Showing items 1 - 14 of 14

Your selections:

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

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
  • Full Text: false
  • Reviewed:
  • 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
  • Full Text:
  • Reviewed:
  • 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.

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.
  • Full Text:
  • Reviewed:
  • 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.

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
  • Full Text:
  • Reviewed:
  • 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.

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
  • Full Text: false
  • Reviewed:
  • 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
  • Full Text:
  • Reviewed:
  • 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.
  • Description: 2003011132

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

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
  • Full Text: false
  • Reviewed:
  • 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.

Pathway analysis shows association between FGFBP1 and hypertension

- Tomaszewski, Maciej, Charchar, Fadi, Nelson, Christopher, Barnes, Timothy, Denniff, Matthew, Kaiser, Michael, Debiec, Radoslaw, Christofidou, Paraskevi, Rafelt, Suzanne, Van Harst, Pim Der, Wang, William, Maric, Christine, Zukowska-Szczechowska, Ewa, Samani, Nilesh

  • Authors: Tomaszewski, Maciej , Charchar, Fadi , Nelson, Christopher , Barnes, Timothy , Denniff, Matthew , Kaiser, Michael , Debiec, Radoslaw , Christofidou, Paraskevi , Rafelt, Suzanne , Van Harst, Pim Der , Wang, William , Maric, Christine , Zukowska-Szczechowska, Ewa , Samani, Nilesh
  • Date: 2011
  • Type: Text , Journal article
  • Relation: Journal of the American Society of Nephrology Vol. 22, no. 5 (2011), p. 947-955
  • Full Text: false
  • Reviewed:
  • Description: Variants in the gene encoding fibroblast growth factor 1 (FGF1) co-segregate with familial susceptibility to hypertension, and glomerular upregulation of FGF1 associates with hypertension. To investigate whether variants in other members of the FGF signaling pathway may also associate with hypertension, we genotyped 629 subjects from 207 Polish families with hypertension for 79 single nucleotide polymorphisms in eight genes of this network. Family-based analysis showed that parents transmitted the major allele of the rs16892645 polymorphism in the gene encoding FGF binding protein 1 (FGFBP1) to hypertensive offspring more frequently than expected by chance (P = 0.005). An independent cohort of 807 unrelated Polish subjects validated this association. Furthermore, compared with normotensive subjects, hypertensive subjects had approximately 1.5- and 1.4-fold higher expression of renal FGFBP1 mRNA and protein (P = 0.04 and P = 0.001), respectively. By immunohistochemistry, hypertensionrelated upregulation of FGFBP1 was most apparent in the glomerulus and juxtaglomerular space. Taken together, these data suggest that FGFBP1 associates with hypertension and that systematic analysis of signaling pathways can identify previously undescribed genetic associations. Copyright © 2011 by the American Society of Nephrology.

Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure

- Tomaszewski, Maciej, Eales, James, Denniff, Matthew, Myers, Stephen, Chew, Guatsiew, Nelson, Christopher, Christofidou, Paraskevi, Desai, Aishwarya, Büsst, Cara, Wojnar, Lukasz, Musialik, Katarzyna, Jozwiak, Jacek, Debiec, Radoslaw, Dominiczak, Anna, Navis, Gerjan, van Gilst, Wiek, van der Harst, Pim, Samani, Nilesh, Harrap, Stephen, Bogdanski, Pawel, Zukowska-Szczechowska, Ewa, Charchar, Fadi

Signatures of miR-181a on the renal transcriptome and blood pressure

- Marques, Francine, Romaine, Simon, Denniff, Matthew, Eales, James, Dormer, John, Garrelds, Ingrid, Wojnar, Lukasz, Musialik, Katarzyna, Duda-Raszewska, Barbara, Kiszka, Bartlomiej, Duda, Magdalena, Morris, Brian, Samani, Nilesh, Danser, Jan, Bogdanski, Pawel, Zukowska-Szczechowska, Ewa, Charchar, Fadi, Tomaszewski, Maciej

  • Authors: Marques, Francine , Romaine, Simon , Denniff, Matthew , Eales, James , Dormer, John , Garrelds, Ingrid , Wojnar, Lukasz , Musialik, Katarzyna , Duda-Raszewska, Barbara , Kiszka, Bartlomiej , Duda, Magdalena , Morris, Brian , Samani, Nilesh , Danser, Jan , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Charchar, Fadi , Tomaszewski, Maciej
  • Date: 2015
  • Type: Journal article
  • Relation: Molecular Medicine Vol. 21, no. (2015), p. 739-748
  • Full Text: false
  • Reviewed:
  • Description: MicroRNA-181a binds to the 3’ untranslated region of messenger RNA (mRNA) for renin, a rate-limiting enzyme of the renin-angiotensin system. Our objective was to determine whether this molecular interaction translates into a clinically meaningful effect on blood pressure and whether circulating miR-181a is a measurable proxy of blood pressure. In 200 human kidneys from the TRANScriptome of renaL humAn TissuE (TRANSLATE) study, renal miR-181a was the sole negative predictor of renin mRNA and a strong correlate of circulating miR-181a. Elevated miR-181a levels correlated positively with systolic and diastolic blood pressure in TRANSLATE, and this association was independent of circulating renin. The association between serum miR-181a and systolic blood pressure was replicated in 199 subjects from the Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) study. Renal immunohistochemistry and in situ hybridization showed that colocalization of miR-181a and renin was most prominent in collecting ducts where renin is not released into the systemic circulation. Analysis of 69 human kidneys characterized by RNA sequencing revealed that miR-181a was associated with downregulation of four mitochondrial pathways and upregulation of 41 signaling cascades of adaptive immunity and inflammation. We conclude that renal miR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR-181a are both a measurable proxy of renal miR-181a expression and a novel biochemical correlate of blood pressure.

Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets

- Xu, Xiaoguang, Khunsriraksakul, Chachrit, Eales, James, Rubin, Sebastien, Scannali, David, Saluja, Sushant, Talavera, David, Markus, Havell, Wang, Lida, Drzal, Maciej, Maan, Akhlag, Lay, Abigail, Prestes, Priscilla, Regan, Jeniece, Diwadkar, Avantika, Denniff, Matthew, Rempega, Grzegorz, Ryszawy, Jakub, Król, Robert, Dormer, John, Szulinska, Monika, Walczak, Marta, Antczak, Andrzej, Matías-García, Pamela, Waldenberger, Melanie, Woolf, Adrian, Keavney, Bernard, Zukowska-Szczechowska, Ewa, Wystrychowski, Wojciech, Charchar, Fadi

  • 1