Pub Date : 2016-04-01DOI: 10.1161/HCG.0000000000000029
Jennifer L. Hall, J. Ryan, B. Bray, Candice Brown, D. Lanfear, L. Newby, M. Relling, Neil Risch, D. Roden, S. Shaw, J. Tcheng, J. Tenenbaum, Thomas N Wang, W. Weintraub
The process of scientific discovery is rapidly evolving. The funding climate has influenced a favorable shift in scientific discovery toward the use of existing resources such as the electronic health record. The electronic health record enables long-term outlooks on human health and disease, in conjunction with multidimensional phenotypes that include laboratory data, images, vital signs, and other clinical information. Initial work has confirmed the utility of the electronic health record for understanding mechanisms and patterns of variability in disease susceptibility, disease evolution, and drug responses. The addition of biobanks and genomic data to the information contained in the electronic health record has been demonstrated. The purpose of this statement is to discuss the current challenges in and the potential for merging electronic health record data and genomics for cardiovascular research.
{"title":"Merging Electronic Health Record Data and Genomics for Cardiovascular Research: A Science Advisory From the American Heart Association","authors":"Jennifer L. Hall, J. Ryan, B. Bray, Candice Brown, D. Lanfear, L. Newby, M. Relling, Neil Risch, D. Roden, S. Shaw, J. Tcheng, J. Tenenbaum, Thomas N Wang, W. Weintraub","doi":"10.1161/HCG.0000000000000029","DOIUrl":"https://doi.org/10.1161/HCG.0000000000000029","url":null,"abstract":"The process of scientific discovery is rapidly evolving. The funding climate has influenced a favorable shift in scientific discovery toward the use of existing resources such as the electronic health record. The electronic health record enables long-term outlooks on human health and disease, in conjunction with multidimensional phenotypes that include laboratory data, images, vital signs, and other clinical information. Initial work has confirmed the utility of the electronic health record for understanding mechanisms and patterns of variability in disease susceptibility, disease evolution, and drug responses. The addition of biobanks and genomic data to the information contained in the electronic health record has been demonstrated. The purpose of this statement is to discuss the current challenges in and the potential for merging electronic health record data and genomics for cardiovascular research.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"193–202"},"PeriodicalIF":0.0,"publicationDate":"2016-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/HCG.0000000000000029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64429167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-04-01DOI: 10.1161/CIRCGENETICS.115.001263
A. Milano, M. Blom, Elisabeth M. Lodder, D. A. van Hoeijen, J. Barc, T. Koopmann, A. Bardai, L. Beekman, P. Lichtner, M. P. van den Berg, A. Wilde, C. Bezzina, H. Tan
Background—Sudden cardiac arrest (SCA) ranks among the most common causes of death worldwide. Because SCA is most often lethal, yet mostly occurs in individuals without previously known cardiac disease, the identification of patients at risk for SCA could save many lives. In unselected SCA victims from the community, common genetic variants (which are not disease-causing per se, but may increase susceptibility to ventricular fibrillation) are found to be associated with increased SCA risk. However, whether rare genetic variants contribute to SCA risk in the community is largely unexplored. Methods and Results—We here investigated the involvement of rare genetic variants in SCA risk at the population level by studying the prevalence of 6 founder genetic variants present in the Dutch population (PLN-p.Arg14del, MYBPC3-p.Trp792fsX17, MYBPC3-p.Arg943X, MYBPC3-p.Pro955fsX95, PKP2-p.Arg79X, and the Chr7q36 idiopathic ventricular fibrillation risk haplotype) in a cohort of 1440 unselected Dutch SCA victims included in the Amsterdam Resuscitation Study (ARREST). The six studied founder mutations were found to be more prevalent (1.1%) in the ARREST SCA cohort compared with an ethnically and geographically matched set of controls (0.4%, n=1379; P<0.05) or a set of Dutch individuals drawn from the Genome of the Netherlands (GoNL) study (0%, n=500; P<0.02). Conclusions—This finding provides proof-of-concept for the notion that rare genetic variants contribute to some extent to SCA risk in the community.
