Specificity of DNA methylation in the hypertensive kidney

Background: Evidence suggests that DNA methylation (5mC) is important in the development of essential hypertension (EH). The 5mC percentage, a measurement for global methylation studies, in peripheral blood leukocytes (PBL) has been previously associated with hypertension. Methylation patterns are tissue-specific, contributing to differences in transcriptional regulation and cellular differentiation. So far, there have been no studies of 5mC in the kidney – an important effector organ in EH. Furthermore, there has been no investigation of the relationship between 5mC patterns in the hypertensive kidney and PBLs. Aims: (i) To determine if global 5mC in the kidney is correlated to hypertension diagnosis and blood pressure (BP) regulation. (ii) To determine whether PBLs provide a surrogate for cross-tissue patterns of 5mC in the kidney. Methods: We used 96 human kidney and 76 human PBL samples from the TRANSLATE study to investigate global 5mC percentage. TRANSLATE consists of carefully characterized collections of "apparently healthy" specimens of human kidneys. Global methylation was determined using the 5mC ELISA kit (Zymo Research) that measures the total amount of 5mC present in a sample. Results: We found no association of global 5mC percentage in kidney (P=0.18) and PBL (P=0.54) with hypertension diagnosis, nor between PBL 5mC percentage and BP. However, a negative correlation was found between kidney 5mC percentage and systolic BP (r= –0.246; P <0.05), and diastolic BP (r= –0.319; P <0.01). This association was still evident after adjustment for antihypertensive medication for systolic BP (r= –0.210; P <0.05) and diastolic BP (r= –0.273; P <0.01). Furthermore, we found a strong positive correlation between normotensive kidneys and leukocyte 5mC percentages (r=0.864; P<0.01). Similarly, a strong positive correlation was evident for hypertensive kidneys and leukocyte 5mC percentages (r=0.916; P <0.01). Conclusion: Our findings show that kidney 5mC, but not PBL 5m C, is correlated to BP regulation. No relationship was evident for global 5mC and hypertension diagnosis, regardless of the tissue type studied. Furthermore, PBL 5mC global methylation percentage was highly correlated to kidney 5mC percentage. These results highlight the importance of further studies on the involvement of kidney DNA methylation in hypertension, as well as further investigation of the relationship between methylation patterns in the kidney and blood

Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array.

Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈50 000 single nucleotide polymorphisms in &gt;2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P=1.2×10(-8)). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4×10(-6)). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: &lt;0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure

Association of the human Y chromosome with cholesterol levels in the general population

Objective— Males are at higher risk of cardiovascular diseases than females. The aim of the study was to test whether the potential of the Y chromosome to affect cardiovascular risk could be attributed to its influence on lipids. Methods and Results— 1288 Polish men (1157 subjects from young healthy cohort and 131 individuals from middle-aged hypertensive population) were phenotyped for determinants of cardiovascular risk including BMI, blood pressures, lipids, and testosterone. Each subject was genotyped for the HindIII(+/−) polymorphism within the nonrecombining region of the Y chromosome. Men with the HindIII(−) variant exhibited significantly higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels than subjects with the HindIII(+) genotype in both populations. The differences between the genotypes were 0.15 mmol/L (P=0.0107) and 0.45 mmol/L (P=0.0377) in TC and 0.15 mmol/L (P=0.0059) and 0.41 mmol/L (P=0.0432) in LDL among young apparently healthy men and middle-aged hypertensive men, respectively. The HindIII(+) was associated with a significant increase in blood pressure of the middle-aged men. Testosterone serum concentrations correlated positively with HDL-cholesterol levels, and this association was independent of the Y chromosome. Conclusions— The results indicate that a locus/loci on the Y chromosome may influence LDL levels, independent of testosterone levels

May Measurement Month 2017: Results of 39 national blood pressure screening programmes

Raised blood pressure is the biggest single risk factor responsible for mortality worldwide. Despite this, the majority of people with hypertension are unaware of having it, are untreated, or are on treatment but uncontrolled. May Measurement Month is a global campaign initiated by the International Society of Hypertension with the aim of raising awareness of high blood pressure. In the first year of the campaign in 2017, over 1.2 million people were screened in 80 countries across the world, finding over 100 000 people with hypertension who were not on treatment and over 150 000 people on anti-hypertensive treatment who were not controlled. The individual national results from 39 countries are presented in this supplement. In this article, we discuss the background to the campaign, along with some of the logistical and methodological challenges that were faced in setting up the campaign, and in collecting and analysing the data from such a large cross-sectional study. With the lessons learned from the 2017 campaign, the campaign was repeated in 2018 and is to be repeated again in 2019. © The Author(s) 2019

Strikingly low circulating CRP concentrations in ultramarathon runners independent of markers of adiposity - How low can you go?

