The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform
James E Loyd - One of the best experts on this subject based on the ideXlab platform.
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connectivity map analysis of nonsense mediated decay positive bmpr2 related hereditary pulmonary arterial hypertension provides insights into disease Penetrance
American Journal of Respiratory Cell and Molecular Biology, 2012Co-Authors: Charles R Flynn, Eric D Austin, Joy D Cogan, James E Loyd, Siyuan Zheng, Lora K Hedges, Bethany Womack, Josh Fessel, James West, Zhongming ZhaoAbstract:The molecular mechanisms underlying the reduced Penetrance seen in the nonsense-mediated decay–positive (NMD+) BMPR2 mutation–associated hereditary pulmonary arterial hypertension (HPAH) remain unknown. We reasoned that the cellular and genetic mechanisms behind this phenomenon could be uncovered by combining expression profiling with Connectivity Map (cMap) analysis. Cultured lymphocytes from 10 patients with HPAH and 10 matched familial control subjects, all with NMD+ BMPR2 mutations, were subjected to expression analysis. For each group, the expression data were combined before analysis. This generated a signature of 23 up-regulated and 12 down-regulated genes in patients with HPAH compared with control subjects (the “PAH Penetrance signature”). Although gene set enrichment analysis of this signature was not uniquely informative, cMap analysis identified drugs with expression signatures similar to the PAH Penetrance signature. Several of these drugs were predicted to influence reactive oxygen species (ROS) formation. This hypothesis was tested and confirmed in the same cells initially subjected to the expression analysis using quantitative biochemical detection of ROS concentration. We conclude that expression of the PAH Penetrance signature represents an increased risk of developing clinical HPAH and that ROS formation may play a role in pathogenesis of HPAH. These results provide the first molecular insights into NMD+ BMPR2 related HPAH Penetrance and highlight the potential utility of cMap analyses in pulmonary research.
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synergistic heterozygosity for tgfβ1 snps and bmpr2 mutations modulates the age at diagnosis and Penetrance of familial pulmonary arterial hypertension
Genetics in Medicine, 2008Co-Authors: John A Phillips, Justin S Poling, Charles A Phillips, Krista C Stanton, Eric D Austin, Joy D Cogan, Lisa Wheeler, John H Newman, Harry C Dietz, James E LoydAbstract:Purpose: We hypothesized that functional TGFβ1 SNPs increase TGFβ/BMP signaling imbalance in BMPR2 mutation heterozygotes to accelerate the age at diagnosis, increase the Penetrance and SMAD2 expression in familial pulmonary arterial hypertension. Methods: Single nucleotide polymorphism genotypes of BMPR2 mutation heterozygotes, age at diagnosis, and Penetrance of familial pulmonary arterial hypertension were compared and SMAD2 expression was studied in lung sections. Results: BMPR2 mutation heterozygotes with least active -509 or codon 10 TGFβ1 SNPs had later mean age at diagnosis of familial pulmonary arterial hypertension (39.5 and 43.2 years) than those with more active genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively). Kaplan-Meier analysis also showed that those with the less active single nucleotide polymorphisms had later age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated decay resistant BMPR2 mutations and the least, intermediate and most active -509 TGFβ1 SNP genotypes had Penetrances of 33, 72, and 80%, respectively (P = 0.003), whereas those with 0–1, 2, or 3–4 active single nucleotide polymorphism alleles had Penetrances of 33, 72, and 75% (P = 0.005). The relative expression of TGFβ1 dependent SMAD2 was increased in lung sections of those with familial pulmonary arterial hypertension compared with controls. Conclusions: The TGFβ1 SNPs studied modulate age at diagnosis and Penetrance of familial pulmonary arterial hypertension in BMPR2 mutation heterozygotes, likely by affecting TGFβ/BMP signaling imbalance. This modulation is an example of Synergistic Heterozygosity.
Mauro Galeazzi - One of the best experts on this subject based on the ideXlab platform.
