2
HPO:Diabetes mellitus Type II diabetes mellitus

In particular, sulfonylureas may have differential effects on individuals depending on the allelic variant they carry at KCNJ11 E23K; conversely, because TCF7L2 is postulated to influence insulin secretion by regulating the action of glucagon-like peptide 1 (GLP-1), and sulfonylureas act at a different step in the insulin secretion pathway, the effect of sulfonylureas on insulin secretion could be independent of genetic variation at TCF7L2. --- E23K ---

Primary Outcomes

Description: Investigators will measure insulin and glucose levels for 240 minutes after Glipizide administration on Visit 1, and compare them by genotype at selected loci.

Measure: Glipizide response

Time: Between 0-240 minutes, Visit 1

Description: Investigators will measure the change in glycemic measures between Visit 1 and Visit 2 as an index of Metformin response, and compare them by genotype at selected loci.

Measure: Metformin response

Time: 7 days

Secondary Outcomes

Description: Investigators will measure GLP-1 and GIP during the 120 minutes of Visit 2, and compare them by genotype at selected loci.

Measure: Incretin levels

Time: 120 minutes, Visit 2

Description: Investigators will measure proinsulin and glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.

Measure: Proinsulin, glucagon

Time: 7 days

Description: Investigators will perform metabolomic profiling of plasma samples at regular intervals in Visits 1 and 2, by using initially a targeted approach on an existing platform that measures ~400 metabolites (both polar and non-polar); they will compare their relative concentrations by genotype at selected loci before and after the interventions.

Measure: Metabolomics

Time: 7 days

Description: Investigators will measure 25-hydroxy vitamin D levels at baseline, and examine its effects on glycemic measures during Visits 1 and 2.

Measure: Vitamin D

Time: Baseline

2 Sulphonylurea Receptor Mutation and Responsiveness to Gliclazide - a Pilot Proof of Concept, Randomised Cross-over Study

Gliclazide has greater glucose lowering efficacy than glibenclamide among type 2 diabetes mellitus patients with minor haplotype (K23/A1369) at the KCNJ11/ABCC gene locations.

NCT02201602 Diabetes Drug: Gliclazide Drug: Glibenclamide

Interestingly, the KCNJ11 E23K (rs5219) variant was shown to confer susceptibility to T2DM and the ABCC8 S1369A (rs757110) variant was found to be in complete linkage disequilibrium with it i.e. inherited together as a genetic block (haplotype). --- E23K ---

Primary Outcomes

Measure: Mean blood glucose level

Time: 6 days

Secondary Outcomes

Description: Glycemic variability will be assessed using the EasyGV software (http://www.phc.ox.ac.uk/research/diabetes/software/easygv/) which is capable of calculating 10 different measures of glycemic variability from continuous glucose monitoring data, such as Standard Deviation (SD) and M-value, mean amplitude of glycemic excursions (MAGE).

Measure: Glycemic variability

Time: 6 days

3 Study of Sulphonylurea Synergy With Incretins

The Study of Sulphonylurea Synergy with Incretins (LOGIC) is a Proof-of-Concept Physiological study in the form of two matched isoglycaemic clamps. A matched clamp consists of an of oral glucose tolerance test followed by an isoglycaemic intravenous glucose infusion (IGII). The study will investigate whether there is synergy between a physiological sulphonylurea (SU) stimulus and the incretin effect, causing augmentation of insulin secretion in patients with type 2 diabetes mellitus (T2DM). The study will take place at The Clinical Research Centre at Ninewells Hospital in Dundee over five visits. It will evaluate 20 patients with T2DM on no diabetes therapy, or metformin monotherapy. All participants will undergo two matched clamps. The first matched clamp will be with no intervention. The second intervention matched clamp, low-dose liquid gliclazide will be administered 1-hour prior to each test. The sulphonylurea, Gliclazide, in this this instance will be used as a physiological stimulus and will only be given on two occasions as part of the second matched clamp. The first eight participants will participate in the dose-ranging phase. They will receive either 10mg or 20mg gliclazide as a stimulus to augment the incretin effect. A further twelve participants will then be recruited to complete the study utilising the dose which caused the greatest increment in insulin secretion. LOGIC will also evaluate the cohort for effect of KCNJ11 genotype on physiological response.

