Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study
- Fox, Ervin, Young, J. Hunter, Li, Yali, Dreisbach, Albert, Charchar, Fadi
- Authors: Fox, Ervin , Young, J. Hunter , Li, Yali , Dreisbach, Albert , Charchar, Fadi
- Date: 2011
- Type: Text , Journal article
- Relation: Human molecular genetics Vol. 20, no. 11 (June 2011), p. 2273
- Full Text:
- Reviewed:
- Description: The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
- Authors: Fox, Ervin , Young, J. Hunter , Li, Yali , Dreisbach, Albert , Charchar, Fadi
- Date: 2011
- Type: Text , Journal article
- Relation: Human molecular genetics Vol. 20, no. 11 (June 2011), p. 2273
- Full Text:
- Reviewed:
- Description: The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
- Gielen, Marij, Hageman, Geja, Antoniou, Evangelia, Nordfjall, Katarina, Mangino, Massimo, Balasubramanyam, Muthuswamy, De Meyer, Tim de, Hendricks, Audrey, Giltay, Erik, Hunt, Steven, Nettleton, Jennifer, Salpea, Klelia, Diaz, Vanessa, Farzaneh-Far, Ramin, Atzmon, Gil, Harris, Sarah, Hou, Lifang, Gilley, David, Hovatta, Iiris, Kark, Jeremy, Nassar, Hisham, Kurz, David, Mather, Karen, Willeit, Peter, Zheng, Yun-Ling, Pavanello, Sofia, Demerath, Ellen, Rode, Line, Bunout, Daniel, Steptoe, Andrew, Boardman, Lisa, Marti, Amelia, Needham, Belinda, Zheng, Wei, Ramsey-Goldman, Rosalind, Pellatt, Andrew, Kaprio, Jaakko, Hofmann, Jonathan, Gieger, Christian, Paolisso, Giuseppe, Hjelmborg, Jacob, Mirabello, Lisa, Seeman, Teresa, Wong, Jason, Van Der Harst, Pim, Broer, Linda, Kronenberg, Florian, Kollerits, Barbara, Strandberg, Timo, Eisenberg, Dan, Duggan, Catherine, Verhoeven, Josine, Schaakxs, Roxanne, Zannolli, Raffaela, Dos Reis, Rosana, Charchar, Fadi, Tomaszewski, Maciej, Mons, Ute, Demuth, Ilja, Molli, Andrea, Cheng, Guo, Krasnienkov, Dmytro, D'Antono, Bianca, Kasielski, Marek, McDonnell, Barry, Ebstein, Richard, Sundquist, Kristina, Pare, Guillaume, Chong, Michael, Zeegers, Maurice
- Authors: Gielen, Marij , Hageman, Geja , Antoniou, Evangelia , Nordfjall, Katarina , Mangino, Massimo , Balasubramanyam, Muthuswamy , De Meyer, Tim de , Hendricks, Audrey , Giltay, Erik , Hunt, Steven , Nettleton, Jennifer , Salpea, Klelia , Diaz, Vanessa , Farzaneh-Far, Ramin , Atzmon, Gil , Harris, Sarah , Hou, Lifang , Gilley, David , Hovatta, Iiris , Kark, Jeremy , Nassar, Hisham , Kurz, David , Mather, Karen , Willeit, Peter , Zheng, Yun-Ling , Pavanello, Sofia , Demerath, Ellen , Rode, Line , Bunout, Daniel , Steptoe, Andrew , Boardman, Lisa , Marti, Amelia , Needham, Belinda , Zheng, Wei , Ramsey-Goldman, Rosalind , Pellatt, Andrew , Kaprio, Jaakko , Hofmann, Jonathan , Gieger, Christian , Paolisso, Giuseppe , Hjelmborg, Jacob , Mirabello, Lisa , Seeman, Teresa , Wong, Jason , Van Der Harst, Pim , Broer, Linda , Kronenberg, Florian , Kollerits, Barbara , Strandberg, Timo , Eisenberg, Dan , Duggan, Catherine , Verhoeven, Josine , Schaakxs, Roxanne , Zannolli, Raffaela , Dos Reis, Rosana , Charchar, Fadi , Tomaszewski, Maciej , Mons, Ute , Demuth, Ilja , Molli, Andrea , Cheng, Guo , Krasnienkov, Dmytro , D'Antono, Bianca , Kasielski, Marek , McDonnell, Barry , Ebstein, Richard , Sundquist, Kristina , Pare, Guillaume , Chong, Michael , Zeegers, Maurice
- Date: 2018
- Type: Text , Journal article
- Relation: American Journal of Clinical Nutrition Vol. 108, no. 3 (2018), p. 453-475
- Relation: http://purl.org/au-research/grants/nhmrc/1123472
- Full Text: false
- Reviewed:
- Description: Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectionalmeta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Studyspecific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a-3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI:-10.03,-5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10-3 unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10-3, -1.01 × 10-3) difference in ageand sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10-3 unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10-3, -1.25 × 10-3). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL arewarranted.
