Search

BACKGROUND: UMOD (uromodulin) has been linked to hypertension through potential activation of Na+-K+-2Cl- cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction. METHODS: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897). RESULTS: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m²), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mm Hg [95% CI, -8.44 to -4.69]; P<0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; P=0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mm Hg ([95% CI, -6.64 to -0.05]; P=0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group (P=0.004 for difference in trajectories). CONCLUSIONS: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management. [ABSTRACT FROM AUTHOR]

PCSK9-inhibitors (PCSK9i) are new drugs recently approved to lower LDL-cholesterol levels. However, due to the lack of long-term clinical data, the potential adverse effects of long-term use are still unknown. The PCSK9 genetic locus has been recently implicated in mood disorders and hence we wanted to assess if the effect of PCSK9i that block the PCSK9 protein can lead to an increase in the incidence of mood disorders. We used genetically-reduced PCSK9 protein levels (pQTLs) in plasma, serum, cerebrospinal fluid as a proxy for the effect of PCSK9i. We performed Mendelian randomization analyses using PCSK9 levels as exposure and mood disorder traits major depressive disorder, mood instability, and neuroticism score as outcomes. We find no association of PCSK9 levels with mood disorder traits in serum, plasma, and cerebrospinal fluid. We can conclude that genetically proxied on-target effect of pharmacological PCSK9 inhibition is unlikely to contribute to mood disorders. [ABSTRACT FROM AUTHOR]

Interindividual differences in generation of new fat cells determine body fat and type 2 diabetes risk. In the GENetics of Adipocyte Lipolysis (GENiAL) cohort, which consists of participants who have undergone abdominal adipose biopsy, we performed a genome-wide association study (GWAS) of fat cell number (n = 896). Candidate genes from the genetic study were knocked down by siRNA in human adipose-derived stem cells. We report 318 single nucleotide polymorphisms (SNPs) and 17 genetic loci displaying suggestive (P < 1 × 10-5) association with fat cell number. Two loci pass threshold for GWAS significance, on chromosomes 2 (lead SNP rs149660479-G) and 7 (rs147389390-deletion). We filtered for fat cell number-associated SNPs (P < 1.00 × 10-5) using evidence of genotype-specific expression. Where this was observed we selected genes for follow-up investigation and hereby identified SPATS2L and KCTD18 as regulators of cell proliferation consistent with the genetic data. Furthermore, 30 reported type 2 diabetes-associated SNPs displayed nominal and consistent associations with fat cell number. In functional follow-up of candidate genes, RPL8, HSD17B12, and PEPD were identified as displaying effects on cell proliferation consistent with genetic association and gene expression findings. In conclusion, findings presented herein identify SPATS2L, KCTD18, RPL8, HSD17B12, and PEPD of potential importance in controlling fat cell numbers (plasticity), the size of body fat, and diabetes risk. [ABSTRACT FROM AUTHOR]

BACKGROUND Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the uromodulin gene (UMOD) affecting uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb (TAL) of the loop of Henle and its effect on BP appears to be mediated via the TAL sodium transporter, NKCC2. Loop-diuretics block NKCC2 but are not commonly used in hypertension management. Volume overload is one of the primary drivers for uncontrolled hypertension, so targeting loop-diuretics to individuals who are more likely to respond to this drug class, using the UMOD genotype, could be an efficient precision medicine strategy. METHODS The BHF UMOD Trial is a genotype-blinded, multicenter trial comparing BP response to torasemide between individuals possessing the AA genotype of the SNP rs13333226 and those possessing the G allele. 240 participants (≥18 years) with uncontrolled BP, on ≥1 antihypertensive agent for ≥3 months, will receive treatment with Torasemide, 5 mg daily for 16 weeks. Uncontrolled BP is average home systolic BP (SBP) >135 mmHg and/or diastolic BP >85 mmHg. The primary outcome is the change in 24-hour ambulatory SBP area under the curve between baseline and end of treatment. Sample size was calculated to detect a 4 mmHg difference between groups at 90% power. Approval by West of Scotland Research Ethics Committee 5 (16/WS/0160). RESULTS The study should conclude August 2021. CONCLUSIONS If our hypothesis is confirmed, a genotype-based treatment strategy for loop diuretics would help reduce the burden of uncontrolled hypertension. CLINICAL TRIALS REGISTRATION https://clinicaltrials.gov/ct2/show/NCT03354897. [ABSTRACT FROM AUTHOR]

Previously, our comprehensive cardiovascular characterization study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesized at the thick ascending limb of the loop of Henle and is encoded by the Umod gene. Umod -/- mice have significantly lower blood pressure than Umod +/+ mice, are resistant to salt-induced changes in blood pressure, and show a leftward shift in pressure-natriuresis curves reflecting changes of sodium reabsorption. Salt stress triggers transcription factors and genes that alter renal sodium reabsorption. To date there are no studies on renal transcriptome responses to salt stress. Here we aimed use RNA-Seq to delineate salt stress pathways in tubules isolated from Umod +/+ mice (a model of sodium retention) and Umod -/- mice (a model of sodium depletion) ± 300 mosmol sodium chloride ( n = 3 per group). In response to salt stress, the tubules of Umod +/+ mice displayed an upregulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, P = 2.48 e -12 ) and Hspa1b (Log2 fold change 4.05, P = 2.48 e -12 ). This response was absent in tubules of Umod -/- mice. Interestingly, seven of the genes discordantly expressed in the Umod -/- tubules were electrolyte transporters. Our results are the first to show that salt stress in renal tubules alters the transcriptome, increasing the expression of heat shock genes. This direction of effect in Umod +/+ tubules suggest the difference is due to the presence of Umod facilitating greater sodium entry into the tubule cell reflecting a specific response to salt stress.