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Runs of Homozygosity : Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages

- Christofidou, Paraskevi, Nelson, Christopher, Nikpay, Majid, Qu, Liming, Li, Mingyao, Loley, Christina, Debiec, Radoslaw, Braund, Peter, Denniff, Matthew, Charchar, Fadi, Arjo, Ares Rocanin, Trégouët, David-Alexandre, Goodall, Alison, Cambien, Francois, Ouwehand, Willem, Roberts, Robert, Schunkert, Heribert, Hengstenberg, Christian, Reilly, Muredach, Erdmann, Jeanette, McPherson, Ruth, König, Inke, Thompson, John, Samani, Nilesh, Tomaszewski, Maciej

Common allelic variant in the gene underlying rare monogenic form of coronary artery disease cosegregates with elevated LDL cholesterol in families with high cardiovascular risk

- Tomaszewski, Maciej, Charchar, Fadi, Barnes, Timothy, Gawron-Kiszka, Magdalena, Sedkowska, Agnieszka, Grzeszczak, Wladyslaw, Samani, Nilesh, Zukowska-Szczechowska, Ewa

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

- Tomaszewski, Maciej, Debiec, Radoslaw, Braund, Peter, Nelson, Christopher, Hardwick, Robert, Christofidou, Paraskevi, Denniff, Matthew, Codd, Veryan, Rafelt, Suzanne, van der Harst, Pim, Waterworth, Dawn, Song, Kijoung, Vollenweider, Peter, Waeber, Gerard, Zukowska-Szczechowska, Ewa, Burton, Paul, Mooser, Vincent, Charchar, Fadi, Thompson, John, Tobin, Martin, Samani, Nilesh

  • Authors: Tomaszewski, Maciej , Debiec, Radoslaw , Braund, Peter , Nelson, Christopher , Hardwick, Robert , Christofidou, Paraskevi , Denniff, Matthew , Codd, Veryan , Rafelt, Suzanne , van der Harst, Pim , Waterworth, Dawn , Song, Kijoung , Vollenweider, Peter , Waeber, Gerard , Zukowska-Szczechowska, Ewa , Burton, Paul , Mooser, Vincent , Charchar, Fadi , Thompson, John , Tobin, Martin , Samani, Nilesh
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Hypertension Vol. 56, no. 6 (2010), p. 1069-U146
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  • Description: 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 approximate to 50 000 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 mm Hg lower mean 24-hour diastolic blood pressure (P=1.2 x 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 x 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: <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.

Human Y Chromosome Exerts Pleiotropic Effects on Susceptibility to Atherosclerosis

- Eales, James, Maan, Akhlaq, Xu, Xiaoguang, Michoel, Tom, Hallast, Pille, Batini, C, Zadik, Daniel, Prestes, Priscilla, Molina, Elsa, Denniff, Matthew, Schroeder, Juliane, Bjorkegren, Johan, Thompson, John, Maffia, Pasquale, Guzik, Tomasz, Keavney, Bernard, Jobling, Mark, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej

