SNPMiner Trials by Shray Alag


SNPMiner SNPMiner Trials (Home Page)


Report for SNP rs3751143

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 2 clinical trials

Clinical Trials


1 Pure-Heart-1: A P2X7R Single Nucleotide Mutation Promotes Chronic Allograft Vasculopathy

Heart transplantation (HT) is a lifesaving procedure for patients with end-stage heart failure and provides a better survival and quality of life if compared to medical treatment. HT is subject to alloimmune response, which, if left uncontrolled, is capable of jeopardizing long-term cardiac function. Advances in immunosuppression have enhanced the survival of HT patients. Nearly 2500 HT per year have been performed in the US during the last 10 years and despite significant improvements, long-term survival rates remain poor. More than 20% of patients do not survive more than 3 years, and those who survive are afflicted by long-term complications of alloimmunity and chronic immunosuppression. Life expectancy of patients who lose cardiac allografts is dramatically poor due to the absence of any therapeutic tool apart from re-transplantation, which is plagued by poor outcomes. The identification of novel therapeutic targets is thus mandatory. ATP/P2X7R signaling in T cells is highly relevant for cardiac allograft survival. ATP is a small molecule present at high concentrations inside cells; it is released as extracellular ATP (eATP) following cell damage or death where it acts as a danger signal. ATP is sensed by the P2X receptors (seven receptors named P2X1-7), mainly expressed by T lymphocytes. We have recently demonstrated that the ATP/P2X7R axis has a key role in cardiac allograft survival in humans and mice. Cardiac allograft vasculopathy (CAV) is a major limiting factor for HT survival; indeed CAV occurs in 50% of HT recipients by 5 years after transplantation and invariably results in allograft failure. CAV is clearly of immunological origin, as syngeneic murine grafts do not develop it. Once CAV occurs, the most definitive treatment is re-transplantation, but survival remains poor. We hypothesize that a single nucleotide polymorphysm (SNP) loss-of-function P2X7R mutation (p.Glu496Ala / c.1513A>C, rs3751143) generates a compensatory upregulation of the other purinergic receptors (P2XsR), thus creating a state of hypersensitivity to eATP. This eATP hypersensitivity results in an abnormal generation of Th1/Th17 cells, that leads to CAV and early cardiac allograft loss. Our study will answer a fundamental question: What is the effect of the P2X7R loss-of-function mutation on the immune system? Our goal is to generate the first targeted-therapy for a selected group of cardiac transplant recipients.

NCT02082821 Cardiac Allograft Vasculopathy
MeSH: Vascular Diseases

We hypothesize that a single nucleotide polymorphysm (SNP) loss-of-function P2X7R mutation (p.Glu496Ala / c.1513A>C, rs3751143) generates a compensatory upregulation of the other purinergic receptors (P2XsR), thus creating a state of hypersensitivity to eATP.

Loss-of-function single nucleotide mutations (SNPs) have been detected for P2X7R gene; particularly the Glu496 to Ala 1513A>C (rs3751143) P2X7R loss-of-function mutation is relatively common (1-3% of individuals are mutated omozygous and 25% are heterozygous).

To test this hypothesis, we will follow two main paths: i) we will evaluate in the CTOT-05 cohort of cardiac transplant recipients the effect of the Glu496 to Ala 1513A>C (rs3751143) P2X7R loss-of-function mutation on clinical end points (development of coronary artery vasculopathy, death, re-transplantation or re-listed for transplantation, any rejection) in the first year post transplant; ii) we will explore in vivo and ex vivo in the CTOT-05 cohort of cardiac transplant recipients the effects of P2X7R loss-of-function mutation on the immune system.

Primary Outcomes

Description: nominal change from baseline to 1 year in percent atheroma volume measured by intravascular ultrasound

Measure: Cardiac Allograft Vasculopathy

Time: 1 year

Secondary Outcomes

Description: Death re-transplant biopsy proven acute rejection antibody mediated rejection cellular rejection; treated rejection hemodynamic compromise-associated rejection chronic allograft vasculaopathy at 12-months total atheroma volume; change in average maximal intimal thickness rapid progressive chronic allograft vasculaopathy (change in maximal intimal thickness) ≥0.5 mm in the first year (intravascular ultrasound) histological changes of antibody mediated rejection (Immunohistochemistry).