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the expanding spectrum of low Penetrance tnfrsf1a gene variants in adults presenting with recurrent inflammatory attacks clinical manifestations and long term follow up
Seminars in Arthritis and Rheumatism, 2014Co-Authors: Luca Cantarini, Francesco Caso, Orso Maria Lucherini, Antonio Vitale, Bruno Frediani, Donato Rigante, Giampaolo Merlini, Paolo Sfriso, Leonardo Punzi, Mauro GaleazziAbstract:Abstract Objective To analyze the clinical manifestations and response to treatment in a cohort of adult patients presenting with recurrent inflammatory attacks and carrying low-Penetrance TNFRSF1A variants, as well as to provide data on their long-term follow-up. Methods We performed a retrospective chart review of 36 patients carrying low-Penetrance TNFRSF1A variants. Moreover, 60 genetically negative patients treated for recurrent inflammatory attacks and 13 patients with structural TNFRSF1A mutations were also analyzed. Detailed demographic and clinical data were collected at the time of molecular screening and at each follow-up visit. Treatments and markers of inflammation were also assessed. Results Individuals with low-Penetrance TNFRSF1A variants have a lower family history for inflammatory attacks and present with a later disease onset compared with patients with structural mutations, but do not differ, in this respect, with genetically negative individuals. Moreover, low-Penetrance variants are less frequently associated with a chronic disease course, with clinical manifestations such as abdominal pain and myalgia, and with amyloidosis. A distinctive clinical feature is a higher rate of pericarditis. Interestingly, mutation-negative patients were found to present with a significant history of recurrent pharyngitis during childhood. Patients with low-Penetrance variants are mostly managed with short courses of steroids or non-steroidal anti-inflammatory drugs on attacks. Although the need for a biological treatment is significantly lower compared with patients with structural mutations, still approximately 20% of individuals with recurrent inflammatory attacks carrying low-Penetrance variants ultimately require these therapies. Conclusions Our study confirms that low-Penetrance TNFRSF1A variants can be associated with an autoinflammatory phenotype. Although a chronic disease course is rarely observed, some patients ultimately benefit from a biological treatment.
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The expanding spectrum of low-Penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: Clinical manifestations and long-term follow-up
Seminars in arthritis and rheumatism, 2013Co-Authors: Luca Cantarini, Francesco Caso, Orso Maria Lucherini, Antonio Vitale, Bruno Frediani, Donato Rigante, Giampaolo Merlini, Paolo Sfriso, Leonardo Punzi, Mauro GaleazziAbstract:To analyze the clinical manifestations and response to treatment in a cohort of adult patients presenting with recurrent inflammatory attacks and carrying low-Penetrance TNFRSF1A variants, as well as to provide data on their long-term follow-up. We performed a retrospective chart review of 36 patients carrying low-Penetrance TNFRSF1A variants. Moreover, 60 genetically negative patients treated for recurrent inflammatory attacks and 13 patients with structural TNFRSF1A mutations were also analyzed. Detailed demographic and clinical data were collected at the time of molecular screening and at each follow-up visit. Treatments and markers of inflammation were also assessed. Individuals with low-Penetrance TNFRSF1A variants have a lower family history for inflammatory attacks and present with a later disease onset compared with patients with structural mutations, but do not differ, in this respect, with genetically negative individuals. Moreover, low-Penetrance variants are less frequently associated with a chronic disease course, with clinical manifestations such as abdominal pain and myalgia, and with amyloidosis. A distinctive clinical feature is a higher rate of pericarditis. Interestingly, mutation-negative patients were found to present with a significant history of recurrent pharyngitis during childhood. Patients with low-Penetrance variants are mostly managed with short courses of steroids or non-steroidal anti-inflammatory drugs on attacks. Although the need for a biological treatment is significantly lower compared with patients with structural mutations, still approximately 20% of individuals with recurrent inflammatory attacks carrying low-Penetrance variants ultimately require these therapies. Our study confirms that low-Penetrance TNFRSF1A variants can be associated with an autoinflammatory phenotype. Although a chronic disease course is rarely observed, some patients ultimately benefit from a biological treatment. Copyright © 2014 Elsevier Inc. All rights reserved.