  • Authors: Eales, James , Maan, Akhlaq , Xu, Xiaoguang , Michoel, Tom , Hallast, Pille , Batini, C , Zadik, Daniel , Prestes, Priscilla , Molina, Elsa , Denniff, Matthew , Schroeder, Juliane , Bjorkegren, Johan , Thompson, John , Maffia, Pasquale , Guzik, Tomasz , Keavney, Bernard , Jobling, Mark , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
  • Date: 2019
  • Type: Text , Journal article
  • Relation: Arteriosclerosis, thrombosis, and vascular biology Vol. 39, no. 11 (2019), p. 2386-2401
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  • Description: OBJECTIVE: The male-specific region of the Y chromosome (MSY) remains one of the most unexplored regions of the genome. We sought to examine how the genetic variants of the MSY influence male susceptibility to coronary artery disease (CAD) and atherosclerosis. Approach and Results: Analysis of 129 133 men from UK Biobank revealed that only one of 7 common MSY haplogroups (haplogroup I1) was associated with CAD-carriers of haplogroup I1 had ≈11% increase in risk of CAD when compared with all other haplogroups combined (odds ratio, 1.11; 95% CI, 1.04-1.18; P=6.8×10-4). Targeted MSY sequencing uncovered 235 variants exclusive to this haplogroup. The haplogroup I1-specific variants showed 2.45- and 1.56-fold respective enrichment for promoter and enhancer chromatin states, in cells/tissues relevant to atherosclerosis, when compared with other MSY variants. Gene set enrichment analysis in CAD-relevant tissues showed that haplogroup I1 was associated with changes in pathways responsible for early and late stages of atherosclerosis development including defence against pathogens, immunity, oxidative phosphorylation, mitochondrial respiration, lipids, coagulation, and extracellular matrix remodeling. UTY was the only Y chromosome gene whose blood expression was associated with haplogroup I1. Experimental reduction of UTY expression in macrophages led to changes in expression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune costimulatory signal. CONCLUSIONS: Haplogroup I1 is enriched for regulatory chromatin variants in numerous cells of relevance to CAD and increases cardiovascular risk through proatherosclerotic reprogramming of the transcriptome, partly through UTY.

The epithelial sodium channel y-subunit gene and blood pressure : Family based association, renal gene expression, and physiological analyses

- Büsst, Cara, Bloomer, Lisa, Scurrah, Katrina, Ellis, Justine, Barnes, Timothy, Charchar, Fadi, Braund, Peter, Hopkins, Paul, Samani, Nilesh, Hunt, Steven, Tomaszewski, Maciej, Harrap, Stephen

  • Authors: Büsst, Cara , Bloomer, Lisa , Scurrah, Katrina , Ellis, Justine , Barnes, Timothy , Charchar, Fadi , Braund, Peter , Hopkins, Paul , Samani, Nilesh , Hunt, Steven , Tomaszewski, Maciej , Harrap, Stephen
  • Date: 2011
  • Type: Text , Journal article
  • Relation: Hypertension Vol. 58, no. 6 (2011), p. 1073-1078
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  • Description: Variants in the gene encoding the y-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the 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 single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index-adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (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. © 2011 American Heart Association, Inc.

Fibroblast growth factor binding protein 1 gene (FGFBP1) and hypertension d from pathway analysis to renal glomerulus

- Tomaszewski, Maciej, Charchar, Fadi, Barnes, Timothy, Maric, Christine, Zukowska-Szczechowska, Ewa, Samani, Nilesh

  • Authors: Tomaszewski, Maciej , Charchar, Fadi , Barnes, Timothy , Maric, Christine , Zukowska-Szczechowska, Ewa , Samani, Nilesh
  • Date: 2010
  • Type: Text , Conference paper
  • Relation: Paper presented at British Cardiovascular Society Annual Conference 2010, Manchester Central, Manchester, UK : 7th-9th June 2010
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  • Description: Essential hypertension is a complex, multifactorial disease with a strong genetic component. Fibroblast growth factor 1 gene (FGF1) is one of the most relevant candidates having been associated not only with familial susceptibility to hypertension but also with up-regulation within the glomerulus of the human hypertensive kidney/Circulation 2007;116:1915e24/. We have hypothesised that systematic analysis of genes interacting with FGF1 may uncover novel variants underlying essential hypertension. Seventy-nine common (minor allele frequency$0.1) tagging (r2$0.8) and functional single nucleotide polymorphisms (SNPs) spanning eight critical components of the FGF (fibroblast growth factor) pathway (FGF2, FGFR1, FGFR2, FGFR3, FGFR4, FGFBP1, FIBP, SPRY1) were genotyped by MALDI-TOF mass spectrometry in 629 subjects from 207 Polish hypertensive families (Silesian Hypertension Study d SHS). 83.5% of genotyped SNPs that passed quality control filters provided 92.9% genetic coverage of FGF pathway loci. Family-based analysis in SHS revealed that alleles of three SNPs (rs2956724, rs2245964 and rs16892645) in two loci (FGFR1 and FGFBP1) were transmitted to hypertensive offspring more frequently than expected by chance. However, only one association survived correction for multiple testing e major allele of rs16892645 in FGFBP1 was over-transmitted from heterozygous parents to hypertensive offspring more frequently than expected by chance (p¼0.0048, false discovery rate<0.25). The association between rs16892645 and hypertension was replicated in an independent cohort of 807 Polish subjects from Silesian Cardiovascular Study d each major allele copy of rs16892645 increased the odds of hypertension approximately by 1.5 (odds ratio: 1.5; 95% CI: 1.1 to to 2.2, p¼0.04). Association between FGFBP1 and hypertension was also apparent at the protein expression level d compared with normotensive patients, hypertensives from Silesian Renal Tissue Bank showed approximately 1.4-fold higher renal abundance of FGFBP1 in Western blotting (p¼0.001). Immunohistochemical analysis revealed that hypertension-related up-regulation of FGFBP1 was exclusive to renal glomeruli. These data show that FGFBP1da gene that encodes a carrier protein for FGF1 d is associated with human hypertension. We also reveal that up-regulation of FGFBP1 maps to the same histological compartment where FGF1 was shown to be most abundant (renal glomeruli). Our study also proves that systematic genetic analysis of signalling pathways is a strategy with a potential to identify novel molecular mechanisms underlying blood pressure elevation.

