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

Objective In 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. Methods Metabolomic 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. Results Amlodipine (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. Conclusions Although 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.Peer reviewe

Effect of hydrochlorothiazide on serum uric acid concentration : a genome-wide association study

Aim: To recognize genetic associations of hydrochlorothiazide-induced change in serum uric acid (SUA) concentration. Patients & methods: We conducted a genome-wide association study on hydrochlorothiazide-induced change in SUA in 214 Finnish men from the GENRES study. Replication analyses were performed in 465 Finns from the LIFE study. Results: In GENRES, we identified 31 loci associated with hydrochlorothiazide-induced change in SUA at p <5 x 10(-5). rs1002976 near VEGFC associated with the change in GENRES and in LIFE. rs950569 near BRINP3 associated with the change in SUA in GENRES and LIFE. The analysis of previously reported SNPs and candidate genes provided some proof for PADI4 and ABCC4. Conclusion: We report genetic markers that may predict the increase in SUA concentration during thiazide treatment.Peer reviewe

Strategies for the introduction of human papillomavirus vaccination: modelling the optimum age- and sex-specific pattern of vaccination in Finland

Phase III trials have demonstrated the efficacy of human papillomavirus (HPV) vaccines in preventing transient and persistent high-risk (hr) HPV infection and precancerous lesions. A mathematical model of HPV type 16 infection and progression to cervical cancer, parameterised to represent the infection in Finland, was used to explore the optimal age at vaccination and pattern of vaccine introduction. In the long term, the annual proportion of cervical cancer cases prevented is much higher when early adolescents are targeted. Vaccinating against hr HPV generates greater long-term benefits if vaccine is delivered before the age at first sexual intercourse. However, vaccinating 12 year olds delays the predicted decrease in cervical cancer, compared to vaccinating older adolescents or young adults. Vaccinating males as well as females has more impact on the proportion of cases prevented when vaccinating at younger ages. Implementing catch-up vaccination at the start of a vaccination programme would increase the speed with which a decrease in HPV and cervical cancer incidence is observed

Pharmacoepigenetics of hypertension : genome-wide methylation analysis of responsiveness to four classes of antihypertensive drugs using a double-blind crossover study design

Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-related ACY3 gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to the ACY3 TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts: the GENRES (; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P < 1E-5) with either systolic or diastolic BP responses to a particular study drug in GENRES. These associations did not replicate in LIFE-Fin . Three methylation sites close to the ACY3 TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P < 0.05). No robust associations between DNA methylation and BP responses to four different antihypertensive drugs were identified. However, the findings on the methylation sites close to the ACY3 TSS may support the role of ACY3 genetic and epigenetic variation in BP response to bisoprolol.Peer reviewe

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

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 similar to 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.Peer reviewe

Replicated evidence for aminoacylase 3 and nephrin gene variations to predict antihypertensive drug responses

Peer reviewe

Predictive simulations of NBI ion power load to the ICRH antenna in Wendelstein 7-X

In Wendelstein 7-X (W7-X), a new ion cyclotron resonance heating (ICRH) antenna will be commissioned during the operational campaign OP2.1. The antenna will have to sustain power loads not only from thermal plasma and radiation but also fast ions. Predictive simulations of fast-ion power loads to the antenna components are therefore important to establish safe operational limits. In this work, the fast-ion power loads from the W7-X neutral beam injection (NBI) system to the ICRH antenna was simulated using the ASCOT suite of codes. Five reference magnetic configurations and five antenna positions were considered to provide an overview of power load behavior under various operating conditions. The NBI power load was found to have an exponential dependence on the antenna insertion depth. Differences between magnetic configurations were significant, with the antenna limiter power load varying between 380 W and 100 kW depending on the configuration. Qualitative differences in power load patterns between configurations were also observed, with the low mirror and low iota configurations exhibiting higher loads to the sensitive antenna straps. The local fast-ion power flux to the antenna limiter was also considered and found to exceed the 2.0 MW m−2 steady-state safety limit only in specific cases. The NBI system might thus pose a safety concern to the ICRH antenna during concurrent NBI-ICRH operation, but additional heat propagation simulations of antenna components are needed to establish more realistic operational time limits

Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients

Abstract Background Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported. Methods To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P < 1 × 10− 5 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES. Results In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (β = − 4.8%, P = 9.6 × 10− 9 for systolic and β = − 4.3%, P = 2.2 × 10− 6 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 × 10− 5. The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (β = − 0.8%, P = 0.4 for systolic and β = − 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (β = − 7.6 g/m2, P = 0.02). Conclusions rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology

Employment status and differences in the one-year coverage of physician visits: different needs or unequal access to services?

BACKGROUND: The dichotomy employed vs. unemployed is still a relevant, but rather crude measure of status in current labour markets. Also, studies concerning the association of employment status with health have to specify the type of the employment as well as the characteristics of the unemployment. This study aims to reveal differences and potential inequalities in physician visits among seven groups in the core-periphery structures of the labour markets. METHODS: A total of 16 000 Finns responded to a postal survey in 2003. Their visits to physicians in public primary health care, occupational health care, private health services, hospital outpatient clinics and dental care services during previous year were measured as indicators of service utilisation. Participants were classified as employees having a permanent or fixed-term and full-time or part-time contract and as those experiencing short-term, prolonged or long-term unemployment. Differences in the one-year coverage of physician visits between these groups of employees were analysed using logistic regression analyses where differences in the need for services were controlled for by including demographics and self-rated health assessments in the models. RESULTS: Permanently employed respondents had visited a physician most often, and the need-adjusted regression models showed significantly lower odds ratios for a visit among fixed-term employees (OR 0.65, 95% CI 0.53–0.81) and in particular among the long-term unemployed (OR 0.21, 95% CI 0.14–0.31). A stratified analysis according to health care sector showed the lowest odds ratios in occupational health care and private physicians (ORs between 0.05 and 0.73) and also low odds ratios for dentists (ORs between 0.45 and 0.91), whereas visits to public primary health care were more common among non-permanent employees and the unemployed (ORs between 1.46 and 2.39). CONCLUSION: The use of physician services varies according to labour market status, being relatively low among the non-permanently employed and the unemployed. This underuse is emphasised when clinical need is taken into account. The main reasons for the variance evidently lie in the structures of the Finnish health service system. The result may indicate non-optimal health care of the population on the periphery of the labour market, but it may also reflect the importance of employment status as a context for need and the decision to visit a physician