PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-9 (9)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Urotensin-II System in Genetic Control of Blood Pressure and Renal Function 
PLoS ONE  2013;8(12):e83137.
Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.
doi:10.1371/journal.pone.0083137
PMCID: PMC3877024  PMID: 24391740
2.  Longer Leukocyte Telomeres Are Associated with Ultra-Endurance Exercise Independent of Cardiovascular Risk Factors 
PLoS ONE  2013;8(7):e69377.
Telomere length is recognized as a marker of biological age, and shorter mean leukocyte telomere length is associated with increased risk of cardiovascular disease. It is unclear whether repeated exposure to ultra-endurance aerobic exercise is beneficial or detrimental in the long-term and whether it attenuates biological aging. We quantified 67 ultra-marathon runners’ and 56 apparently healthy males’ leukocyte telomere length (T/S ratio) using real-time quantitative PCR. The ultra-marathon runners had 11% longer telomeres (T/S ratio) than controls (ultra-marathon runners: T/S ratio = 3.5±0.68, controls: T/S ratio = 3.1±0.41; β = 0.40, SE = 0.10, P = 1.4×10−4) in age-adjusted analysis. The difference remained statistically significant after adjustment for cardiovascular risk factors (P = 2.2×10−4). The magnitude of this association translates into 16.2±0.26 years difference in biological age and approximately 324–648bp difference in leukocyte telomere length between ultra-marathon runners and healthy controls. Neither traditional cardiovascular risk factors nor markers of inflammation/adhesion molecules explained the difference in leukocyte telomere length between ultra-marathon runners and controls. Taken together these data suggest that regular engagement in ultra-endurance aerobic exercise attenuates cellular aging.
doi:10.1371/journal.pone.0069377
PMCID: PMC3729964  PMID: 23936000
3.  Elderly dialysis patients: analysis of factors affecting long-term survival in 4-year prospective observation 
Purpose
To assess factors influencing the long-term survival of elderly dialysis patients.
Methods
The study group consisted of 51 prevalent dialysis patients aged over 70 years (32 F and 19 M, all caucasians), who had been on a chronic hemodialysis (27) or peritoneal dialysis program (24) for at least 2 months; median age was 77 years, median time on dialysis before inclusion was 16 months, and median residual diuresis was 600 ml. The patients were prospectively followed up to 4 years, and an analysis of factors affecting survival was performed.
Results
Thirteen patients from the initial cohort of 51 (25.5 %) survived the whole 48-month observation period: 10 HD patients (37 %) and 3 PD patients (12.5 %). Annual mortality rate was 28.2 %: 37.4 % on PD vs. 20.9 % on HD. The dialysis modality had a significant impact on patients’ survival (p = 0.049; Cox F-test). The independent mortality risk factors in the Cox proportional hazard regression model were higher plasma pro-atrial natriuretic peptide (pro-ANP) (p = 0.006), lower residual diuresis (p = 0.048), and lower systolic blood pressure (BP) value (p = 0.039).
Conclusions
Paramount for the survival of the elderly on dialysis is adequate extracellular volume control. Residual renal function is a protective factor for the survival of elderly HD patients. This observation is novel, not previously reported in an elderly dialysis population.
doi:10.1007/s11255-012-0166-4
PMCID: PMC3358559  PMID: 22528579
Elderly; Hemodialysis; Peritoneal dialysis; Survival; Extracellular volume control
4.  FGF21 signalling pathway and metabolic traits – genetic association analysis 
European Journal of Human Genetics  2010;18(12):1344-1348.
Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol – LDL-C, HDL-cholesterol – HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.
doi:10.1038/ejhg.2010.130
PMCID: PMC2988092  PMID: 20717167
fibroblast growth factor 21; fibroblast growth factor receptor 2; cholesterol; single-nucleotide polymorphism; genome-wide association studies
5.  GENETIC ARCHITECTURE OF AMBULATORY BLOOD PRESSURE IN THE GENERAL POPULATION – INSIGHTS FROM CARDIOVASCULAR GENE-CENTRIC ARRAY 
Hypertension  2010;56(6):1069-1076.
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 BP in 2020 individuals from 520 white European nuclear families (the GRAPHIC Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array which contains approximately 50000 single nucleotide polymorphisms in >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 mmHg 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 GRAPHIC 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 GRAPHIC Study showed that cell survival control signalling cascades could play a role in blood pressure regulation. There was also a significant over-representation of rare variants (minor allele frequency <0.05) amongst 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.
doi:10.1161/HYPERTENSIONAHA.110.155721
PMCID: PMC3035934  PMID: 21060006
gene; genetics; blood pressure; single nucleotide polymorphism; association; heritability
6.  FGF21 signalling pathway and metabolic traits - genetic association analysis 
Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGF receptor 2 (FGFR2) and FGF receptor 3 (FGFR3). We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage we examined associations between 63 common single nucleotide polymorphisms (SNPs) in 5 genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and 4 metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol, triglycerides and body mass index - BMI) in 629 individuals from Silesian Hypertension Study. Replication analyses were performed in 5,478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3,030 directly genotyped individuals of the German Myocardial Infarction Family Study. Of 54 SNPs that met quality control criteria after genotyping in Silesian Hypertension Study, four (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (p=0.0006, p=0.0013, p=0.0055, p=0.011, respectively) and one (rs2608819 in KLB) was associated with BMI (p=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both the CoLaus cohort (p=0.009) and men from the German Myocardial Infarction Family Study (p=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variation in FGFR2 may be associated with LDL-C in subjects of white European ancestry.
doi:10.1038/ejhg.2010.130
PMCID: PMC2988092  PMID: 20717167
fibroblast growth factor 21; fibroblast growth factor receptor 2; cholesterol; single nucleotide polymorphism; genome-wide association studies
7.  A common variant in low density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol 
Objective
A rare mutation in low density lipoprotein receptor-related protein 6 gene (LRP6) was identified as the primary molecular defect underlying monogenic form of coronary artery disease. We hypothesised that common variants in LRP6 could predispose subjects to elevated LDL-cholesterol (LDL-C).