Cardiac telomere length in heart development, function, and disease
- Booth, Scott, Charchar, Fadi
- Authors: Booth, Scott , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article , Review
- Relation: Physiological Genomics Vol. 49, no. 7 (2017), p. 368-384
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
- Full Text: false
- Reviewed:
- Description: Telomeres are repetitive nucleoprotein structures at chromosome ends, and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells, which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, that need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury. © 2017 the American Physiological Society.
Cardiomyocyte functional etiology in heart failure with preserved ejection fraction is distinctive - A new preclinical model
- Curl, Claire, Danes, Vennetia, Bell, James, Raaijmakers, Antonia, Ip, Wendy, Chandramouli, Chanchal, Harding, Tristan, Porrello, Enzo, Erickson, Jeffrey, Charchar, Fadi, Kompa, Andrew, Edgley, Amanda, Crossman, David, Soeller, Christian, Mellor, Kimberley, Kalman, Jonathan, Harrap, Stephen, Delbridge, Lea
- Authors: Curl, Claire , Danes, Vennetia , Bell, James , Raaijmakers, Antonia , Ip, Wendy , Chandramouli, Chanchal , Harding, Tristan , Porrello, Enzo , Erickson, Jeffrey , Charchar, Fadi , Kompa, Andrew , Edgley, Amanda , Crossman, David , Soeller, Christian , Mellor, Kimberley , Kalman, Jonathan , Harrap, Stephen , Delbridge, Lea
- Date: 2018
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 7, no. 11 (2018), p. 1-32
- Full Text:
- Reviewed:
- Description: Background--Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. Methods and Results--The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca
- Authors: Curl, Claire , Danes, Vennetia , Bell, James , Raaijmakers, Antonia , Ip, Wendy , Chandramouli, Chanchal , Harding, Tristan , Porrello, Enzo , Erickson, Jeffrey , Charchar, Fadi , Kompa, Andrew , Edgley, Amanda , Crossman, David , Soeller, Christian , Mellor, Kimberley , Kalman, Jonathan , Harrap, Stephen , Delbridge, Lea
- Date: 2018
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 7, no. 11 (2018), p. 1-32
- Full Text:
- Reviewed:
- Description: Background--Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. Methods and Results--The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca
Cardiovascular diseases and G-protein beta 3 subunit gene (GNB3) in the era of genomewide scans
- Tomaszewski, Maciej, Charchar, Fadi, Padmanabhan, Sandosh, Zukowska-Szczechowska, Ewa, Grzeszczak, Wladyslaw, Dominiczak, Anna
- 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
- Full Text: false
- Reviewed:
Changes in the leukocyte methylome and its effect on cardiovascular-related genes after exercise
- Denham, Joshua, O'Brien, Brendan, Marques, Francine, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Marques, Francine , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 118, no. 4 (2015), p. 475-488
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Physical exercise has proven cardiovascular benefits, yet there is no clear understanding of the related molecular mechanisms leading to this. Here we determined the beneficial epigenetic effects of exercise after sprint interval training, a form of exercise known to improve cardiometabolic health. We quantified genome-wide leukocyte DNA methylation of 12 healthy young (18-24 yr) men before and after 4 wk (thrice weekly) of sprint interval training using the 450K BeadChip (Illumina) and validated gene expression changes in an extra seven subjects. Exercise increased subjects' cardiorespiratory fitness and maximal running performance, and decreased low-density lipoprotein cholesterol concentration in conjunction with genome-wide DNA methylation changes. Notably, many CpG island and gene promoter regions were demethylated after exercise, indicating increased genome-wide transcriptional changes. Among genes with DNA methylation changes, epidermal growth factor (EGF), a ligand of the epidermal growth factor receptor known to be involved in cardiovascular disease, was demethylated and showed decreased mRNA expression. Additionally, we found that in microRNAs miR-21 and miR-210, gene DNA methylation was altered by exercise causing a cascade effect on the expression of the mature microRNA involved in cardiovascular function. Our findings demonstrate that exercise alters DNA methylation in circulating blood cells in microRNA and protein-coding genes associated with cardiovascular physiology. Copyright © 2015 the American Physiological Society
- 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
- Full Text: false
- Reviewed:
- 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.
