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

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

Peer reviewe

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

Effect of antihypertensive drugs on selected plasma acylcarnitines.

<p>Plasma metabolite level is presented as relative units: the median of all analyzed samples was set to 1. Box-and-whisker plots are presented. P values <0.05 from Wilcoxon signed-rank test are included. P, placebo (mean of three periods); A, amlodipine; B, bisoprolol; H, hydrochlorothiazide; L, losartan.</p

Effect of antihypertensive drugs on selected plasma long-chain fatty acids.

<p>Plasma metabolite level is presented as relative units: the median of all analyzed samples was set to 1. Box-and-whisker plots are presented. P values <0.05 from Wilcoxon signed-rank test are included. P, placebo (mean of three periods); A, amlodipine; B, bisoprolol; H, hydrochlorothiazide; L, losartan.</p

Correlation of the change of plasma cysteinylglycine and hexadecanedioate levels with the antihypertensive effect of amlodipine.

<p>Correlation coefficients (r) and P values from partial correlation, calculated with normalized metabolite change values and controlling for metabolite baseline level, are included. dASBP, change of 24-hour ambulatory systolic blood pressure; dADBP, change of 24-hour ambulatory diastolic blood pressure.</p

Characteristics of the study subjects.

<p>Characteristics of the study subjects.</p