Whole genome survey of copy number variation in the spontaneously hypertensive rat

- Charchar, Fadi, Samani, Nilesh

Association between lipid profile and circulating concentrations of estrogens in young men

- Tomaszewski, Maciej, Maric, Christine, Zuzniewicz, Roman, Gola, Mateusz, Grzeszczak, Wladyslaw, Samani, Nilesh, Zukowska-Szczechowska, Ewa, Charchar, Fadi

Urotensin-II system in genetic control of blood pressure and renal function

- Debiec, Radoslaw, Christofidou, Paraskevi, Denniff, Matthew, Bloomer, Lisa, Bogdanski, Pawel, Wojnar, Lukasz, Musialik, Katarzyna, Charchar, Fadi, Thompson, John, Waterworth, Dawn, Song, Kijoung, Vollenweider, Peter, Waeber, Gerard, Zukowska-Szczechowska, Ewa, Samani, Nilesh, Lambert, David, Tomaszewski, Maciej

  • Authors: Debiec, Radoslaw , Christofidou, Paraskevi , Denniff, Matthew , Bloomer, Lisa , Bogdanski, Pawel , Wojnar, Lukasz , Musialik, Katarzyna , Charchar, Fadi , Thompson, John , Waterworth, Dawn , Song, Kijoung , Vollenweider, Peter , Waeber, Gerard , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Lambert, David , Tomaszewski, Maciej
  • Date: 2013
  • Type: Text , Journal article
  • Relation: PLoS ONE Vol. 8, no. 12 (2013), p.
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  • Description: 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 familybased 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. © 2013 Debiec et al.

A common intronic variant in the gene underlying a rare monogenic form of coronary artery disease is associated with low-density lipoprotein cholesterol

- Tomaszewski, Maciej, Charchar, Fadi, Barnes, Timothy, Nasmith, W. E., Grzeszczak, Wladyslaw, Zukowska-Szczechowska, Ewa, Samani, Nilesh

Molecular insights into genome-wide association studies of chronic kidney disease-defining traits

- Xu, Xiaoguang, Eales, James, Akbarov, Artur, Guo, Hui, Becker, Lorenz, Talavera, David, Ashraf, Fehzan, Nawaz, Jabran, Pramanik, Sanjeev, Bowes, John, Jiang, Xiao, Dormer, John, Denniff, Matthew, Antczak, Andrzej, Szulinska, Monika, Wise, Ingrid, Prestes, Priscilla, Glyda, Maciej, Bogdanski, Pawel, Zukowska-Szczechowska, Ewa, Berzuini, Carlo, Woolf, Adrian, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej

Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics

- Rowland, Joshua, Akbarov, Artur, Eales, James, Xu, Xiaoguang, Dormer, John, Guo, Hui, Denniff, Matthew, Jiang, Xiao, Ranjzad, Parisa, Nazgiewicz, Alicja, Prestes, Priscilla, Antczak, Andrzej, Szulinska, Monika, Wise, Ingrid, Zukowska-Szczechowska, Ewa, Bogdanski, Pawel, Woolf, Adrian, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej

  • Authors: Rowland, Joshua , Akbarov, Artur , Eales, James , Xu, Xiaoguang , Dormer, John , Guo, Hui , Denniff, Matthew , Jiang, Xiao , Ranjzad, Parisa , Nazgiewicz, Alicja , Prestes, Priscilla , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Zukowska-Szczechowska, Ewa , Bogdanski, Pawel , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
  • Date: 2019
  • Type: Text , Journal article
  • Relation: Kidney International Vol. 95, no. 3 (2019), p. 624-635
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  • Description: Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.

Systematic genetic analysis of fibroblast growth factor signalling pathway uncovers fibroblast growth factor binding protein 1 (FGFBP1) as a novel gene of essential hypertension

- Tomaszewski, Maciej, Charchar, Fadi, Barnes, Timothy, Maric, Christine, Samani, Nilesh, Zukowska-Szczechowska, Ewa

Circulating microRNAs and hypertension - From new insights into blood pressure regulation to biomarkers of cardiovascular risk

- Romaine, Simon, Charchar, Fadi, Samani, Nilesh, Tomaszewski, Maciej

  • Authors: Romaine, Simon , Charchar, Fadi , Samani, Nilesh , Tomaszewski, Maciej
  • Date: 2016
  • Type: Text , Journal article
  • Relation: Current Opinion in Pharmacology Vol. 27, no. (2016), p. 1-7
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: Hypertension is a leading cause of cardiovascular morbidity and mortality worldwide, yet the molecular mechanisms underpinning the development of high blood pressure remain incompletely understood. MicroRNAs are small, non-coding RNA molecules approximately 22 nucleotides in length that act as post-transcriptional regulators of gene expression. We highlight, through a review of recent literature, that studies on circulating microRNAs have provided novel insights into blood pressure regulation. They have also complemented tissue-based and animal-based experiments in shedding new light on our understanding of established pathways in hypertension, such as the renin-angiotensin system. Despite a number of challenges, we believe microRNAs herald particular potential in becoming effective biomarkers of target-organ damage in hypertension. © 2016 Elsevier Ltd. All rights reserved.

Inheritance of coronary artery disease in men : An analysis of the role of the y chromosome

- Charchar, Fadi, Bloomer, Lisa, Barnes, Timothy, Cowley, Mark, Nelson, Christopher, Wang, Yanzhong, Denniff, Matthew, Debiec, Radoslaw, Christofidou, Paraskevi, Nankervis, Scott, Dominiczak, Anna, Bani-Mustafa, Ahmed, Balmforth, Anthony, Hall, Alistair, Erdmann, Jeanette, Cambien, Francois, Deloukas, Panos, Hengstenberg, Christian, Packard, Chris, Schunkert, Heribert, Ouwehand, Willem, Ford, Ian, Goodall, Alison, Jobling, Mark, Samani, Nilesh, Tomaszewski, Maciej

  • Authors: Charchar, Fadi , Bloomer, Lisa , Barnes, Timothy , Cowley, Mark , Nelson, Christopher , Wang, Yanzhong , Denniff, Matthew , Debiec, Radoslaw , Christofidou, Paraskevi , Nankervis, Scott , Dominiczak, Anna , Bani-Mustafa, Ahmed , Balmforth, Anthony , Hall, Alistair , Erdmann, Jeanette , Cambien, Francois , Deloukas, Panos , Hengstenberg, Christian , Packard, Chris , Schunkert, Heribert , Ouwehand, Willem , Ford, Ian , Goodall, Alison , Jobling, Mark , Samani, Nilesh , Tomaszewski, Maciej
  • Date: 2012
  • Type: Text , Journal article
  • Relation: The Lancet Vol. 379, no. 9819 (2012), p. 915-922
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: 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. © 2012 Elsevier Ltd.