- Tomaszewski, Maciej, Charchar, Fadi, Barnes, Timothy, Gawron-Kiszka, Magdalena, Sedkowska, Agnieszka, Grzeszczak, Wladyslaw, Samani, Nilesh, Zukowska-Szczechowska, Ewa
- 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
- Full Text: false
- Reviewed:
- Description: C1
Consumption of a low glycaemic index diet in late life extends lifespan of Nalb/c mice with differential effects on DNA damage
- Nankervis, Scott, Mitchell, Jenée, Charchar, Fadi, McGlynn, Maree, Lewandowski, Paul
- Authors: Nankervis, Scott , Mitchell, Jenée , Charchar, Fadi , McGlynn, Maree , Lewandowski, Paul
- Date: 2013
- Type: Text , Journal article
- Relation: Longevity & Healthspan. 2(4) p. 1-13
- Full Text:
- Reviewed:
- Description: Background Caloric restriction is known to extend the lifespan of all organisms in which it has been tested. Consequently, current research is investigating the role of various foods to improve health and lifespan. The role of various diets has received less attention however, and in some cases may have more capacity to improve health and longevity than specific foods alone. We examined the benefits to longevity of a low glycaemic index (GI) diet in aged Balb/c mice and examined markers of oxidative stress and subsequent effects on telomere dynamics. Results In an aged population of mice, a low GI diet extended average lifespan by 12%, improved glucose tolerance and had impressive effects on amelioration of oxidative damage to DNA in white blood cells. Telomere length in quadriceps muscle showed no improvement in the dieted group, nor was telomerase reactivated. Conclusion The beneficial effects of a low GI diet are evident from the current study and although the impact to telomere dynamics late in life is minimal, we expect that earlier intervention with a low GI diet would provide significant improvement in health and longevity with associated effects to telomere homeostasis.
- Authors: Nankervis, Scott , Mitchell, Jenée , Charchar, Fadi , McGlynn, Maree , Lewandowski, Paul
- Date: 2013
- Type: Text , Journal article
- Relation: Longevity & Healthspan. 2(4) p. 1-13
- Full Text:
- Reviewed:
- Description: Background Caloric restriction is known to extend the lifespan of all organisms in which it has been tested. Consequently, current research is investigating the role of various foods to improve health and lifespan. The role of various diets has received less attention however, and in some cases may have more capacity to improve health and longevity than specific foods alone. We examined the benefits to longevity of a low glycaemic index (GI) diet in aged Balb/c mice and examined markers of oxidative stress and subsequent effects on telomere dynamics. Results In an aged population of mice, a low GI diet extended average lifespan by 12%, improved glucose tolerance and had impressive effects on amelioration of oxidative damage to DNA in white blood cells. Telomere length in quadriceps muscle showed no improvement in the dieted group, nor was telomerase reactivated. Conclusion The beneficial effects of a low GI diet are evident from the current study and although the impact to telomere dynamics late in life is minimal, we expect that earlier intervention with a low GI diet would provide significant improvement in health and longevity with associated effects to telomere homeostasis.
Contribution of microRNA to pathological fibrosis in cardiorenal syndrome : Impact of uremic toxins
- Rana, Indrajeetsinh, Kompa, Andrew, Skommer, Joanna, Wang, Bing, Lekawanvijit, Suree, Kelly, Darren, Krum, Henry, Charchar, Fadi
- Authors: Rana, Indrajeetsinh , Kompa, Andrew , Skommer, Joanna , Wang, Bing , Lekawanvijit, Suree , Kelly, Darren , Krum, Henry , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Physiological Reports Vol. 3, no. 4 (2015), p. 1-15
- Full Text:
- Reviewed:
- Description: Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and micro- RNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis. © 2015 The Authors.
- Authors: Rana, Indrajeetsinh , Kompa, Andrew , Skommer, Joanna , Wang, Bing , Lekawanvijit, Suree , Kelly, Darren , Krum, Henry , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Physiological Reports Vol. 3, no. 4 (2015), p. 1-15
- Full Text:
- Reviewed:
- Description: Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and micro- RNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis. © 2015 The Authors.
