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1.  The Relation of Rapid Changes in Obesity Measures to Lipid Profile - Insights from a Nationwide Metabolic Health Survey in 444 Polish Cities 
PLoS ONE  2014;9(1):e86837.
Objective
The impact of fast changes in obesity indices on other measures of metabolic health is poorly defined in the general population. Using the Polish accession to the European Union as a model of political and social transformation we examined how an expected rapid increase in body mass index (BMI) and waist circumference relates to changes in lipid profile, both at the population and personal level.
Methods
Through primary care centres in 444 Polish cities, two cross-sectional nationwide population-based surveys (LIPIDOGRAM 2004 and LIPIDOGRAM 2006) examined 15,404 and 15,453 adult individuals in 2004 and 2006, respectively. A separate prospective sample of 1,840 individuals recruited in 2004 had a follow-up in 2006 (LIPIDOGRAM PLUS).
Results
Two years after Polish accession to European Union, mean population BMI and waist circumference increased by 0.6% and 0.9%, respectively. This tracked with a 7.6% drop in HDL-cholesterol and a 2.1% increase in triglycerides (all p<0.001) nationwide. The direction and magnitude of the population changes were replicated at the personal level in LIPIDOGRAM PLUS (0.7%, 0.3%, 8.6% and 1.8%, respectively). However, increases in BMI and waist circumference were both only weakly associated with HDL-cholesterol and triglycerides changes prospectively. The relation of BMI to the magnitude of change in both lipid fractions was comparable to that of waist circumference.
Conclusions
Moderate changes in obesity measures tracked with a significant deterioration in measures of pro-atherogenic dyslipidaemia at both personal and population level. These associations were predominantly driven by factors not measureable directly through either BMI or waist circumference.
doi:10.1371/journal.pone.0086837
PMCID: PMC3908946  PMID: 24497983
2.  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
3.  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
4.  THE EPITHELIAL SODIUM CHANNEL γ-SUBUNIT GENE (SCNN1G) AND BLOOD PRESSURE: FAMILY-BASED ASSOCIATION, RENAL GENE EXPRESSION AND PHYSIOLOGICAL ANALYSES 
Hypertension  2011;58(6):1073-1078.
Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in four cohorts of 1611 white European families comprising a total of 8199 individuals, we undertook staged testing of candidate SNPs for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes as well as expression of SCNN1G in human kidneys. We found that an intronic SNP of SCNN1G (rs13331086) was significantly associated with age-, sex- and BMI-adjusted blood pressure in each of the four populations (P < 0.05). In an inverse variance-weighted meta-analysis of this SNP in all four populations each additional minor allele copy was associated with a 1 mmHg increase in systolic blood pressure and 0.52 mmHg increase in diastolic blood pressure (SE = 0.33, P = 0.002 for SBP; SE = 0.21, P = 0.011 for DBP). The same allele was also associated with higher 12-h overnight urinary potassium excretion (P = 0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a non-significant (P = 0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.
doi:10.1161/HYPERTENSIONAHA.111.176370
PMCID: PMC3220739  PMID: 22006290
blood pressure; genetics; meta-analysis; risk factors; cardiovascular diseases
5.  Dense Genotyping of Candidate Gene Loci Identifies Variants Associated with High-Density Lipoprotein Cholesterol 
Background
Plasma levels of high density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high density genotyping array containing SNPs from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging-SNPs but also included low-frequency nonsynonymous SNPs.
Methods and Results
Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in three additional populations for a total meta-analysis in 7,857 individuals. We replicated the majority of loci identified through genome wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664), and provide evidence suggestive of association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in five loci, including association with low frequency nonsynonymous variants.
Conclusions
Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts composed of extreme individuals may be efficiently used in a case-control discovery of quantitative traits.
doi:10.1161/CIRCGENETICS.110.957563
PMCID: PMC3319351  PMID: 21303902
lipids; genetic association; HDL cholesterol; cardiovascular diseases
6.  Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome 
Lancet  2012;379(9819):915-922.
Summary
Background
A sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.
Methods
We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.
Findings
Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis.
Interpretation
The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.
Funding
British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.
doi:10.1016/S0140-6736(11)61453-0
PMCID: PMC3314981  PMID: 22325189
7.  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
8.  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
9.  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
10.  Large-Scale Candidate Gene Analysis of HDL Particle Features 
PLoS ONE  2011;6(1):e14529.
Background
HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis.
Methodology/Principal Findings
We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10−15) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10−6). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10−9), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10−8) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10−6). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170).
Conclusions
We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C.
doi:10.1371/journal.pone.0014529
PMCID: PMC3024972  PMID: 21283740
11.  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
12.  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
13.  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 1-14 (14)