{"title":"Sudden Cardiac Arrest and Rare Genetic Variants in the Community","authors":"A. Milano, M. Blom, Elisabeth M. Lodder, D. A. van Hoeijen, J. Barc, T. Koopmann, A. Bardai, L. Beekman, P. Lichtner, M. P. van den Berg, A. Wilde, C. Bezzina, H. Tan","doi":"10.1161/CIRCGENETICS.115.001263","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001263","url":null,"abstract":"Background—Sudden cardiac arrest (SCA) ranks among the most common causes of death worldwide. Because SCA is most often lethal, yet mostly occurs in individuals without previously known cardiac disease, the identification of patients at risk for SCA could save many lives. In unselected SCA victims from the community, common genetic variants (which are not disease-causing per se, but may increase susceptibility to ventricular fibrillation) are found to be associated with increased SCA risk. However, whether rare genetic variants contribute to SCA risk in the community is largely unexplored. Methods and Results—We here investigated the involvement of rare genetic variants in SCA risk at the population level by studying the prevalence of 6 founder genetic variants present in the Dutch population (PLN-p.Arg14del, MYBPC3-p.Trp792fsX17, MYBPC3-p.Arg943X, MYBPC3-p.Pro955fsX95, PKP2-p.Arg79X, and the Chr7q36 idiopathic ventricular fibrillation risk haplotype) in a cohort of 1440 unselected Dutch SCA victims included in the Amsterdam Resuscitation Study (ARREST). The six studied founder mutations were found to be more prevalent (1.1%) in the ARREST SCA cohort compared with an ethnically and geographically matched set of controls (0.4%, n=1379; P<0.05) or a set of Dutch individuals drawn from the Genome of the Netherlands (GoNL) study (0%, n=500; P<0.02). Conclusions—This finding provides proof-of-concept for the notion that rare genetic variants contribute to some extent to SCA risk in the community.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"147–153"},"PeriodicalIF":0.0,"publicationDate":"2016-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-03-24DOI: 10.1161/CIRCGENETICS.116.001381
H. Schwertz, M. Rondina, J. Millar, Beauséjour Ladouceur, D. Abrams, Wei Wang, S. Oh, M. Koester, Sandra Abramowicz, Nan Wang, A. Tall, E. Theusch, Celia C. Cubitt, A. Dosé, K. Stevens, Devesh Naidoo, G. D. Smith, M. Ala-Korpela, J. Kettunen, P. Würtz, P. Soininen, A. Kangas, C. Dale, D. Lawlor, T. Gaunt, Emil M Degoma, Z. Ahmad, Emily C. O'Brien, I. Kindt, P. Shrader, C. Newman, Y. Pokharel, S. Baum, L. Hemphill, L. Hudgins, C. Ahmed, S. Gidding, Danielle Duffy, W. Neal, K. Wilemon, M. Roe, D. Rader, C. Ballantyne, M. Linton, P. Duell, P. Moriarty, Chenyi Xue, R. McPherson, H. Watkins, H. Schunkert
Background— Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. Methods and Results— We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08–2.82) and hypertension (2.48; 1.92–3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86–28.86) and use of >1 LDL-lowering medication (1.80; 1.34–2.41). Conclusions— FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.
{"title":"Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry","authors":"H. Schwertz, M. Rondina, J. Millar, Beauséjour Ladouceur, D. Abrams, Wei Wang, S. Oh, M. Koester, Sandra Abramowicz, Nan Wang, A. Tall, E. Theusch, Celia C. Cubitt, A. Dosé, K. Stevens, Devesh Naidoo, G. D. Smith, M. Ala-Korpela, J. Kettunen, P. Würtz, P. Soininen, A. Kangas, C. Dale, D. Lawlor, T. Gaunt, Emil M Degoma, Z. Ahmad, Emily C. O'Brien, I. Kindt, P. Shrader, C. Newman, Y. Pokharel, S. Baum, L. Hemphill, L. Hudgins, C. Ahmed, S. Gidding, Danielle Duffy, W. Neal, K. Wilemon, M. Roe, D. Rader, C. Ballantyne, M. Linton, P. Duell, P. Moriarty, Chenyi Xue, R. McPherson, H. Watkins, H. Schunkert","doi":"10.1161/CIRCGENETICS.116.001381","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001381","url":null,"abstract":"Background— Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. Methods and Results— We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08–2.82) and hypertension (2.48; 1.92–3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86–28.86) and use of >1 LDL-lowering medication (1.80; 1.34–2.41). Conclusions— FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"240–249"},"PeriodicalIF":0.0,"publicationDate":"2016-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001381","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-03-24DOI: 10.1161/CIRCGENETICS.115.001374
J. Golbus, N. Stitziel, Wei Zhao, Chenyi Xue, M. Farrall, R. McPherson, J. Erdmann, P. Deloukas, H. Watkins, H. Schunkert, N. Samani, D. Saleheen, S. Kathiresan, M. Reilly
