Replicated Evidence for Aminoacylase 3 and Nephrin Gene Variations to Predict Antihypertensive Drug Responses

Rimpelä, Jenni M; Kontula, Kimmo; Fyhrquist, F; Donner, Kati; Tuiskula, Annukka M.; Sarin, Antti‐Pekka; Mohney, Robert P.; Stirdivant, Steven M.; Hiltunen, Timo P.

doi:10.2217/pgs-2016-0204

Cited by 20 publications

(14 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…No metabolite in placebo plasma samples was shown to associate with an antihypertensive drug response at statistical significance level of P < 2 x 10 −5 . The potential association of baseline levels of aromatic amino acids, phenylalanine and N-acetylphenylalanine in particular, as already reported by us [ 42 ], to a favorable response to bisoprolol is of some interest due to our previous findings of association between ACY3 (coding for aminoacylase 3) variation and bisoprolol responsiveness [ 13 ]; aminoacylase 3 is the enzyme catalyzing conversion of N-acetylphenylalanine to phenylalanine. It is of note that while the levels of a number of long-chain acylcarnitines were diminished in a relatively systematic fashion by amlodipine, bisoprolol and losartan, their baseline levels were not predictive for a good antihypertensive response to any of these drugs.…”

Section: Discussionmentioning

confidence: 78%

Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension

et al. 2017

View full text Add to dashboard Cite

ObjectiveIn order to search for metabolic biomarkers of antihypertensive drug responsiveness, we measured >600 biochemicals in plasma samples of subjects participating in the GENRES Study. Hypertensive men received in a double-blind rotational fashion amlodipine, bisoprolol, hydrochlorothiazide and losartan, each as a monotherapy for one month, with intervening one-month placebo cycles.MethodsMetabolomic analysis was carried out using ultra high performance liquid chromatography-tandem mass spectrometry. Full metabolomic signatures (the drug cycles and the mean of the 3 placebo cycles) became available in 38 to 42 patients for each drug. Blood pressure was monitored by 24-h recordings.ResultsAmlodipine (P values down to 0.002), bisoprolol (P values down to 2 x 10−5) and losartan (P values down to 2 x 10−4) consistently decreased the circulating levels of long-chain acylcarnitines. Bisoprolol tended to decrease (P values down to 0.002) the levels of several medium- and long-chain fatty acids. Hydrochlorothiazide administration was associated with an increase of plasma uric acid level (P = 5 x 10-4) and urea cycle metabolites. Decreases of both systolic (P = 0.06) and diastolic (P = 0.04) blood pressure after amlodipine administration tended to associate with a decrease of plasma hexadecanedioate, a dicarboxylic fatty acid recently linked to blood pressure regulation.ConclusionsAlthough this systematic metabolomics study failed to identify circulating metabolites convincingly predicting favorable antihypertensive response to four different drug classes, it provided accumulating evidence linking fatty acid metabolism to human hypertension.

show abstract

Section: Discussionmentioning

confidence: 78%

Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension

et al. 2017

View full text Add to dashboard Cite

show abstract

“…S4 online). A pharmacogenetic substudy was done in Scandinavia, including 1,146 Finnish patients whose DNA samples were available for GWAS 20 . Of this group, a total of 401 patients on monotherapy at 2 months' visit (losartan, n = 200; atenolol, n = 201) were selected for analysis of BP responses in the current study.…”

Section: Methodsmentioning

confidence: 99%

Human essential hypertension: no significant association of polygenic risk scores with antihypertensive drug responses