Contributions of obesity to kidney health and disease: insights from Mendelian randomization and the human kidney transcriptomics
- Xu, Xiaoguang, Eales, James, Jiang, Xiao, Sanderson, Eleanor, Drzal, Maciej, Saluja, Sushant, Scannali, David, Williams, Bryan, Morris, Andrew, Guzik, Tomasz, Charchar, Fadi, Holmes, Michael, Tomaszewski, Maciej
- Authors: Xu, Xiaoguang , Eales, James , Jiang, Xiao , Sanderson, Eleanor , Drzal, Maciej , Saluja, Sushant , Scannali, David , Williams, Bryan , Morris, Andrew , Guzik, Tomasz , Charchar, Fadi , Holmes, Michael , Tomaszewski, Maciej
- Date: 2022
- Type: Text , Journal article
- Relation: Cardiovascular research Vol. 118, no. 15 (2022), p. 3151-3161
- Full Text:
- Reviewed:
- Description: AIMS: Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney. METHODS AND RESULTS: We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in
- Authors: Xu, Xiaoguang , Eales, James , Jiang, Xiao , Sanderson, Eleanor , Drzal, Maciej , Saluja, Sushant , Scannali, David , Williams, Bryan , Morris, Andrew , Guzik, Tomasz , Charchar, Fadi , Holmes, Michael , Tomaszewski, Maciej
- Date: 2022
- Type: Text , Journal article
- Relation: Cardiovascular research Vol. 118, no. 15 (2022), p. 3151-3161
- Full Text:
- Reviewed:
- Description: AIMS: Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney. METHODS AND RESULTS: We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in
Coronary artery disease : Why we should consider the Y chromosome
- Molina, Elsa, Clarence, Elyse, Ahmady, Farah, Chew, Guatsiew, Charchar, Fadi
- Authors: Molina, Elsa , Clarence, Elyse , Ahmady, Farah , Chew, Guatsiew , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Heart Lung and Circulation Vol. 25, no. 8 (Aug 2016), p. 791-801
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality globally. In the last few years our understanding of the genetic and molecular mechanisms that promote CAD in individuals has increased with the advent of the genome era. This complex inflammatory disease has well-defined environmental risk factors. However, in the last 10 years, studies including genome-wide association studies (GWAS) have clearly demonstrated a genetic influence on CAD. Recently, studies on the human Y chromosome have also demonstrated that genetic variation within the male-specific region of the Y chromosome (MSY) could play a part in determining cardiovascular risk in men, confirming the notion that the increased risk for CAD in men cannot be fully explained through common CAD risk factors. Here, we review the literature about the pathophysiology of CAD, its potential causes and environmental risk factors known so far. Furthermore, we review the genetics of CAD, especially the latest discoveries regarding the implication of the Y chromosome, the most underexplored portion of the human genome to date, highlighting methods and difficulties arising in this research field, and discussing the importance of considering the Y chromosome in CAD research.
- Authors: Molina, Elsa , Clarence, Elyse , Ahmady, Farah , Chew, Guatsiew , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Heart Lung and Circulation Vol. 25, no. 8 (Aug 2016), p. 791-801
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality globally. In the last few years our understanding of the genetic and molecular mechanisms that promote CAD in individuals has increased with the advent of the genome era. This complex inflammatory disease has well-defined environmental risk factors. However, in the last 10 years, studies including genome-wide association studies (GWAS) have clearly demonstrated a genetic influence on CAD. Recently, studies on the human Y chromosome have also demonstrated that genetic variation within the male-specific region of the Y chromosome (MSY) could play a part in determining cardiovascular risk in men, confirming the notion that the increased risk for CAD in men cannot be fully explained through common CAD risk factors. Here, we review the literature about the pathophysiology of CAD, its potential causes and environmental risk factors known so far. Furthermore, we review the genetics of CAD, especially the latest discoveries regarding the implication of the Y chromosome, the most underexplored portion of the human genome to date, highlighting methods and difficulties arising in this research field, and discussing the importance of considering the Y chromosome in CAD research.
- 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.