NCT03705195 Type 2 Diabetes Mellitus Drug: Gliclazide
MeSH:Diabetes Mellitus, Type 2
HPO:Type II diabetes mellitus

Insulin secretory response analysed by KCNJ11 Genotype (E23K, E23E, K23K). --- E23K ---

insulin secretory response for E23K, E23E, K23K variants.. Inclusion Criteria: - Age 40 - 80, - Age of Diabetes Diagnoses ≥ 35 - T2DM on no treatment or metformin monotherapy - White British - HbA1c ≤ 8% (64mmol/mol) - eGFR ≥ 50ml/min-1 - ALT ≤ 2.5 x ULN - Able to consent Exclusion Criteria: - Type 1 Diabetes Mellitus - HbA1c > 8.0% (> 64mmol/mol) - eGFR <50ml/min-1 - ALT >2.5 x ULN - Anaemia (Haemoglobin <12.0 g/dL for women, <13.0 g/dL for men) - Pregnancy, lactation or a female planning to conceive within the study period - Established pancreatic disease - Participating in clinical phase of another interventional trial/study or have done so within the last 30 days - Any other significant medical reason for exclusion as determined by the investigator Inclusion Criteria: - Age 40 - 80, - Age of Diabetes Diagnoses ≥ 35 - T2DM on no treatment or metformin monotherapy - White British - HbA1c ≤ 8% (64mmol/mol) - eGFR ≥ 50ml/min-1 - ALT ≤ 2.5 x ULN - Able to consent Exclusion Criteria: - Type 1 Diabetes Mellitus - HbA1c > 8.0% (> 64mmol/mol) - eGFR <50ml/min-1 - ALT >2.5 x ULN - Anaemia (Haemoglobin <12.0 g/dL for women, <13.0 g/dL for men) - Pregnancy, lactation or a female planning to conceive within the study period - Established pancreatic disease - Participating in clinical phase of another interventional trial/study or have done so within the last 30 days - Any other significant medical reason for exclusion as determined by the investigator Type 2 Diabetes Mellitus Diabetes Mellitus, Type 2 The Study of Sulphonylurea Synergy with Incretins (LOGIC) is a Proof-of-Concept Physiological study in the form of two matched isoglycaemic clamps. --- E23K ---

Primary Outcomes

Description: Comparison of two matched clamps (oral glucose tolerance test + isoglycaemic intravenous glucose infusion). Matched clamp 1 - control. Matched clamp 2 - low dose gliclazide. Levels of insulin/c-peptide, incretin hormones and plasma glucose will be compared in the presence and absence of low dose gliclazide

Measure: Difference in insulin secretion and incretin effect between two matched clamps (presence and absence of low dose gliclazide)

Time: Through four study visits completed over 4 weeks

Secondary Outcomes

Description: Difference in insulin secretory response to low dose gliclazide calculated by insulin/cpeptide levels in matched clamp(gliclazide). Differences will then be compared by participants genotype e.g. insulin secretory response for E23K, E23E, K23K variants.

Measure: Insulin secretory response analysed by KCNJ11 Genotype (E23K, E23E, K23K)

Time: Through four study visits completed over 4 weeks

4 Study of Sulphonylurea Synergy With DPP4 Inhibitors

The Study of Sulphonylurea Synergy with DPP4 Inhibitors (SSS Study) will establish whether a very low dose of sulphonylurea will have a synergistic role on augmentation of insulin secretion when given in combination with a DPP4 inhibitor as a primary outcome. The study will recruit 30 patients with type 2 diabetes mellitus controlled with no treatment or metformin monotherapy with an HbA1c <64mmol/mol (<8%). In this unblinded, randomised physiological study, participants will receive four 14-day intervention blocks: low dose sulphonylurea alone, DPP4 inhibitor alone, low dose sulphonylurea + DPP4 inhibitor or no treatment change. The primary outcome will be assessed through evaulation of insulin secretion and sensitivity at mixed meal test at the end of each treatment block. Glycaemic variability on continuous glucose monitoring for each intervention block will be evaluated as a secondary outcome. In addition, the primary outcome will be evaulated for KCNJ11 genotype as an additional secondary outcome.