Tähtisalo

Ruotsalainen

Mars

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Polygenic risk scores (PRSs) for essential hypertension, calculated from > 900 genomic loci, were recently found to explain a significant fraction of hypertension heritability and complications. To investigate whether variation of hypertension PRS also captures variation of antihypertensive drug responsiveness, we calculated two different PRSs for both systolic and diastolic blood pressure: one based on the top 793 independent hypertension-associated single nucleotide polymorphisms and another based on over 1 million genome-wide variants. Using our pharmacogenomic GENRES study comprising four different antihypertensive monotherapies (n ~ 200 for all drugs), we identified a weak, but (after Bonferroni correction) statistically nonsignificant association of higher genome-wide PRSs with weaker response to a diuretic. In addition, we noticed a correlation between high genome-wide PRS and electrocardiographic left ventricular hypertrophy. Finally, using data of the Finnish arm of the LIFE study (n = 346), we found that PRSs for systolic blood pressure were slightly higher in patients with drug-resistant hypertension than in those with drug-controlled hypertension (p = 0.03, not significant after Bonferroni correction). In conclusion, our results indicate that patients with elevated hypertension PRSs may be predisposed to difficult-to-control hypertension and complications thereof. No general association between a high PRS and less efficient drug responsiveness was noticed. Elevated blood pressure (BP) has emerged as the leading risk factor for global disease burden, with a prevalence of 24% in males and 20% in females and totalling 1.1 billion affected adults worldwide 1. Hypertension has been estimated to account for approximately 9.4 million deaths annually 2. The insidious nature of hypertension is underscored by its high prevalence, its mostly asymptomatic nature, and slow progress in achievement of targets of treatment, calling for need of fundamental transformation in attempts of hypertension control 3. There is much hope that better understanding of the underlying genetic mechanisms would result in more precise ways of screening, diagnostic classification and drug treatment of hypertension. Although major progress has been encountered in studies on pathophysiology and individualized treatment of monogenic forms of hypertension 4-6 , the clinical usefulness of genomic techniques in patients with essential hypertension has remained limited. Genome-wide association studies (GWASs) have revealed up to 900 genetic loci associated

show abstract

“…More recently, an intriguing finding from the GENRES study of in Finnish men randomized to several different antihypertensive drugs found in an unbiased genome analysis that carriers of a C allele at rs3814995 had greater BP response to losartan [47]. This class effect was replicated in American and European cohorts, and also in a separate analysis of Finnish patients in the LIFE (Losartan Intervention For Endpoint reduction in Hypertension) trial [48]. rs3814995 is a SNP within NPHS1, where the A allele codes for a missense mutation from glutamine to lysine at amino acid 117 in nephrin, a crucial protein in the glomerular slit diaphragm.…”

Section: Inhibitors Of the Renin-angiotensin Systemmentioning

confidence: 90%

Pharmacogenomics in Hypertension: Where We Stand Today

Cunningham¹,

Chapman²

2019

Preprint

View full text Add to dashboard Cite

Hypertension is a common and growing medical problem that leads to enormous cardiovascular and kidney disease worldwide. While many drugs exist to treat hypertension, there is large individual variation in how a given individual responds to different agents, which contributes to dismal rates of hypertension control. While demographic factors predict which drugs may work better in certain individuals, a great degree of this variation has a genetic basis. In recent years, genome wide association studies have begun to identify specific gene variants that predict drug response to particular agents. This review identifies the major genetic variants influencing antihypertensive response that have emerged from this growing body of work. For novel genetic variants without a previously known biologic basis in blood pressure, it is crucial to validate initial findings in subsequent studies. This information may eventually lead to a more personalized approach to hypertension management that will improve blood pressure control and patient outcomes. The integration of this large amount of data and its real world application will be highly challenging, but strategies to accomplish this are discussed.

show abstract

Replicated Evidence for Aminoacylase 3 and Nephrin Gene Variations to Predict Antihypertensive Drug Responses

Abstract: We provide support for two pharmacogenomic markers for beta-blockers and angiotensin receptor antagonists.

Cited by 20 publications

References 49 publications

Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension

Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension

Human essential hypertension: no significant association of polygenic risk scores with antihypertensive drug responses

Pharmacogenomics in Hypertension: Where We Stand Today

Contact Info

Product

Resources

About