- Veerabhadrappa, Praveen, Burger, Dylan, Charchar, Fadi, Tomaszewski, Maciej, Carlberg, Bo, Harrap, Stephen, Touyz, Rhian
- Authors: Veerabhadrappa, Praveen , Burger, Dylan , Charchar, Fadi , Tomaszewski, Maciej , Carlberg, Bo , Harrap, Stephen , Touyz, Rhian
- Date: 2012
- Type: Text , Journal article
- Relation: Hypertension Vol. 59, no. 2 SUPPL. 1 (2012), p. 382-383
- Full Text: false
- Reviewed:
Deficiency of MicroRNA-181a results in transcriptome-wide cell-specific changes in the kidney and increases blood pressure
- Paterson, Madeleine, Jackson, Kristy, Dona, Malathi, Farrugia, Gabriella, Visniauskas, Bruna, Watson, Anna, Johnson, Chad, Prieto, Minolfa, Evans, Roger, Charchar, Fadi, Pinto, Alexander, Marques, Francine, Head, Geoffrey
- Authors: Paterson, Madeleine , Jackson, Kristy , Dona, Malathi , Farrugia, Gabriella , Visniauskas, Bruna , Watson, Anna , Johnson, Chad , Prieto, Minolfa , Evans, Roger , Charchar, Fadi , Pinto, Alexander , Marques, Francine , Head, Geoffrey
- Date: 2021
- Type: Text , Journal article
- Relation: Hypertension Vol. 78, no. 5 (Nov 2021), p. 1322-1334
- Full Text:
- Reviewed:
- Description: MicroRNA miR-181a is downregulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here, we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a KO (knockout) mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radiotelemetry probes were implanted in 12-week-old C57BL/6J WT (wild type) and miR-181a/b-1 KO mice. Systolic and diastolic BP were 4- to 5-mm Hg higher in KO compared with WT mice over 24 hours (P<0.01). Compared with WT mice, renal renin was higher in the juxtaglomerular cells of KO mice. BP was similar in WT mice on a high- (3.1%) versus low- (0.3%) sodium diet (+0.4 +/- 0.8 mm Hg), but KO mice showed salt sensitivity (+3.3 +/- 0.8 mm Hg; P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA sequencing in 6699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, and Smad4. We observed upregulation of pathways related to the immune system, inflammatory response, reactive oxygen species, and nerve development, consistent with higher tyrosine hydroxylase in the kidney. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.
- Authors: Paterson, Madeleine , Jackson, Kristy , Dona, Malathi , Farrugia, Gabriella , Visniauskas, Bruna , Watson, Anna , Johnson, Chad , Prieto, Minolfa , Evans, Roger , Charchar, Fadi , Pinto, Alexander , Marques, Francine , Head, Geoffrey
- Date: 2021
- Type: Text , Journal article
- Relation: Hypertension Vol. 78, no. 5 (Nov 2021), p. 1322-1334
- Full Text:
- Reviewed:
- Description: MicroRNA miR-181a is downregulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here, we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a KO (knockout) mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radiotelemetry probes were implanted in 12-week-old C57BL/6J WT (wild type) and miR-181a/b-1 KO mice. Systolic and diastolic BP were 4- to 5-mm Hg higher in KO compared with WT mice over 24 hours (P<0.01). Compared with WT mice, renal renin was higher in the juxtaglomerular cells of KO mice. BP was similar in WT mice on a high- (3.1%) versus low- (0.3%) sodium diet (+0.4 +/- 0.8 mm Hg), but KO mice showed salt sensitivity (+3.3 +/- 0.8 mm Hg; P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA sequencing in 6699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, and Smad4. We observed upregulation of pathways related to the immune system, inflammatory response, reactive oxygen species, and nerve development, consistent with higher tyrosine hydroxylase in the kidney. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.
Dietary fatty acids and mortality risk from heart disease in US adults : an analysis based on NHANES
- Wang, Yutang, Fang, Yan, Witting, Paul, Charchar, Fadi, Sobey, Christopher, Drummond, Grant, Golledge, Jonothan
- Authors: Wang, Yutang , Fang, Yan , Witting, Paul , Charchar, Fadi , Sobey, Christopher , Drummond, Grant , Golledge, Jonothan
- Date: 2023
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 13, no. 1 (2023), p.