NCT04192292 Type 2 Diabetes Drug: Sulfonylurea Drug: DPP4 Inhibitor

insulin secretory response for E23K, E23E, K23K variants.. Variation in blood glucose during intervention blocks analysed by continuous glucose monitoring. --- E23K ---

Primary Outcomes

Description: Comparison of four mixed meal tests performed at the end of each intervention block. Meal tests will evaluate 1) No intervention 2) Low dose sulphonylurea alone 3) DPP4 inhibitor alone 4) Low dose sulphonylurea + DPP4 inhibitor. Measures of the incretin effect will be compared between the different blocks.

Measure: Difference in incretin effect between mixed meal tests

Time: Through four mixed meal tests which take place at the end of each 14 day intervention block. The four intervention blocks will be completed during an 8 week clinical phase of study.

Secondary Outcomes

Description: Difference in insulin secretory response to low dose gliclazide calculated by insulin/cpeptide levels in each meal test visit. Differences will then be compared by participants genotype e.g. insulin secretory response for E23K, E23E, K23K variants.

Measure: Insulin secretory response analysed by KCNJ11 genotype

Time: Through 4 meal test visits completed over an 8 week clinical phase of study. Outcome will also be evaluated through variability of glucose levels observed on continuous glucose monitoring worn for duration of 8 week clinical phase.

Description: Comparison time-in-range of blood sugars as low, target and high on continuous glucose monitoring between each intervention block

Measure: Variation in blood glucose during intervention blocks analysed by continuous glucose monitoring

Time: Meansurements taken via continuous glucose monitoring sensors worn by participants for duration of 8 week clinical phase