Background— The chemokine receptors CCR2, CCR5, and CX3CR1 coordinate monocyte trafficking in homeostatic and inflammatory states. Multiple small human genetic studies have variably linked single nucleotide polymorphisms in these genes to cardiometabolic disease. We interrogated genome-wide association, exome sequencing, and exome array genotyping studies to ascertain the relationship between variation in these genes and coronary artery disease (CAD), myocardial infarction (MI), and glucometabolic traits. Methods and Results— We interrogated the CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) (60 801 cases and 123 504 controls), the MIGen and CARDIoGRAM Exome consortia (42 335 cases and 78 240 controls), and Exome Sequencing Project and Early-Onset Myocardial Infarction (ESP EOMI; 4703 cases and 5090 controls) data sets to ascertain the relationship between common, low frequency, and rare variation in CCR2, CCR5, or CX3CR1 with CAD and MI. We did not identify any variant associated with CAD or MI. We then explored common and low-frequency variation in South Asians through Pakistan Risk of Myocardial Infarction Study (PROMIS; 9058 cases and 8379 controls), identifying 6 variants associated with MI including CX3CR1 V249I. Finally, reanalysis of the European HapMap imputed Diabetes Genetics Replication and Meta-Analysis (DIAGRAM), Global Lipids Genetics Consortium (GLGC), Genetic Investigation of Anthropometric Traits (GIANT), and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) data sets revealed no association with glucometabolic traits although 3 single nucleotide polymorphisms in PROMIS were associated with type II diabetes mellitus. Conclusions— No chemokine receptor variant was associated with CAD, MI, or glucometabolic traits in large European ancestry cohorts. In a South Asian cohort, we identified single nucleotide polymorphism associations with MI and type II diabetes mellitus but these did not meet significance in cohorts of European ancestry. These findings suggest the need for larger studies in South Asians but exclude clinically meaningful associations with CAD and glucometabolic traits in Europeans.
{"title":"Common and Rare Genetic Variation in CCR2, CCR5, or CX3CR1 and Risk of Atherosclerotic Coronary Heart Disease and Glucometabolic Traits","authors":"J. Golbus, N. Stitziel, Wei Zhao, Chenyi Xue, M. Farrall, R. McPherson, J. Erdmann, P. Deloukas, H. Watkins, H. Schunkert, N. Samani, D. Saleheen, S. Kathiresan, M. Reilly","doi":"10.1161/CIRCGENETICS.115.001374","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001374","url":null,"abstract":"Background— The chemokine receptors CCR2, CCR5, and CX3CR1 coordinate monocyte trafficking in homeostatic and inflammatory states. Multiple small human genetic studies have variably linked single nucleotide polymorphisms in these genes to cardiometabolic disease. We interrogated genome-wide association, exome sequencing, and exome array genotyping studies to ascertain the relationship between variation in these genes and coronary artery disease (CAD), myocardial infarction (MI), and glucometabolic traits. Methods and Results— We interrogated the CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) (60 801 cases and 123 504 controls), the MIGen and CARDIoGRAM Exome consortia (42 335 cases and 78 240 controls), and Exome Sequencing Project and Early-Onset Myocardial Infarction (ESP EOMI; 4703 cases and 5090 controls) data sets to ascertain the relationship between common, low frequency, and rare variation in CCR2, CCR5, or CX3CR1 with CAD and MI. We did not identify any variant associated with CAD or MI. We then explored common and low-frequency variation in South Asians through Pakistan Risk of Myocardial Infarction Study (PROMIS; 9058 cases and 8379 controls), identifying 6 variants associated with MI including CX3CR1 V249I. Finally, reanalysis of the European HapMap imputed Diabetes Genetics Replication and Meta-Analysis (DIAGRAM), Global Lipids Genetics Consortium (GLGC), Genetic Investigation of Anthropometric Traits (GIANT), and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) data sets revealed no association with glucometabolic traits although 3 single nucleotide polymorphisms in PROMIS were associated with type II diabetes mellitus. Conclusions— No chemokine receptor variant was associated with CAD, MI, or glucometabolic traits in large European ancestry cohorts. In a South Asian cohort, we identified single nucleotide polymorphism associations with MI and type II diabetes mellitus but these did not meet significance in cohorts of European ancestry. These findings suggest the need for larger studies in South Asians but exclude clinically meaningful associations with CAD and glucometabolic traits in Europeans.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"33 1","pages":"250–258"},"PeriodicalIF":0.0,"publicationDate":"2016-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001374","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-03-11DOI: 10.1161/CIRCGENETICS.115.001323
Nicole J Boczek, N. Gómez-Hurtado, D. Ye, Melissa L Calvert, D. Tester, D. O. Kryshtal, H. Hwang, Christopher N. Johnson, W. Chazin, Christina G Loporcaro, M. Shah, Andrew L. Papez, Y. Lau, R. Kanter, B. Knollmann, M. Ackerman
Background—Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca2+ and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants. Methods and Results—Thirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in Ca2+-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release. Conclusions—Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history.