Male-specific region of the y chromosome and cardiovascular risk phylogenetic analysis and gene expression studies

- Bloomer, Lisa, Nelson, Christopher, Eales, James, Denniff, Matthew, Christofidou, Paraskevi, Debiec, Radoslaw, Moore, Jasbir, Consortium, Cardiogenics, Zukowska-Szczechowska, Ewa, Goodall, Alison, Thompson, John, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej

  • Authors: Bloomer, Lisa , Nelson, Christopher , Eales, James , Denniff, Matthew , Christofidou, Paraskevi , Debiec, Radoslaw , Moore, Jasbir , Consortium, Cardiogenics , Zukowska-Szczechowska, Ewa , Goodall, Alison , Thompson, John , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
  • Date: 2013
  • Type: Text , Journal article
  • Relation: Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, no. 7 (2013), p. 1722-1727
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: Objective-Haplogroup I of male-specific region of the human Y chromosome is associated with 50% increased risk of coronary artery disease. It is not clear to what extent conventional cardiovascular risk factors and genes of the malespecific region may explain this association. Approach and Results-A total of 1988 biologically unrelated men from 4 white European populations were genotyped using 11 Y chromosome single nucleotide polymorphisms and classified into 13 most common European haplogroups. Approximately 75% to 93% of the haplotypic variation of the Y chromosome in all cohorts was attributable to I, R1a, and R1b1b2 lineages. None of traditional cardiovascular risk factors, including body mass index, blood pressures, lipids, glucose, C-reactive protein, creatinine, and insulin resistance, was associated with haplogroup I of the Y chromosome in the joint inverse variance meta-analysis. Fourteen of 15 ubiquitous single-copy genes of the male-specific region were expressed in human macrophages. When compared with men with other haplogroups, carriers of haplogroup I had 0.61- and 0.64-fold lower expression of ubiquitously transcribed tetratricopeptide repeat, Y-linked gene (UTY) and protein kinase, Y-linked, pseudogene (PRKY) in macrophages (P=0.0001 and P=0.002, respectively). Conclusions-Coronary artery disease predisposing haplogroup I of the Y chromosome is associated with downregulation of UTY and PRKY genes in macrophages but not with conventional cardiovascular risk factors. © 2013 American Heart Association, Inc.
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Longer leukocyte telomeres are associated with ultra-endurance exercise independent of cardiovascular risk factors

- Denham, Joshua, Nelson, Christopher, O'Brien, Brendan, Nankervis, Scott, Denniff, Matthew, Harvey, Jack, Marques, Francine, Codd, Veryan, Zukowska-Szczechowska, Ewa, Samani, Nilesh, Tomaszewski, Maciej, Charchar, Fadi

Whole genome survey of copy number variation in the spontaneously hypertensive rat relationship to quantitative trait loci, gene expression, and blood pressure

- Charchar, Fadi, Kaiser, Michael, Bingham, Andrew, Fotinatos, Nina, Ahmady, Fahima, Tomaszewski, Maciej, Samani, Nilesh