HPO Nodes


HP:0000819: Diabetes mellitus
Genes 528
PLIN1 ABCC8 CASR PRSS1 ELMO2 LIMK1 SOX3 PDX1 SLC2A2 PDX1 PDX1 HNF1A HYMAI SPINK1 GNAS COX1 REEP6 PRPF6 STAT3 ND2 SPINK1 KLF11 KIAA1549 WRN KCNJ11 LIG4 ARL6 EDA2R ELN KCNJ11 FOXH1 WFS1 PWAR1 HMGA1 RRM2B GPR35 LIPE PRSS2 WRAP53 STAT3 HAMP TRNC PPP1R3A ATM PAX4 MMP14 RDH12 CP ZNF408 BRAF TRNK TRNL1 ND4 TTC7A NDUFS3 NDUFV2 AEBP1 SPINK1 PSTPIP1 HMGA2 LRP6 LIPE PALLD TCF4 TRNQ CDKN2A TRNK TTPA INS NDUFB11 GJA1 PAX4 CEL PTCH1 PRSS2 XRCC4 BSCL2 SLC7A14 LMNB2 BBS2 PALB2 INSR TIMMDC1 NDUFAF8 NDUFB10 SIX3 AGBL5 WRN GAS1 COX3 PLAGL1 TREX1 PDX1 SMAD4 SLC19A2 LMNA CORIN PDE8B IL6 BEST1 CRX PRKAR1A WFS1 TGIF1 MST1 NDN GCK NDUFS6 CFTR RETN FOXRED1 RBP3 CNGB1 LIPC ZNF513 GPD2 UBR1 NDUFAF4 WFS1 FOS ABCC8 CISD2 TRNQ IFT140 HFE HYMAI IRS1 HNF4A RNASEH2B FGF8 ARMC5 APOA5 LEMD3 DCAF17 PPARG EDA TP53 DCAF17 AGPAT2 GLRX5 OFD1 TINF2 TRNS1 MAGEL2 APPL1 MAPK8IP1 ARL6 GTF2IRD1 PPARG TRNH NDUFS8 NDUFAF3 TDGF1 CDHR1 SNORD115-1 ZFYVE26 TMEM126B CP IGF2BP2 PTPN22 CAV1 CNGA1 DHDDS RFC2 KIZ MEN1 HBB XRCC4 TRNW PRPF8 FOXP1 ABCC8 LMNA NEK2 SNRPN LMNA MAK FGFR1 MMP2 CLIP2 GCK BBS2 HESX1 KCNJ11 ZFP57 PRKACA GLIS3 HNF1A VANGL1 NDUFS2 NEUROD1 NDUFV1 ABCA4 C8ORF37 TRNS2 DMPK LEP BRCA1 ADAR IFIH1 GCK CERKL NRL COX1 CTRC INS GJB4 WFS1 AIP RAC1 GJB3 SBDS ND5 PTF1A LMNA ITCH PROM1 PRSS1 PIK3R1 NEUROD1 HBB GCK CISD2 ND6 IMPDH1 TERT LEPR ALMS1 BRCA2 PRCD BMP2 CAT ELN KCNJ11 TRNL1 PNPLA6 PAX4 NDUFAF2 FOXP3 GATA6 PRPF4 PLAGL1 NODAL HNF1A CA4 TUB CAV1 RNASEH2C TTC8 POLR3A PIK3R1 NR2E3 HNF4A NDUFB3 POLA1 PWRN1 PRKACA PCARE AR INSR COX2 STOX1 IL2RA PDE4D BSCL2 HGSNAT CTNS DNAJC3 IGF1R KLF11 IPW GJA1 GCK DLL1 PEX10 HNF1B CTC1 DNM1L ND6 ARHGEF18 RP1 SLC25A4 NSMCE2 TRNL1 CLRN1 AHR STAT1 NDUFS7 ND1 OPA1 DNAJC3 NDUFAF5 ABCC8 AMACR NOP10 EIF2AK3 MKKS ABCC8 PPARG TRNF ALMS1 GUCA1B PDE6G CTNNB1 CCDC28B ND3 INSR LHX1 CDON APOE HNF4A CPA1 SLC29A3 DMXL2 TOPORS IDH3B NEUROG3 HFE SCAPER ND1 ARL2BP PDE6B BLK TRNE HNF1B HNF1B SAMHD1 PEX6 NEUROD1 NPAP1 COX3 GPR101 CNOT1 EIF2S3 PRPF3 IL2RA HLA-DRB1 ZIC2 NDUFS1 SPATA7 TRMT10A BLM CYP19A1 FUZ PRKAR1A CYTB PTRH2 LMNA TRNV FBN1 MLXIPL ZFP57 AIP KCNJ11 KCNJ11 KRAS FLT1 FXN PLIN1 INS WFS1 TWNK RPGR HNF4A DISP1 BLK PNPLA2 POLG MC4R POLG2 BAZ1B NSMCE2 RTEL1 TRNS2 PROKR2 ND1 PPARG NDP AHI1 SOX2 SAG SLC29A3 HERC2 UBR1 IER3IP1 KCTD1 ABCC8 CFTR CNBP CAVIN1 SLC12A3 MKRN3-AS1 FOXP3 SLC16A2 TWNK PROK2 PCNT EYS COX2 TRNF RGR GTF2I STAT1 PAX4 DHX38 IDH3A ZMPSTE24 PPP1R15B XRCC4 PTPN1 CLCNKB HJV ERGIC1 LEPR RHO SHH NPM1 ZBTB20 ATM NDUFA6 INS AIRE RP9 PTF1A TCF7L2 KLHL7 DNAJC21 AKT2 RLBP1 AKT2 TP53 PLCD1 NKX2-5 CDH23 NDUFS4 FOXC2 HNF1A LMNA LMNA MTNR1B HNF1A TRNW MKRN3 SRP54 GLI2 NDUFA1 IRS2 NDUFA11 TERC USH2A CTRC POC1A RP2 ITPR3 MOG PDX1 IFT172 APPL1 ARNT2 ATP6 ND5 SNORD116-1 CIDEC BBS1 NDUFAF1 PDE11A FAM161A RPE65 PDE4D PARN INS PRPH2 ROM1 TBL2 OTX2 POLD1 MAFA HNF4A KDSR CEP19 GCK SEMA4A ARL3 CEL LRAT HNF1A GATA6 TULP1 SNRNP200 IFT88 AGPAT2 TRNE FSCN2 TRNS1 NDUFB9 GATA3 STUB1 ENPP1 MERTK RNASEH2A KCNJ11 HLA-DQB1 NHP2 FXN IMPG2 SUFU POMGNT1 EIF2AK3 SARS2 HYMAI GCK TKT USB1 ZMPSTE24 PRPF31 HNF1B PDX1 SLC30A8 PNPLA2 SLC19A2 DKC1 PDE6A USP8 EFL1 FGFR1 CRB1 PEX1 NUBPL