Objective-This study was undertaken to evaluate to what extent C-reactive protein (CRP) can be reduced by exercise by examining its circulating concentrations in male ultramarathon runners and to determine if low leptin as a robust circulating marker of fat mass could account for low CRP in such men. Methods and Results-Sixty-seven male ultramarathon runners and 63 sedentary male controls of similar age and body mass index were recruited. CRP and leptin were measured by ELISA and radioimmunoassay, respectively. Median CRP concentration in lean (body mass index lt 25 kg/m(2)) marathon runners was less than half control median (0.4 [0.2 to 0.9] mg/L versus 0.9 [0.5 to 2.7] mg/L, P=0.0013) and, more strikingly, in nonlean runners was approximately 26% of control median (0.4 [0.3 to 0.8] mg/L versus 1.5 [0.9 to 2.5] mg/L, P=0.0002). Circulating leptin levels were also substantially lower in lean (45% less) and nonlean (63% less, both P=0.0001) ultramarathon runners. However, interleukin-6 levels were not different. Furthermore, leptin adjustment only minimally attenuated the case-control difference in CRP, suggesting that mechanisms other than fat mass reduction contribute to low concentrations of CRP in marathon runners. Conclusions-This study suggests that circulating CRP concentrations can be markedly suppressed, independently of total adiposity or indeed fat mass, by intense regular physical exercise

The Y chromosome effect on blood pressure in two European populations

Higher blood pressure (BP) in males compared with females is well documented and is thought to be influenced in part by the Y chromosome. To examine whether there is an association between BP and a polymorphic HindIII biallelic marker in the nonrecombining region of the Y chromosome, we genotyped 155 males from a Polish study group and 762 males from a Scottish study group. We also tested for possible interaction between the Y chromosome and a mutation in the steroidogenic factor binding site of the aldosterone synthase gene by genotyping the same group from Scotland. There was no significant difference in age or body mass index between 2 Y chromosome genotypes in both study groups. Men with the HindIII(+) genotype had significantly higher systolic and diastolic pressures than those with the HindIII(−) genotype in both the Polish and Scottish studies. This difference between the genotypes was 5.27 mm Hg (P=0.0014) and 3.14 mm Hg (P=0.0005) for adjusted systolic BP and 2.6 mm Hg (P=0.0045) and 1.44 mm Hg (P=0.0084) for adjusted diastolic BP in the Polish and the Scottish studied, respectively. On binary logistic regression analysis, males with the HindIII(+)/TT SF1 genotype combination had an odds ratio for elevated BP of 3.92 (CI 1.21 to 12.68, P=0.023). Our results indicate that the Y chromosome harbors a locus or loci that contribute to BP variation in hypertensive and normotensive men. The polymorphism in the aldosterone synthase gene may interact with the Y chromosome to increase the odds of an individual’s developing higher BP

Glomerular hyperfiltration: A new marker of metabolic risk

Chronic kidney disease coexists with metabolic syndrome and this relationship may be apparent before overt manifestations of cardiovascular disease. To investigate early stages of the natural history of associations between renal function and metabolic syndrome, we phenotyped 1572 young (mean age=18.4 years), apparently healthy men for metabolic risk factors and estimated their creatinine clearance based on the Cockcroft–Gault equation. High metabolic risk (clustering of at least three metabolic risk factors) was revealed in 8.7% (137) of the subjects and was associated with a 6.9-fold increase in the odds of glomerular hyperfiltration (95% confidence interval (CI): 3.9–11.5) when compared to reference (from none to two metabolic risk factors). Overweight, elevated blood pressure, and low high-density lipoprotein (HDL) cholesterol increased the multivariate-adjusted odds ratio of glomerular hyperfiltration to 6.6 (95% CI: 3.8–11.6), 1.8 (95% CI: 1.0–3.0), and 2.5 (95% CI: 1.5–4.3), respectively. Systolic and diastolic blood pressures clustered together with leptin in the factor analysis and this blood pressure–adiposity component correlated with estimated creatinine clearance (r=0.329, P<0.0001) and explained on its own 10.2% of the variance in the estimated renal function. Our data reveal the silent epidemics of metabolic risk among young, apparently healthy men. Furthermore, the results indicate that high metabolic risk is associated with glomerular hyperfiltration before overt manifestations of cardiovascular disease