  • Authors: Charchar, Fadi , Kaiser, Michael , Bingham, Andrew , Fotinatos, Nina , Ahmady, Fahima , Tomaszewski, Maciej , Samani, Nilesh
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Hypertension Vol. 55, no. 5 (2010), p. 1231-1238
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  • Description: Copy number variation has emerged recently as an important genetic mechanism leading to phenotypic heterogeneity. The aim of our study was to determine whether copy number variants (CNVs) exist between the spontaneously hypertensive rat (SHR) and its control strain, the Wistar-Kyoto rat, whether these map to quantitative trait loci in the rat and whether CNVs associate with gene expression or blood pressure differences between the 2 strains. We performed a comparative genomic hybridization assay between SHR and Wistar-Kyoto strains using a whole-genome array. In total, 16 CNVs were identified and validated (6 because of a relative loss of copy number in the SHR and 10 because of a relative gain). CNVs were present on rat autosomes 1, 3, 4, 6, 7, 10, 14, and 17 and varied in size from 10.0 kb to 1.6 Mb. Most of these CNVs mapped to chromosomal regions within previously identified quantitative trait loci, including those for blood pressure in the SHR. Transcriptomic experiment! s confirmed differences in the renal expression of several genes (including Ms4a6a, Ndr3, Egln1, Cd36, Sema3a, Ugt2b, and Idi21) located in some of the CNVs between STIR and Wistar-Kyoto rats. In F-2 animals derived from an SHRXWistar-Kyoto cross, we also found a significant increase in blood pressure associated with an increase in copy number in the Egln1 gene. Our findings suggest that, CNVs may play a role in the susceptibility to hypertension and related trails in the SHR. (Hypertension. 2010;55:1231-1238.)

FGF21 signalling pathway and metabolic traits - genetic association analysis

- Kaess, Bernhard, Barnes, Timothy, Stark, Klaus, Charchar, Fadi, Waterworth, Dawn, Song, Kijoung, Wang, William, Vollenweider, Peter, Waeber, Gerard, Mooser, Vincent, Zukowska-Szczechowska, Ewa, Samani, Nilesh, Hengstenberg, Christian, Tomaszewski, Maciej

  • Authors: Kaess, Bernhard , Barnes, Timothy , Stark, Klaus , Charchar, Fadi , Waterworth, Dawn , Song, Kijoung , Wang, William , Vollenweider, Peter , Waeber, Gerard , Mooser, Vincent , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Hengstenberg, Christian , Tomaszewski, Maciej
  • Date: 2010
  • Type: Text , Journal article
  • Relation: European Journal of Human Genetics Vol. 18, no. 12 (2010), p. 1344-1348
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  • Description: 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

Coronary artery disease predisposing haplogroup I of the Y chromosome, aggression and sex steroids - Genetic association analysis

- Bloomer, Lisa, Nelson, Christopher, Denniff, Matthew, Christofidou, Paraskevi, Debiec, Radoslaw, Thompson, John, Zukowska-Szczechowska, Ewa, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej

  • Authors: Bloomer, Lisa , Nelson, Christopher , Denniff, Matthew , Christofidou, Paraskevi , Debiec, Radoslaw , Thompson, John , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Atherosclerosis Vol. 233, no. 1 (2014), p. 160-164
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: Objective: Amongst middle-aged men, haplogroup I is associated with approximate to 50% higher risk of coronary artery disease than other paternal lineages of Y chromosome. We hypothesised that carriers of haplogroup I had higher levels of aggression and estrogens and/or lower levels of androgens early in life and thus might be more prone to cardiovascular disease than men with other lineages of Y chromosome. Methods: We reconstructed phylogenetic tree of the Y chromosome in > 1000 young apparently healthy white men from the general population. Each Y chromosome was classified into one of 13 most common European lineages. Androgens (DHEA-S, androstenedione, total testosterone) and their metabolites (total estradiol, estrone) were measured by radioimmunoassays. Information on five dimensions of aggression (total, physical, verbal, anger and hostility) was collected using Buss and Perry questionnaire. Results: Approximately 17% men inherited haplogroup I from their fathers. Carriers of haplogroup I showed lower scores of verbal aggression than men with other haplogroups (beta = -0.72, SE = 0.29, P = 0.012) and when further compared to carriers of most common R1a lineage and other haplogroups (beta = -1.03, SE = 0.34, P = 0.003). However, these associations did not survive a correction for multiple testing. Sex steroids did not show even nominal level of association with haplogroup I. Conclusion: Our data show no overall association between haplogroup I and sex-related phenotypes in young white men. These results also suggest that the previously identified association between haplogroup I and coronary artery disease is not likely mediated by unfavourable profile of sex steroids or heightened aggression early in life. (C) 2014 Elsevier Ireland Ltd. All rights reserved.