{"title":"Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome–Associated Calmodulin Missense Variant, E141G","authors":"Nicole J Boczek, N. Gómez-Hurtado, D. Ye, Melissa L Calvert, D. Tester, D. O. Kryshtal, H. Hwang, Christopher N. Johnson, W. Chazin, Christina G Loporcaro, M. Shah, Andrew L. Papez, Y. Lau, R. Kanter, B. Knollmann, M. Ackerman","doi":"10.1161/CIRCGENETICS.115.001323","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001323","url":null,"abstract":"Background—Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca2+ and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants. Methods and Results—Thirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in Ca2+-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release. Conclusions—Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"136–146"},"PeriodicalIF":0.0,"publicationDate":"2016-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001323","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-03-01DOI: 10.1161/CIRCGENETICS.115.001193
Yuan Xue, B. Schoser, Aliz R. Rao, R. Quadrelli, A. Vaglio, Verena Rupp, Christine Beichler, S. Nelson, Gudrun Schapacher-Tilp, C. Windpassinger, W. Wilcox
Background—Previously, we reported a rare X-linked disorder, Uruguay syndrome in a single family. The main features are pugilistic facies, skeletal deformities, and muscular hypertrophy despite a lack of exercise and cardiac ventricular hypertrophy leading to premature death. Methods and Results—An ≈19 Mb critical region on X chromosome was identified through identity-by-descent analysis of 3 affected males. Exome sequencing was conducted on one affected male to identify the disease-causing gene and variant. A splice site variant (c.502-2A>G) in the FHL1 gene was highly suspicious among other candidate genes and variants. FHL1A is the predominant isoform of FHL1 in cardiac and skeletal muscle. Sequencing cDNA showed the splice site variant led to skipping of exons 6 of the FHL1A isoform, equivalent to the FHL1C isoform. Targeted analysis showed that this splice site variant cosegregated with disease in the family. Western blot and immunohistochemical analysis of muscle from the proband showed a significant decrease in protein expression of FHL1A. Real-time polymerase chain reaction analysis of different isoforms of FHL1 demonstrated that the FHL1C is markedly increased. Conclusions—Mutations in the FHL1 gene have been reported in disorders with skeletal and cardiac myopathy but none has the skeletal or facial phenotype seen in patients with Uruguay syndrome. Our data suggest that a novel FHL1 splice site variant results in the absence of FHL1A and the abundance of FHL1C, which may contribute to the complex and severe phenotype. Mutation screening of the FHL1 gene should be considered for patients with uncharacterized myopathies and cardiomyopathies.
{"title":"Exome Sequencing Identified a Splice Site Mutation in FHL1 that Causes Uruguay Syndrome, an X-Linked Disorder With Skeletal Muscle Hypertrophy and Premature Cardiac Death","authors":"Yuan Xue, B. Schoser, Aliz R. Rao, R. Quadrelli, A. Vaglio, Verena Rupp, Christine Beichler, S. Nelson, Gudrun Schapacher-Tilp, C. Windpassinger, W. Wilcox","doi":"10.1161/CIRCGENETICS.115.001193","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001193","url":null,"abstract":"Background—Previously, we reported a rare X-linked disorder, Uruguay syndrome in a single family. The main features are pugilistic facies, skeletal deformities, and muscular hypertrophy despite a lack of exercise and cardiac ventricular hypertrophy leading to premature death. Methods and Results—An ≈19 Mb critical region on X chromosome was identified through identity-by-descent analysis of 3 affected males. Exome sequencing was conducted on one affected male to identify the disease-causing gene and variant. A splice site variant (c.502-2A>G) in the FHL1 gene was highly suspicious among other candidate genes and variants. FHL1A is the predominant isoform of FHL1 in cardiac and skeletal muscle. Sequencing cDNA showed the splice site variant led to skipping of exons 6 of the FHL1A isoform, equivalent to the FHL1C isoform. Targeted analysis showed that this splice site variant cosegregated with disease in the family. Western blot and immunohistochemical analysis of muscle from the proband showed a significant decrease in protein expression of FHL1A. Real-time polymerase chain reaction analysis of different isoforms of FHL1 demonstrated that the FHL1C is markedly increased. Conclusions—Mutations in the FHL1 gene have been reported in disorders with skeletal and cardiac myopathy but none has the skeletal or facial phenotype seen in patients with Uruguay syndrome. Our data suggest that a novel FHL1 splice site variant results in the absence of FHL1A and the abundance of FHL1C, which may contribute to the complex and severe phenotype. Mutation screening of the FHL1 gene should be considered for patients with uncharacterized myopathies and cardiomyopathies.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"10 1","pages":"130–135"},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-02-10DOI: 10.1161/CIRCGENETICS.115.001218
Ashfaq Ali, T. Varga, Ivana A. Stojkovic, Christina-Alexandra Schulz, G. Hallmans, I. Barroso, A. Poveda, F. Renström, M. Orho-Melander, P. Franks
Background—Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability. Methods and Results—We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene–Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmö Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRSTG) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRSTG were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m2) associated with 2.8% (P=8.4×10–84) higher triglyceride concentration and each additional WGRSTG unit with 2% (P=7.6×10–48) higher triglyceride concentration. Each unit of the WGRSTG was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (Pinteraction=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRSTG×BMI interaction effect (Pinteraction=6.0×10–4), which was strengthened by including data from the Danish cohorts (Pinteraction=6.5×10–7). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRSTG×BMI×sex) was observed (Pinteraction=0.03), where the WGRSTG×BMI interaction was only statistically significant in females. Using protein–protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci. Conclusions—Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females.
