SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03683069

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Salt Sensitive Hypertension and Striatin

Salt sensitivity of blood pressure is a substantial risk factor for cardiovascular morbidity and mortality. Inappropriate increases in renal sodium reabsorption lead to volume expansion, hypertension and salt sensitive blood pressure. Key homeostatic mechanisms that regulate renal sodium reabsorption are: first, hormonal, e.g., renin-angiotensin-aldosterone system and second, vascular, e.g., renal vasculature. Dysfunction in one or both mechanisms leads to hypertension and salt sensitive blood pressure. The investigators recently documented that striatin plays a novel role in the development of salt sensitive blood pressure. However, the mechanisms that lead to striatin-mediated salt sensitive blood pressure are not clear; defining these mechanisms is the overall goal of this proposal. Striatin is a calmodulin- and caveolin-binding protein that can function as either a scaffolding and/or signaling protein, specifically in relation to the mechanism of action of steroids. In a large study of well characterized subjects from the HyperPATH cohort, the investigators documented that hypertensive and normotensive humans who are striatin risk allele carriers have salt sensitive blood pressure. The investigators then developed a striatin heterozygous knockout mouse as a tool to identify potential mechanisms for the salt sensitive blood pressure. The investigators documented that these mice also have salt sensitive blood pressure with higher blood pressure levels and inappropriately increased aldosterone levels on a liberal salt diet.

NCT03683069 Hypertension Genetics Hypertension
MeSH: Hypertension
HPO: Hypertension

1 Interventions

Name: Eplerenone vs Amlodipine

Description: We posit that decreases in striatin activity/levels increases aldosterone secretion resulting in hypertension and salt sensitive blood pressure. Thus, our mechanistic clinical study will assess whether hypertensive striatin risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine). To test this hypothesis, we will perform a randomized, double-blind, active controlled study in hypertensive carriers of the striatin risk allele using a novel two-limb, proof-of-principle study. Our primary outcome will be a liberal salt diet systolic blood pressure with a secondary outcome of salt sensitive blood pressure. Therefore, this mechanistic trial will provide support for using a genetic marker that identifies individuals who are uniquely responsive to mineralocorticoid receptor blockade--personalized, precision medicine.

Type: Drug

Epleronone Arm Amlodipine Arm


Primary Outcomes

Description: Subjects will be counseled regarding liberal salt dietary intake to ensure similar intakes in all subjects [Na+ (200 mEq), potassium (K+, 100 mEq) and calcium (800 mg)]. This or a greater level of Na+ intake was consumed by 60-70% of subjects before entering the HyperPATH protocol. After completion of this diet for 7 days, the subject will come to the Center for Clinical Investigation (CCI) Ambulatory Clinical Center between 7-8 AM, fasting, and after remaining supine for 60-90 mins will have blood samples obtained for future analyses, and their BP measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses. Procedure will be performed before randomization and at the completion of 16 weeks of therapy.

Measure: Systolic supine morning liberal salt automated blood pressure

Time: Change in blood pressure between baseline and 16 weeks of randomized drug therapy

Other Outcomes

Description: First step: subjects will ingest a liberal salt intake [Na+ (200 mEq/day)] for 7 days. The subject will come to the study unit between 7-8 AM, fasting. After remaining supine for 60-90 mins, their BP will be measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses. Second step: subjects will then be fed a restricted salt diet (10 mEq Na+/day) for 7 days. On the morning of the 7th day, the subjects will come fasting to the study unit between 7-8 AM, and the studies performed as detailed above. The BP data from the two diet studies will allow us to calculate SSBP. The procedures will be performed before randomization and at the completion of 16 weeks of therapy.

Measure: Systolic salt sensitive blood pressure

Time: Change in blood pressure between baseline and 16 weeks of randomized drug therapy

Purpose: Basic Science

Allocation: Randomized

Parallel Assignment


There are 2 SNPs

SNPs


1 rs2540923

INCLUSION CRITERIA: 1. rs2540923A allele carrier 2. ages >17 years; 3. hypertension as defined by primary physician; 4. not on more than two anti-hypertensives; 5. normal renal, metabolic, electrolyte, complete blood cell count, and lipid profile laboratory tests; 6. if on an angiotensin converting enzyme inhibitor, angiotensin receptor blocker or mineralocorticoid receptor antagonist, needs to be washed out for 3 months.