Measure: Heart Rejection or Patient Death

Time: 6 months; 12 months

2 A Randomised, Placebo-controlled, Double-blind Trial of the Antidepressant Efficacy of a Novel CNS-penetrant P2X7 Receptor Antagonist, JNJ-54175446, in People With Major Depressive Disorder, an Incomplete Response to Monoaminergic Antidepressant Drugs, and a Biomarker Profile Predictive of Active P2X7 Signalling

Depression is one of the most important causes of disability in the world today, with major personal, social and economic costs. Although some moderately effective drug treatments are already available, about a third of patients with major depressive disorder (MDD) remain depressed despite current treatment. There is growing evidence that inflammation - the response of the body's immune system to physical and social stresses - can cause depressive symptoms in some patients. It is therefore predicted that anti-inflammatory drugs could have anti-depressant effects and the research team aims to test this using a new drug, JNJ-54175446, which blocks the activity of a receptor called P2X7. P2X7 is present on many immune cells and plays a key role in the release of inflammatory molecules during stress, which may be linked to stress-related depression. The research team will recruit approximately up to 142 participants with MDD to this clinical trial. Patients will have moderate-severe depressive symptoms despite ongoing treatment with a conventional anti-depressant drug, and they will have blood test results at screening that indicate they are likely to have active P2X7 signalling in the brain. Eligible participants will be randomly allocated to receive either 50mg/day JNJ-54175446 or placebo for 8 weeks. Participants will be assessed at weeks 2, 5 and 8 using a standard clinical depression scale and the scores compared between those treated with placebo and those treated with JNJ-54175446. To understand more about the effects of JNJ-54175446 on the immune system and the brain, patients will also complete additional blood tests, questionnaires and magnetic resonance imaging (MRI) brain scans at different visits throughout the trial. The trial will be carried out across 5 centres in the UK.

NCT04116606 Depressive Disorder, Major Inflammation Drug: Active JNJ-54175446 Drug: Placebo
MeSH: Inflammation Depressive Disorder Depression Depressive Disorder, Major
HPO: Depressivity

3. Presence of two copies of the loss-of-function C allele at rs3751143, and/or has one copy of the loss-of-function A allele at rs1653624 in the P2RX7 gene.

Primary Outcomes

Description: The Montgomery Asberg Depression Rating Scale (MADRS), a researcher-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. (Visit 4)

Measure: Change from baseline in total score on the MADRS scale at week 8

Time: At baseline and at 8 weeks of treatment

Secondary Outcomes

Description: The Montgomery Asberg Depression Rating Scale (MADRS), a researcher-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Measure: Change from baseline in total score on the MADRS scale

Time: At baseline, 2 and 5 weeks of treatment

Description: Perceived Stress Scale is a questionnaire measure of recent or current social stress. This scale ranges from 0 to 40; scores ranging from 0-13 would be considered low stress; scores ranging from 14-26 would be considered moderate stress; scores ranging from 27-40 would be considered high perceived stress.

Measure: Change in scores on Perceived Stress Scale

Time: At baseline, 2, 5 and 8 weeks of treatment

Description: Snaith-Hamilton Pleasure Scale. SHAPS is an instrument developed for the assessment of hedonic capacity and consists of 14-items. Four major domains are covered in the scale, namely interest/pastimes, social interaction, sensory experience, and food/drink. The score range is 0-14. The higher the score the lower the ability to experience pleasure of the patient.

Measure: Change in scores on SHAPS

Time: At baseline, 2, 5 and 8 weeks of treatment

Description: Chalder Fatigue Questionnaire (CFQ). The Fatigue Scale, sometimes referred to as the Chalder Fatigue Questionnaire, is a self-administered questionnaire for measuring the extent and severity of fatigue within both clinical and non-clinical, epidemiological populations. The respondent's global score can range from 0 to 33. The global score also spans two dimensions—physical fatigue (measured by items 1-7) and psychological fatigue (measured by items 8-11).