Mark E. Robson - One of the best experts on this subject based on the ideXlab platform.
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Moderate-Penetrance Predisposition to Breast Cancer
Current Breast Cancer Reports, 2018Co-Authors: Mark E. RobsonAbstract:Purpose of Review Research over the past 25 years has revealed much about the architecture of predisposition to breast and ovarian cancer. There is now a general understanding that there are three broad categories of germline variation that may increase risk. First, there are the “high-Penetrance” genes associated with a relative risk for cancer of greater than 5 and demonstrating an autosomal dominant pattern of inheritance. At the other end of the spectrum are “low-Penetrance” common variants. These variants are associated with minor increases in risk (commonly less than a relative risk of 1.5). The third group of genes are “moderate-Penetrance” genes, with pathogenic variants seen rarely in the general population (commonly < 1%) and relative risks for cancer generally between 2 and 5. Moderate-Penetrance genes are the focus of this review.
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Counselling framework for moderate-Penetrance cancer-susceptibility mutations
Nature Reviews Clinical Oncology, 2016Co-Authors: Nadine Tung, Susan M. Domchek, Katherine L. Nathanson, Kenneth Offit, Zsofia Stadler, Fergus Couch, Judy E. Garber, Mark E. RobsonAbstract:The use of multigene panels for the assessment of cancer susceptibility is expanding rapidly in clinical practice, particularly in the USA, despite concerns regarding the uncertain clinical validity for some gene variants and the uncertain clinical utility of most multigene panels. So-called 'moderate-Penetrance' gene mutations associated with cancer susceptibility are identified in approximately 2–5% of individuals referred for clinical testing; some of these mutations are potentially actionable. Nevertheless, the appropriate management of individuals harbouring such moderate-Penetrance genetic variants is unclear. The cancer risks associated with mutations in moderate-Penetrance genes are lower and different than those reported for high-Penetrance gene mutations (such as mutations in BRCA1 and BRCA2 , and those associated with Lynch syndrome). The extrapolation of guidelines for the management of individuals with high-Penetrance variants of cancer-susceptibility genes to the clinical care of patients with moderate-Penetrance gene mutations could result in substantial harm. Thus, we provide a framework for clinical decision-making pending the development of a sufficient evidence base to document the clinical utility of the interventions for individuals with inherited moderate-Penetrance gene mutations associated with an increased risk of cancer. The use of multigene panels for the assessment of cancer susceptibility is expanding rapidly in clinical practice. The appropriate management of individuals harbouring moderate-Penetrance genetic variants in individuals referred for clinical testing is unclear. The authors of this Perspectives article provide a framework for clinical decision-making pending the development of a sufficient evidence base to document the clinical utility of the interventions for individuals with inherited moderate-Penetrance gene mutations associated with an increased risk of cancer.
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Counselling framework for moderate-Penetrance cancer-susceptibility mutations
Nature Reviews Clinical Oncology, 2016Co-Authors: Nadine Tung, Susan M. Domchek, Zsofia K. Stadler, Katherine L. Nathanson, Fergus J. Couch, Judy Garber, Kenneth Offit, Mark E. RobsonAbstract:The use of multigene panels for the assessment of cancer susceptibility is expanding rapidly in clinical practice, particularly in the USA, despite concerns regarding the uncertain clinical validity for some gene variants and the uncertain clinical utility of most multigene panels. So-called 'moderate-Penetrance' gene mutations associated with cancer susceptibility are identified in approximately 2-5% of individuals referred for clinical testing; some of these mutations are potentially actionable. Nevertheless, the appropriate management of individuals harbouring such moderate-Penetrance genetic variants is unclear. The cancer risks associated with mutations in moderate-Penetrance genes are lower and different than those reported for high-Penetrance gene mutations (such as mutations in BRCA1 and BRCA2, and those associated with Lynch syndrome). The extrapolation of guidelines for the management of individuals with high-Penetrance variants of cancer-susceptibility genes to the clinical care of patients with moderate-Penetrance gene mutations could result in substantial harm. Thus, we provide a framework for clinical decision-making pending the development of a sufficient evidence base to document the clinical utility of the interventions for individuals with inherited moderate-Penetrance gene mutations associated with an increased risk of cancer.