- Full Text:
- Reviewed:
- Description: We investigated the association of dietary intake of major types of fatty acids with heart disease mortality in a general adult cohort with or without a prior diagnosis of myocardial infarction (MI). This cohort study included US adults who attended the National Health and Nutrition Examination Surveys from 1988 to 2014. Heart disease mortality was ascertained by linkage to the National Death Index records through 31 December 2015. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of fatty acid intake for heart disease mortality. This cohort included 45,820 adults among which 1,541 had a prior diagnosis of MI. Participants were followed up for 532,722 person-years (mean follow-up, 11.6 years), with 2,313 deaths recorded from heart disease being recorded. Intake of saturated (SFAs) and monounsaturated fatty acids (MUFAs) was associated with heart disease mortality after adjustment for all the tested confounders. In contrast, a 5% higher calorie intake from polyunsaturated fatty acids (PUFAs) was associated with a 9% (HR, 0.91; 95% CI 0.83–1.00; P = 0.048) lower multivariate-adjusted risk of heart disease mortality. Sub-analyses showed that this inverse association was present in those without a prior diagnosis of MI (HR,0.89; 95% CI 0.80–0.99) but not in those with the condition (HR, 0.94; 95% CI 0.75–1.16). The lack of association in the MI group could be due to a small sample size or severity and procedural complications (e.g., stenting and medication adherence) of the disease. Higher PUFA intake was associated with a favourable lipid profile. However, further adjustment for plasma lipids did not materially change the inverse association between PUFAs and heart disease mortality. Higher intake of PUFAs, but not SFAs and MUFAs, was associated with a lower adjusted risk of heart disease mortality in a large population of US adults supporting the need to increase dietary PUFA intake in the general public. © 2023, The Author(s).
Dietary fatty acids and mortality risk from heart disease in US adults : an analysis based on NHANES
- Authors: Wang, Yutang , Fang, Yan , Witting, Paul , Charchar, Fadi , Sobey, Christopher , Drummond, Grant , Golledge, Jonothan
- Date: 2023
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 13, no. 1 (2023), p.
- Full Text:
- Reviewed:
- Description: We investigated the association of dietary intake of major types of fatty acids with heart disease mortality in a general adult cohort with or without a prior diagnosis of myocardial infarction (MI). This cohort study included US adults who attended the National Health and Nutrition Examination Surveys from 1988 to 2014. Heart disease mortality was ascertained by linkage to the National Death Index records through 31 December 2015. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of fatty acid intake for heart disease mortality. This cohort included 45,820 adults among which 1,541 had a prior diagnosis of MI. Participants were followed up for 532,722 person-years (mean follow-up, 11.6 years), with 2,313 deaths recorded from heart disease being recorded. Intake of saturated (SFAs) and monounsaturated fatty acids (MUFAs) was associated with heart disease mortality after adjustment for all the tested confounders. In contrast, a 5% higher calorie intake from polyunsaturated fatty acids (PUFAs) was associated with a 9% (HR, 0.91; 95% CI 0.83–1.00; P = 0.048) lower multivariate-adjusted risk of heart disease mortality. Sub-analyses showed that this inverse association was present in those without a prior diagnosis of MI (HR,0.89; 95% CI 0.80–0.99) but not in those with the condition (HR, 0.94; 95% CI 0.75–1.16). The lack of association in the MI group could be due to a small sample size or severity and procedural complications (e.g., stenting and medication adherence) of the disease. Higher PUFA intake was associated with a favourable lipid profile. However, further adjustment for plasma lipids did not materially change the inverse association between PUFAs and heart disease mortality. Higher intake of PUFAs, but not SFAs and MUFAs, was associated with a lower adjusted risk of heart disease mortality in a large population of US adults supporting the need to increase dietary PUFA intake in the general public. © 2023, The Author(s).
Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- Surendran, Praveen, Feofanova, Elena, Lahrouchi, Najim, Ntalla, Ionna, Karthikeyan, Savita, Cook, James, Chen, Lingyan, Mifsud, Borbala, Yao, Chen, Kraja, Aldi, Cartwright, James, Hellwege, Jacklyn, Giri, Ayush, Tragante, Vinicius, Thorleifsson, Gudmar, Liu, Dajiang, Prins, Bram, Stewart, Isobel, Cabrera, Claude, Eales, James, Akbarov, Artur, Auer, Paul, Charchar, Fadi, Howson, Joanna, LifeLines Cohort, Study, Epic, C. V. D., Epic InterAct, Understanding Society Scientific, Group, Million Veteran, Program
- Authors: Surendran, Praveen , Feofanova, Elena , Lahrouchi, Najim , Ntalla, Ionna , Karthikeyan, Savita , Cook, James , Chen, Lingyan , Mifsud, Borbala , Yao, Chen , Kraja, Aldi , Cartwright, James , Hellwege, Jacklyn , Giri, Ayush , Tragante, Vinicius , Thorleifsson, Gudmar , Liu, Dajiang , Prins, Bram , Stewart, Isobel , Cabrera, Claude , Eales, James , Akbarov, Artur , Auer, Paul , Charchar, Fadi , Howson, Joanna , LifeLines Cohort, Study , Epic, C. V. D. , Epic InterAct , Understanding Society Scientific, Group , Million Veteran, Program
- Date: 2020
- Type: Text , Journal article
- Relation: Nature Genetics Vol. 52, no. 12 (2020), p. 1314-1332
- Full Text:
- Reviewed:
- Description: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. There are 286 authors of this articles not all are listed in this record.