Measure: Change in scores on CFQ

Time: At baseline, 2, 5 and 8 weeks of treatment

Description: Quick Inventory of Depressive Symptomatology (QIDS-SR16). The QIDS-SR16 is designed to assess the severity of depressive symptoms and is sensitive to change due to with medications, psychotherapy, or other treatments. Participants will provide responses to each item of this instrument with a 4-point Likert scale, with scores ranging from 0-3 for each item. The total score ranges from 0 to 27. Using a scale of severity of depression of none, mild, moderate, severe, and very severe, corresponding QIDS-SR16 total scores are none 1 to 5, mild 6 to 10, moderate 11 to 15, severe 16 to 20 and very severe 21 to 27.

Measure: Change in scores on QIDS-SR16

Time: At baseline, 2, 5 and 8 weeks of treatment

Description: Generalized Anxiety Disorder 7 (GAD-7). GAD-7 is a self-reported questionnaire for screening and severity measuring of GAD. GAD-7 has seven items, which measure severity of various signs of GAD according to reported response categories with assigned points. Assessment is indicated by the total score, which made up by adding together the scores for all 7 items. The score ranges from 0 to 21. Using a scale of severity of anxiety of none, mild, moderate and severe, corresponding to GAD-7 total scores are none 0 to 4, mild 5 to 9, moderate 10 to 14 and severe 15 to 21.

Measure: Change in scores on GAD-7

Time: At baseline, 2, 5 and 8 weeks of treatment

Description: Participants will be asked to self-assess their depression using the Beck Depression Inventory scale (BDI). BDI is a 21-question multiple-choice self-report inventory, widely used for assessment of depression, including in the NIMA BIODEP study, with a score range of 0-63. Each of the 21 items is rated by the participant on a 4 point scale.

Measure: Change in score on participant self-reported depression scale

Time: At baseline and at 8 weeks of treatment

Description: Revere-D is an application developed by Johnson and Johnson, and consists of a battery of eight validated cognitive tasks that assesses cognitive functions, such as memory and learning, that do not involve cognitive processing of emotionally salient stimuli.

Measure: Change in scores in the cognitive function test ReVeRe-D

Time: At baseline, 2, 5 and 8 weeks of treatment

Description: The continuous performance test is a computerised test of sustained attention which provides a measure of cognitive fatigue.

Measure: Change in scores in Continuous performance test

Time: At baseline, 2, 5 and 8 weeks of treatment

Description: The emotional test battery will consist of 3 validated computerised tasks which are used to assess cognitive functions that involve processing emotionally salient stimuli, such as human faces expressing emotional states.

Measure: Change in scores in Emotional Test battery

Time: At baseline and 2 weeks of treatment

Description: Participants will be asked to provide saliva samples before treatment commencement and during the last week of treatment in order for the cortisol levels to be analysed.

Measure: Change in Salivary cortisol levels as a measure of biological stress

Time: Samples collected within 7 days prior to Baseline visit and within 7 days prior to visit 4

Description: Brain structure and function will be assessed using fMRI/MRI

Measure: Change in Brain structure and function

Time: Baseline and at 8 weeks fo treatment

Description: Heart rate variability will be measured for 15 minutes during rest and whilst completing one of the cognitive tasks.

Measure: Change in heart rate variability

Time: Baseline and at 8 weeks fo treatment

Description: Blood samples will be collected for the analysis of cytokine and chemokine levels with a multiplex immunoassay using the MSD Multi-spot assay system with the Cytokine Panel 1, Proinflammatory panel 1 and Chemokine panel 1 kits providing concentration of all analytes of the panel in pg/ml.

Measure: Measurement of peripheral blood peripheral cytokine and chemokine levels

Time: Baseline and at 8 weeks fo treatment

Description: The immune cellular content of the blood samples will be analysed with mass cytometry using the commercial kit Maxpar® Direct™ Immune Profiling Assay.