Joy D Cogan - One of the best experts on this subject based on the ideXlab platform.
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connectivity map analysis of nonsense mediated decay positive bmpr2 related hereditary pulmonary arterial hypertension provides insights into disease Penetrance
American Journal of Respiratory Cell and Molecular Biology, 2012Co-Authors: Charles R Flynn, Eric D Austin, Joy D Cogan, James E Loyd, Siyuan Zheng, Lora K Hedges, Bethany Womack, Josh Fessel, James West, Zhongming ZhaoAbstract:The molecular mechanisms underlying the reduced Penetrance seen in the nonsense-mediated decay–positive (NMD+) BMPR2 mutation–associated hereditary pulmonary arterial hypertension (HPAH) remain unknown. We reasoned that the cellular and genetic mechanisms behind this phenomenon could be uncovered by combining expression profiling with Connectivity Map (cMap) analysis. Cultured lymphocytes from 10 patients with HPAH and 10 matched familial control subjects, all with NMD+ BMPR2 mutations, were subjected to expression analysis. For each group, the expression data were combined before analysis. This generated a signature of 23 up-regulated and 12 down-regulated genes in patients with HPAH compared with control subjects (the “PAH Penetrance signature”). Although gene set enrichment analysis of this signature was not uniquely informative, cMap analysis identified drugs with expression signatures similar to the PAH Penetrance signature. Several of these drugs were predicted to influence reactive oxygen species (ROS) formation. This hypothesis was tested and confirmed in the same cells initially subjected to the expression analysis using quantitative biochemical detection of ROS concentration. We conclude that expression of the PAH Penetrance signature represents an increased risk of developing clinical HPAH and that ROS formation may play a role in pathogenesis of HPAH. These results provide the first molecular insights into NMD+ BMPR2 related HPAH Penetrance and highlight the potential utility of cMap analyses in pulmonary research.
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synergistic heterozygosity for tgfβ1 snps and bmpr2 mutations modulates the age at diagnosis and Penetrance of familial pulmonary arterial hypertension
Genetics in Medicine, 2008Co-Authors: John A Phillips, Justin S Poling, Charles A Phillips, Krista C Stanton, Eric D Austin, Joy D Cogan, Lisa Wheeler, John H Newman, Harry C Dietz, James E LoydAbstract:Purpose: We hypothesized that functional TGFβ1 SNPs increase TGFβ/BMP signaling imbalance in BMPR2 mutation heterozygotes to accelerate the age at diagnosis, increase the Penetrance and SMAD2 expression in familial pulmonary arterial hypertension. Methods: Single nucleotide polymorphism genotypes of BMPR2 mutation heterozygotes, age at diagnosis, and Penetrance of familial pulmonary arterial hypertension were compared and SMAD2 expression was studied in lung sections. Results: BMPR2 mutation heterozygotes with least active -509 or codon 10 TGFβ1 SNPs had later mean age at diagnosis of familial pulmonary arterial hypertension (39.5 and 43.2 years) than those with more active genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively). Kaplan-Meier analysis also showed that those with the less active single nucleotide polymorphisms had later age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated decay resistant BMPR2 mutations and the least, intermediate and most active -509 TGFβ1 SNP genotypes had Penetrances of 33, 72, and 80%, respectively (P = 0.003), whereas those with 0–1, 2, or 3–4 active single nucleotide polymorphism alleles had Penetrances of 33, 72, and 75% (P = 0.005). The relative expression of TGFβ1 dependent SMAD2 was increased in lung sections of those with familial pulmonary arterial hypertension compared with controls. Conclusions: The TGFβ1 SNPs studied modulate age at diagnosis and Penetrance of familial pulmonary arterial hypertension in BMPR2 mutation heterozygotes, likely by affecting TGFβ/BMP signaling imbalance. This modulation is an example of Synergistic Heterozygosity.