- Authors: Surendran, Praveen , Feofanova, Elena , Lahrouchi, Najim , Ntalla, Ionna , Karthikeyan, Savita , Cook, James , Chen, Lingyan , Mifsud, Borbala , Yao, Chen , Kraja, Aldi , Cartwright, James , Hellwege, Jacklyn , Giri, Ayush , Tragante, Vinicius , Thorleifsson, Gudmar , Liu, Dajiang , Prins, Bram , Stewart, Isobel , Cabrera, Claude , Eales, James , Akbarov, Artur , Auer, Paul , Charchar, Fadi , Howson, Joanna , LifeLines Cohort, Study , Epic, C. V. D. , Epic InterAct , Understanding Society Scientific, Group , Million Veteran, Program
- Date: 2020
- Type: Text , Journal article
- Relation: Nature Genetics Vol. 52, no. 12 (2020), p. 1314-1332
- Full Text:
- Reviewed:
- Description: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. There are 286 authors of this articles not all are listed in this record.
DMD-associated dilated cardiomyopathy : genotypes, phenotypes, and phenocopies
- Johnson, Renee, Otway, Robyn, Chin, Ephrem, Horvat, Claire, Ohanian, Monique, Wilcox, Jon, Su, Zheng, Prestes, Priscilla, Smolnikov, Andrei, Soka, Magdalena, Guo, Guanglan, Rath, Emma, Chakravorty, Samya, Chrzanowski, Lukasz, Hayward, Christopher, Keogh, Anne, MacDonald, Peter, Giannoulatou, Eleni, Chang, Alex, Oates, Emily, Charchar, Fadi, Seidman, Jonathan, Seidman, Christine, Hegde, Madhuri, Fatkin, Diane
- Authors: Johnson, Renee , Otway, Robyn , Chin, Ephrem , Horvat, Claire , Ohanian, Monique , Wilcox, Jon , Su, Zheng , Prestes, Priscilla , Smolnikov, Andrei , Soka, Magdalena , Guo, Guanglan , Rath, Emma , Chakravorty, Samya , Chrzanowski, Lukasz , Hayward, Christopher , Keogh, Anne , MacDonald, Peter , Giannoulatou, Eleni , Chang, Alex , Oates, Emily , Charchar, Fadi , Seidman, Jonathan , Seidman, Christine , Hegde, Madhuri , Fatkin, Diane
- Date: 2023
- Type: Text , Journal article
- Relation: Circulation: Genomic and Precision Medicine Vol. 16, no. 5 (2023), p. 421-430
- Full Text:
- Reviewed:
- Description: Background: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. Methods: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. Results: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. Conclusions: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management. © 2023 American Heart Association, Inc.
- Authors: Johnson, Renee , Otway, Robyn , Chin, Ephrem , Horvat, Claire , Ohanian, Monique , Wilcox, Jon , Su, Zheng , Prestes, Priscilla , Smolnikov, Andrei , Soka, Magdalena , Guo, Guanglan , Rath, Emma , Chakravorty, Samya , Chrzanowski, Lukasz , Hayward, Christopher , Keogh, Anne , MacDonald, Peter , Giannoulatou, Eleni , Chang, Alex , Oates, Emily , Charchar, Fadi , Seidman, Jonathan , Seidman, Christine , Hegde, Madhuri , Fatkin, Diane
- Date: 2023
- Type: Text , Journal article
- Relation: Circulation: Genomic and Precision Medicine Vol. 16, no. 5 (2023), p. 421-430
- Full Text:
- Reviewed:
- Description: Background: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. Methods: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. Results: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. Conclusions: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management. © 2023 American Heart Association, Inc.