Methods and Results
12 common (minor allele frequency ≥0.1) single nucleotide polymorphisms in LRP6 were genotyped in 703 individuals from 213 Polish pedigrees (Silesian Cardiovascular Study families). The family-based analysis revealed that the minor allele of rs10845493 clustered with elevated LDL-C in offspring more frequently than expected by chance (p=0.0053). The quantitative analysis restricted to subjects free of lipid-lowering treatment confirmed the association between rs10845493 and age-, sex- and BMI-adjusted circulating levels of LDL-C in families as well as 2 additional populations - 218 unrelated subjects from Silesian Cardiovascular Study replication panel and 1138 individuals from Young Men Cardiovascular Association cohort (p=0.0268, p=0.0476 and p=0.0472, respectively). In the inverse variance weighted meta-analysis of the 3 populations each extra minor allele copy of rs10845493 was associated with 0.14 mmol/L increase in age-, sex- and BMI-adjusted LDL-C (SE=0.05, p=0.0038).
Conclusions
Common polymorphism in the gene underlying monogenic form of coronary artery disease impacts on risk of LDL-C elevation.
doi:10.1161/ATVBAHA.109.185355
PMCID: PMC2814817  PMID: 19667113
gene; genetics; LDL-cholesterol; lipids; association
8.  Association between lipid profile and circulating concentrations of estrogens in young men 
Atherosclerosis  2008;203(1):257-262.
Objectives
Men show higher rates of cardiovascular morbidity and mortality than pre-menopausal women and this sexual dimorphism may be related to sex-specific effects of sex steroids on cardiovascular risk factors. Unlike androgens, estrogens were not extensively investigated in relation to cardiovascular phenotypes in men.
Methods
We examined associations of estradiol and estrone and their precursors (total testosterone and androstenedione) with traditional cardiovascular risk factors (lipids, blood pressure, body mass) in 933 young (median age – 19 years), apparently healthy Polish men.
Results
Total estradiol was associated with total cholesterol (p=0.006) and HDL-cholesterol (p<0.001) and estrone showed the strongest associations with both total cholesterol (p<0.001) and LDL-cholesterol (p<0.001) in the unadjusted ANOVA analysis. In the multivariable adjusted models in which other independent variables were held as constant one standard deviation increase in estradiol level was associated with 6%-standard deviation increase in total cholesterol (standardized B=0.06, p=0.038) and 6%-standard deviation decrease in HDL-cholesterol (standardized B=-0.06, p=0.036). An increase in estrone levels by one standard deviation was associated with respective 12%- and 13%-standard deviation increases in total cholesterol (standardized B=0.12, p<0.001) and LDL-cholesterol levels (standardized B=0.12, p<0.001) after controlling for other predictors of lipids. Estrone correlated linearly with androstenedione (r=0.28, p<0.001) but there was no correlation between estradiol and testosterone. Estrogens retained their independent associations with lipids after adjustment for their biochemical precursors in the multivariable analysis.
Conclusions
Increased levels of estrogens are associated with unfavourable lipid profile in men and that this association is apparent early in life, before cardiovascular disease manifestations.
doi:10.1016/j.atherosclerosis.2008.06.002
PMCID: PMC2693280  PMID: 18639879
lipids; estrogens; sex steroids; association; risk factors
9.  Inverse Associations Between Androgens and Renal Function: The Young Men Cardiovascular Association (YMCA) Study 
American journal of hypertension  2008;22(1):100-105.
BACKGROUND
Men exhibit higher risk of nondiabetic renal diseases than women. This male susceptibility to renal disease may be mediated by gender-specific factors such as sex hormones.
METHODS
We have undertaken a cross-sectional examination of associations between renal function (creatinine clearance estimated based on Cockcroft–Gault equation) and circulating levels of sex steroids (total testosterone, total estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), and dihydrotestosterone) in 928 young (mean age: 18.5 ± 1.2 years) men.
RESULTS
Both androstenedione and DHEA-S showed inverse linear associations with renal function in the crude analysis of lean men (those with body mass index (BMI) less than median). However, only DHEA-S retained its association with renal function in lean subjects after adjustment—assuming no changes in other independent variables 1 s.d. increase in DHEA-S was associated with 13%-s.d. decrease in creatinine clearance (P = 0.004). Testosterone decreased across tertiles of creatinine clearance only in the crude analysis of nonlean (BMI greater than median) subjects (P < 0.001). The adjusted regression analysis that assumed no changes in other independent variables showed that 1 s.d. increase in total testosterone was associated with 11%-s.d. decrease in creatinine clearance of nonlean men (P = 0.006). Factor analysis confirmed an inverse association of renal function with both sex steroids and a different pattern of their loadings on glomerular filtration–related factors in lean (DHEA-S) and nonlean (testosterone) subjects.
CONCLUSIONS
Our data may suggest that androgens are inversely associated with estimated renal function in apparently healthy men without history of cardiovascular disease.
doi:10.1038/ajh.2008.307
PMCID: PMC2808108  PMID: 19096379

Results 1-9 (9)