Eric D Austin - One of the best experts on this subject based on the ideXlab platform.
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connectivity map analysis of nonsense mediated decay positive bmpr2 related hereditary pulmonary arterial hypertension provides insights into disease Penetrance
American Journal of Respiratory Cell and Molecular Biology, 2012Co-Authors: Charles R Flynn, Eric D Austin, Joy D Cogan, James E Loyd, Siyuan Zheng, Lora K Hedges, Bethany Womack, Josh Fessel, James West, Zhongming ZhaoAbstract:The molecular mechanisms underlying the reduced Penetrance seen in the nonsense-mediated decay–positive (NMD+) BMPR2 mutation–associated hereditary pulmonary arterial hypertension (HPAH) remain unknown. We reasoned that the cellular and genetic mechanisms behind this phenomenon could be uncovered by combining expression profiling with Connectivity Map (cMap) analysis. Cultured lymphocytes from 10 patients with HPAH and 10 matched familial control subjects, all with NMD+ BMPR2 mutations, were subjected to expression analysis. For each group, the expression data were combined before analysis. This generated a signature of 23 up-regulated and 12 down-regulated genes in patients with HPAH compared with control subjects (the “PAH Penetrance signature”). Although gene set enrichment analysis of this signature was not uniquely informative, cMap analysis identified drugs with expression signatures similar to the PAH Penetrance signature. Several of these drugs were predicted to influence reactive oxygen species (ROS) formation. This hypothesis was tested and confirmed in the same cells initially subjected to the expression analysis using quantitative biochemical detection of ROS concentration. We conclude that expression of the PAH Penetrance signature represents an increased risk of developing clinical HPAH and that ROS formation may play a role in pathogenesis of HPAH. These results provide the first molecular insights into NMD+ BMPR2 related HPAH Penetrance and highlight the potential utility of cMap analyses in pulmonary research.
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synergistic heterozygosity for tgfβ1 snps and bmpr2 mutations modulates the age at diagnosis and Penetrance of familial pulmonary arterial hypertension
Genetics in Medicine, 2008Co-Authors: John A Phillips, Justin S Poling, Charles A Phillips, Krista C Stanton, Eric D Austin, Joy D Cogan, Lisa Wheeler, John H Newman, Harry C Dietz, James E LoydAbstract:Purpose: We hypothesized that functional TGFβ1 SNPs increase TGFβ/BMP signaling imbalance in BMPR2 mutation heterozygotes to accelerate the age at diagnosis, increase the Penetrance and SMAD2 expression in familial pulmonary arterial hypertension. Methods: Single nucleotide polymorphism genotypes of BMPR2 mutation heterozygotes, age at diagnosis, and Penetrance of familial pulmonary arterial hypertension were compared and SMAD2 expression was studied in lung sections. Results: BMPR2 mutation heterozygotes with least active -509 or codon 10 TGFβ1 SNPs had later mean age at diagnosis of familial pulmonary arterial hypertension (39.5 and 43.2 years) than those with more active genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively). Kaplan-Meier analysis also showed that those with the less active single nucleotide polymorphisms had later age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated decay resistant BMPR2 mutations and the least, intermediate and most active -509 TGFβ1 SNP genotypes had Penetrances of 33, 72, and 80%, respectively (P = 0.003), whereas those with 0–1, 2, or 3–4 active single nucleotide polymorphism alleles had Penetrances of 33, 72, and 75% (P = 0.005). The relative expression of TGFβ1 dependent SMAD2 was increased in lung sections of those with familial pulmonary arterial hypertension compared with controls. Conclusions: The TGFβ1 SNPs studied modulate age at diagnosis and Penetrance of familial pulmonary arterial hypertension in BMPR2 mutation heterozygotes, likely by affecting TGFβ/BMP signaling imbalance. This modulation is an example of Synergistic Heterozygosity.