Measure: Measurement of peripheral blood immunophenotypes

Time: Baseline and at 8 weeks fo treatment


HPO Nodes


Depressivity
Genes 377
AMACR BAZ1B PDCD1 PRKAR1A KCTD17 AFG3L2 DNAJC13 NSMF PRPH TBP DNA2 TOR1A UBQLN2 MED25 WFS1 TRNL1 ADH1C ND4 GNAS RFC2 FGF14 HMBS PLA2G6 SPAST PRKCG HTR2A SQSTM1 ATRX GABRA1 FGF8 FUS CLCN4 LMNB1 CLN6 TRNS2 GDAP2 PON2 GSN SNCA FAN1 XK TWNK PTS TRNQ RPS6KA3 TBX1 GLT8D1 OPTN PINK1 GTF2IRD1 NHLRC1 GBA TRNN PANK2 CRBN GNRH1 PSAP NDST1 GLUD2 SOD1 DNAJC6 LRRK2 DNMT1 PDE11A TAC3 DRD2 MAN1B1 HTT AP2S1 SPRY4 PGAP1 CBS SQSTM1 TOR1A AIMP1 TUSC3 PDGFB TWNK FMO3 SLC20A2 MECP2 CACNA1G CDH23 C9ORF72 FUS GPR35 TARDBP C9ORF72 HIRA IDUA HLA-DQB1 PRSS12 C9ORF72 CLIP2 PIGC HNMT JRK TRNF PAH CLRN1 ATXN2 CPOX CEP78 MSTO1 ELN CLCN4 CISD2 PROK2 PDGFB SGCE SLC6A4 KCNT1 PDGFRB UCHL1 MATR3 GABRG2 SMPD1 PRNP GNRHR KISS1R COQ2 HS6ST1 TNIK NEFH MAPT C9ORF72 ATP13A2 PARK7 NSUN2 SLC25A4 CCNF ANXA11 HLA-DQB1 TBL2 CPOX SNCAIP FIG4 TARDBP NOTCH3 LINS1 VAPB BMPR1A ARVCF SLC18A2 C19ORF12 MAPT ATXN10 POLG SLC45A1 KDM5B MST1 SEC24C B3GALNT2 MLH3 PPT1 FRRS1L JPH3 WDR11 PODXL ND6 ARMC5 HTRA2 AIP CRADD TTC19 MED23 ZC3H14 JMJD1C PRNP USH2A ATP1A3 TRNS1 ND5 EDC3 COASY UNC13A COMT UFD1 VCP POLG FMR1 PMS1 FMN2 PRNP PRNP CHD7 DCPS METTL23 DCTN1 TRNL2 GBA PPP2R2B ATP7B GTF2I USH1G PTPN22 SRPX2 TACR3 TWNK GNA11 TMEM106B SNCA CSF1R MLH1 TRNH PMS2 CLIP1 POLG2 ATXN8OS CASR VPS13C PON1 RSRC1 PPOX VCP HLA-DRB1 EZR DUSP6 BCS1L DCTN1 EHMT1 TRNL1 PRNP PDZD7 MSH6 MAPT EPHA4 POLG THOC2 CRKL CYP27A1 PLA2G6 ANG CC2D1A DCTN1 MYO7A CACNA1H HTT DNAJC5 COQ2 GRIN2A GP1BB DGUOK PRKN CHMP2B KRAS ARSA NR4A2 HNRNPA1 CHMP2B WASHC4 TRNS2 ATXN10 MSH2 CFAP410 PFN1 HMBS CACNA1G GNAS MYO7A SLC2A1 PINK1 POLG C9ORF72 PSEN1 ANOS1 PIK3CA ALMS1 TBC1D7 VCP TRNS1 PANK2 GBA TK2 LIMK1 CHCHD10 XPR1 PPARGC1A RPS20 USP8 ST3GAL3 ARMC5 HARS1 KCTD17 TAF15 AARS2 PER3 FGF14 CTSF TBP MECP2 MBOAT7 POLG PAH TREM2 USH1C TREM2 COX1 TBK1 C12ORF4 WARS2 STX16 ATXN8 SGCE ND1 ATXN8OS PRKACA TBK1 ARSG MAPK1 ATXN2 GRN ABCA7 OCRL KCNJ2 TRNW CHCHD10 COX3 RREB1 DAO GIGYF2 GPR101 TECR CDH23 ATP1A3 EPCAM ADGRV1 GNAS TCF4 GNAS GABRG2 PRNP KISS1 TGFBR2 SEMA4A TWNK GCH1 CIB2 COX2 FGFR1 PCDH15 WHRN LRRK2 TRAPPC9 RRM2B FMR1 RRM2B WFS1 FA2H FGF17 HBB PDGFRB SARS1 BCR EIF4G1 POLG ERBB4 GLA PER2 FBXO31 PON3 GLE1 PROKR2 VPS35 NEK1 MSTO1 LMAN2L GNAS DNMT1 GABRB3 CP TBX1 EPM2A PDGFRB GRIK2 SNCA VCP