DNA copy number variations – Do these big mutations have a big effect on cardiovascular risk?
- Prestes, Priscilla, Maier, Michelle, Charchar, Fadi
- Authors: Prestes, Priscilla , Maier, Michelle , Charchar, Fadi
- Date: 2019
- Type: Text , Journal article , Editorial
- Relation: International Journal of Cardiology Vol. 298, no. (2019), p. 116-117
- Full Text:
- Reviewed:
- Description: In simple terms, copy number variations or CNVs are replications or deletions in the DNA which, in humans, changes it from the normal number of two gene copies. These CNVs are caused by inherited or de novo structural changes such as duplications, insertions or deletions of repeated portions of genetic material (Fig. 1). These duplications can vary from one to ten or more copies and range in size from 50 DNA base pairs to several million [1]. Since their discovery in 1987 by Nakamura et al. [2], when they were initially named variable number tandem repeats, many studies have investigated their association with rare and common human diseases. Throughout evolution, some of these changes in copy number were beneficial such as the globin gene number duplication, while others such as the CNVs that cause Huntington's disease were not. In 2004, two landmark studies by Iafrate et al. [3] and Sebat et al. [4] found that large-scale copy-number variations, ranging in size from 100 kb to 2 Mb are common throughout the human genome, and that a high proportion of them are in known genes. These findings roused several association studies between CNVs and disease
- Authors: Prestes, Priscilla , Maier, Michelle , Charchar, Fadi
- Date: 2019
- Type: Text , Journal article , Editorial
- Relation: International Journal of Cardiology Vol. 298, no. (2019), p. 116-117
- Full Text:
- Reviewed:
- Description: In simple terms, copy number variations or CNVs are replications or deletions in the DNA which, in humans, changes it from the normal number of two gene copies. These CNVs are caused by inherited or de novo structural changes such as duplications, insertions or deletions of repeated portions of genetic material (Fig. 1). These duplications can vary from one to ten or more copies and range in size from 50 DNA base pairs to several million [1]. Since their discovery in 1987 by Nakamura et al. [2], when they were initially named variable number tandem repeats, many studies have investigated their association with rare and common human diseases. Throughout evolution, some of these changes in copy number were beneficial such as the globin gene number duplication, while others such as the CNVs that cause Huntington's disease were not. In 2004, two landmark studies by Iafrate et al. [3] and Sebat et al. [4] found that large-scale copy-number variations, ranging in size from 100 kb to 2 Mb are common throughout the human genome, and that a high proportion of them are in known genes. These findings roused several association studies between CNVs and disease
- Marques, Francine, Prestes, Priscilla, Lewandowski, Paul, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Prestes, Priscilla , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
- Date: 2015
- Type: Text , Conference paper
- Relation: Cardiac Society of Australia and New Zealand Annual Scientific Meeting and the International Society for Heart Research Australasian Section Annual Scientific Meeting; Melbourne, Victoria, Australia; 13th-16th August 2016; published in Heart, Lung and Circulation. Vol. 24, p. S401-S401
- Full Text: false
- Reviewed:
- Description: Objective: The molecular processes associated with cardiac hypertrophy independent of blood pressure are still largely unknown. The hypertrophic heart rate (HHR) is normotensive and born with a reduced complement of cardiomyocytes that predisposes to cardiac hypertrophy and failure in later life. We investigated the expression of c-kit gene, a marker of cardiac stem cells and myocardial regeneration that could contribute to hypertrophy. Methods: Left ventricular c-kit mRNA expression was measured by real-time PCR in HHR and control strain in neonatal and 38-week old rats (n=7-12/group). We tested for linkage of c-kit expression with neonatal cardiac size in 197 second generation crosses (F2) of HHR and control strain. Results: c-kit mRNA was slightly up-regulated in neonatal (fold change +1.3, P=0.02) and markedly so in 38-week old HHR (+35.5, P=0.0003). Cardiac weight index was positively correlated with neonatal myocardial c-kit mRNA in the F2 population (r=0.19, P=0.007). Conclusions: In HHR hearts c-kit expression appears increased throughout life, but more so in the adult where cardiac hypertrophy is established and leading to failure. In aged hypertrophic hearts, over-expression of c-kit is likely a compensatory mechanism of the failing heart. Previous studies showed an activation of cardiac stem cells in the hypertrophic myocardium. Our study suggests that c-kit might be involved from an early age in mechanisms that lead to cardiac hypertrophy in adulthood.