SUBJECT POPULATION: It is estimated that most of the striatin rs2540923 risk allele carriers will come from our HyperPATH cohort.

Based on our previous studies the investigators estimated that approximately 10% of hypertensives will be carriers of the rs2540923 risk allele.

All subjects will be genotyped at rs2540923, and the risk allele carriers will be entered into the protocol and randomized blindly into one or the other treatment arms.


2 rs254093

The subjects evaluated in this protocol are hypertensive and carry the Striatin rs254093 risk allele.



HPO Nodes


HPO:
Hypertension
Genes 282
MKKS TET2 LDLRAP1 HGD IL12B TMEM67 DNAJB11 POU6F2 MYH7 PDE3A MYH11 ERCC4 PRTN3 ERCC6 DIS3L2 ZMPSTE24 MYLK TRAF3IP1 HLA-B ACAT1 TMEM237 LEMD3 HLA-DPA1 HLA-DPB1 ENPP1 CYP11B1 IFT172 MAT2A CYP11B2 CYP17A1 HLA-DRB1 CYP21A2 MAX SDCCAG8 B2M KIF1B CD2AP TRPC6 ACTA2 MC4R GBA BBS1 BBS2 CDH23 BBS4 HMBS PTPN22 HPSE2 IRF5 ACTN4 GCH1 EXT2 TNFRSF11A KCTD1 ACVRL1 GPR101 MDH2 RREB1 WNK1 NPHP4 TRIP13 ADA2 BBS9 BANF1 NFU1 ALX4 STAT1 PHF21A MKS1 HIRA NOD2 SLC52A3 LRIG2 ARL6 JAK2 SLC2A10 TTC8 ERCC8 KLHL3 GJA1 BMPR2 FBN1 GANAB NF1 CLCN2 GLA GPC3 MGP ALMS1 BRCA2 SDHAF2 FIG4 ARHGAP31 NFIX KCNJ5 SCN2B TMEM70 UFD1 PKD1 PKD2 SCNN1A PKHD1 SCNN1B WDR35 FGA SCNN1G MYMK CC2D2A MAFB CACNA1H NR3C2 CCR6 FGFR2 GNAS HSD11B2 SLC52A2 NME1 FH PLIN1 ADAMTSL4 ABCG5 ABCG8 WNK4 NOTCH1 TBX1 NOTCH2 SDHA FOXF1 NOTCH3 SDHB SDHC SDHD PCSK9 PDE11A GP1BB COL1A1 FOXE3 MPL COL3A1 NPHP1 CUL3 VHL COL4A3 COL4A4 COL4A5 CACNA1D COL5A1 COL5A2 IFT27 KRT8 FMO3 RPGRIP1L FMR1 FN1 COMT OFD1 MLX SH2B3 KRT18 CLIP2 CALR SMARCAL1 LZTFL1 CEP290 WRN WT1 BBIP1 ITGA8 ELP1 FUZ BAZ1B POR ABCB6 APOA1 POU3F4 PAM16 APOB GATA5 AIP CAV1 BBS5 REST CPOX RET NR3C1 PPARG OSGEP RFC2 GTF2IRD1 ECE1 IDUA NSMCE2 SERPINA6 LARS2 TMEM127 EDA CBS LDLR JMJD1C ABCC6 WDPCP CEP164 TNFRSF11B BBS10 WDR19 TGFB2 TGFB3 TGFBR1 TGFBR2 TGFBR3 MFAP5 USP8 MLXIPL ANGPTL6 LIMK1 VAC14 NPHP3 GTF2I THPO TRNC SEC24C LMNA COX1 COX2 COX3 EGFR ARVCF GUCY1A1 SUGCT CYTB LMX1B TRIM32 TRIM28 BBS7 PDE8B VANGL1 LOX ND1 ARMC5 IQCB1 XPNPEP3 ND4 ND5 DYRK1B ND6 PRKACA PRKAR1A NKX2-5 TRNE TRNF YY1AP1 CCN2 BSCL2 TRNH CTLA4 ELN TRNK TRNL1 PRKG1 C8ORF37 TRNQ TRNS1 TRNS2 TRNV TRNW HBB LYZ ENG MUC1 BBS12 G6PC SLC37A4 TBL2 EDA2R H19 COQ7 TP53 SMAD3 CEP19 SMAD4 INVS SMAD6