Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics
- 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.
Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure
- Authors: 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
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of the American Society of Nephrology Vol. 26, no. 12 (2015), p. 3151-3160
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65 x10(-5)) and diastolic BP (P=7.61 x10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0x10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.
Coronary artery disease predisposing haplogroup I of the Y chromosome, aggression and sex steroids - Genetic association analysis
- 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.
Male-specific region of the y chromosome and cardiovascular risk phylogenetic analysis and gene expression studies
- 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.
- Description: 2003011132
121 Telomere attrition is attenuated in ultra-marathon runners
- Authors: Denham, Joshua , Nankervis, Scott , Debiec, Radek , Harvey, Jack , Pascoe, Deborah , Marques, Francine , O’Brien, Brendan , Zukowska-Szczechowska, Ewa , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 30, no. e-Supplement (September 2012), p. e37
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- Description: Background: Leukocyte telomere length is a marker of biological ageing and its shortening is associated with cardiovascular disease. Engagement in regular moderate-intensity physical activity is a recognised method of cardiovascular disease prevention. However, it is not clear whether repeated exposure to ultra-strenuous physical exercise is beneficial long-term and whether it may attenuate biological ageing. Methods: We compared leukocyte telomere length in context of inflammation and endothelial dysfunction between 67 male ultra-marathon runners and 67 age-, sex- and BMI-matched apparently healthy controls. Genomic DNA was extracted from peripheral blood and leukocyte telomere length was measured by quantitative polymerase chain reaction assays. Adhesion molecules (sICAM-1, sE-selectin) and inflammatory markers (IL-6, C-reactive protein) concentrations were measured in 67 ultra-marathon runners by quantitative sandwich enzyme immunoassay technique, high-sensitive immunoassay and ultra-sensitive double antibody sandwich ELISA, respectively. Results: Adjusted (for age, BMI, blood pressure and lipids) leukocyte telomere length was approximately 13.8% greater in the ultra-marathon runners than in the controls (P<0.001). This translates into approximately 32.9 years difference in age-related telomere length attrition. There was a strong negative linear correlation between sICAM-1 and leukocyte telomere length in the ultra-marathon runners (r=-0.33; P=0.007) and this association retained its statistical significance after adjustment for age, BMI, blood pressure and lipids in multiple regression (P=0.026). Conclusion: Prolonged, intense physical exercise may attenuate cellular ageing possibly through a protective effect on endothelial function.
- Description: C1
Novel insights into essential hypertension etiology revealed by genome-wide gene expression profiling of human kidneys: evidence for renin involvement via a microRNA-mediated effect on expression
- Authors: Marques, Francine , Campain, Anna , Tomaszewski, Maciej , Zukowska-Szczechowska, Ewa , Yang, Yee , Charchar, Fadi , Morris, Brian
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Human Hypertension Vol. 26, no. 10 (October 2012 2012), p. 627-627
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Pathway analysis shows association between FGFBP1 and hypertension
- 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
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- 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.
Genetic architecture of ambulatory blood pressure in the general population insights from cardiovascular gene-centric array
- 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.
Association between lipid profile and circulating concentrations of estrogens in young men
- Authors: Tomaszewski, Maciej , Maric, Christine , Zuzniewicz, Roman , Gola, Mateusz , Grzeszczak, Wladyslaw , Samani, Nilesh , Zukowska-Szczechowska, Ewa , Charchar, Fadi
- Date: 2009
- Type: Text , Journal article
- Relation: Atheroclerosis Vol. 203, no. (2009), p. 257-262
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- Description: 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.
- Description: C1
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
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Barnes, Timothy , Gawron-Kiszka, Magdalena , Sedkowska, Agnieszka , Grzeszczak, Wladyslaw , Samani, Nilesh , Zukowska-Szczechowska, Ewa
- Date: 2008
- Type: Text , Journal article
- Relation: Hypertension Vol. 52, no. 4 (Oct 2008), p. E129-E129
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- Description: C1
Orthologues of GSTM expressed in human kidney
- Authors: Brosnan, Julia , Tomaszewski, Maciej , McBride, Martin , Charchar, Fadi , Lacka, Beata , Zukowska-Szczechowska, Ewa , Grzeszczak, Wladyslaw , Lee, Wai , Dominiczak, Anna
- Date: 2004
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 22, no. Suppl. 1 (2004), p. S183
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Cardiovascular diseases and G-protein beta 3 subunit gene (GNB3) in the era of genomewide scans
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Padmanabhan, Sandosh , Zukowska-Szczechowska, Ewa , Grzeszczak, Wladyslaw , Dominiczak, Anna
- Date: 2003
- Type: Text , Journal article
- Relation: Journal of Human Hypertension Vol. 17, no. 6 (2003), p. 379-380
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Strikingly low circulating CRP concentrations in ultramarathon runners independent of markers of adiposity - How low can you go?
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Przybycin, Malgorzata , Crawford, Lynne , Wallace, A. Michael. , Gosek, Katarzyna , Lowe, Gordon. D. , Zukowska-Szczechowska, Ewa , Grzeszczak, Wladyslaw , Sattar, Naveed , Dominiczak, Anna
- Date: 2003
- Type: Text , Journal article
- Relation: Arteriosclerosis Thrombosis and Vascular Biology Vol. 23, no. 9 (2003), p. 1640-1644
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- Description: Objective-This study was undertaken to evaluate to what extent C-reactive protein (CRP) can be reduced by exercise by examining its circulating concentrations in male ultramarathon runners and to determine if low leptin as a robust circulating marker of fat mass could account for low CRP in such men. Methods and Results-Sixty-seven male ultramarathon runners and 63 sedentary male controls of similar age and body mass index were recruited. CRP and leptin were measured by ELISA and radioimmunoassay, respectively. Median CRP concentration in lean (body mass index <25 kg/m(2)) marathon runners was less than half control median (0.4 [0.2 to 0.9] mg/L versus 0.9 [0.5 to 2.7] mg/L, P=0.0013) and, more strikingly, in nonlean runners was approximately 26% of control median (0.4 [0.3 to 0.8] mg/L versus 1.5 [0.9 to 2.5] mg/L, P=0.0002). Circulating leptin levels were also substantially lower in lean (45% less) and nonlean (63% less, both P=0.0001) ultramarathon runners. However, interleukin-6 levels were not different. Furthermore, leptin adjustment only minimally attenuated the case-control difference in CRP, suggesting that mechanisms other than fat mass reduction contribute to low concentrations of CRP in marathon runners. Conclusions-This study suggests that circulating CRP concentrations can be markedly suppressed, independently of total adiposity or indeed fat mass, by intense regular physical exercise.