{"title":"Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia?: Findings From the GLACIER and the MDC Studies","authors":"Ashfaq Ali, T. Varga, Ivana A. Stojkovic, Christina-Alexandra Schulz, G. Hallmans, I. Barroso, A. Poveda, F. Renström, M. Orho-Melander, P. Franks","doi":"10.1161/CIRCGENETICS.115.001218","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001218","url":null,"abstract":"Background—Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability. Methods and Results—We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene–Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmö Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRSTG) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRSTG were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m2) associated with 2.8% (P=8.4×10–84) higher triglyceride concentration and each additional WGRSTG unit with 2% (P=7.6×10–48) higher triglyceride concentration. Each unit of the WGRSTG was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (Pinteraction=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRSTG×BMI interaction effect (Pinteraction=6.0×10–4), which was strengthened by including data from the Danish cohorts (Pinteraction=6.5×10–7). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRSTG×BMI×sex) was observed (Pinteraction=0.03), where the WGRSTG×BMI interaction was only statistically significant in females. Using protein–protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci. Conclusions—Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"162–171"},"PeriodicalIF":0.0,"publicationDate":"2016-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-02-01DOI: 10.1161/CIRCGENETICS.115.001157
Matthew J. Wolf, Dagny Noeth, C. Rammohan, Svati H. Shah
A 59-year-old female with a personal and family history of dilated cardiomyopathy (DCM) was referred by her cardiologist for genetic testing and counseling. The patient was initially diagnosed with DCM after presenting with dyspnea and fatigue. Her symptoms also included mild bilateral pedal edema, but she denied orthopnea, paroxysmal nocturnal dyspnea, palpitations, presyncope, or syncope. An electrocardiogram showed sinus rhythm and a left bundle branch block morphology (Figure 1). She underwent a gadolinium-enhanced cardiac magnetic resonance imaging that showed an enlarged left ventricle (LV; internal diameter at end diastole and systole were 6.5 cm and 5.4 cm, respectively), and the LV ejection fraction was ≈25%. Abnormal septal wall motion consistent with a bundle branch block was noted. All other walls of the LV were diffusely hypokinetic. Mild midmyocardial hyperenhancement suggestive of idiopathic DCM was present. The right ventricle was normal in size and function. There were no valvular abnormalities. Left heart catheterization showed no significant epicardial coronary artery disease. She was treated with a β-adrenergic antagonist, an angiotensinogen inhibitor, a mineralocorticoid antagonist, and a loop diuretic. Her symptoms improved; however, the LV remained enlarged and had poor systolic function with an ejection fraction of ≈30%. She subsequently underwent biventricular implantable cardioverter-defibrillator implantation. Figure 1. ECG of proband. Heart rate (HR) in bpm, P–R interval (PR) in milliseconds (ms), QRS duration (QRS) in ms, Q–T interval (QT) in ms, and corrected Q–T interval using Bazett formula (QTc) in ms are shown. aVF indicates augmented vector foot; aVL, augmented vector left; and aVR, augmented vector right. At the time of her initial diagnosis, the patient’s family history was notable for a 86-year-old mother who had atrial fibrillation and valvular heart disease; a father who died at the age of 89 years with coronary artery disease; a 59-year-old sister who had hypertension; a 50-year-old brother …
{"title":"Complexities of Genetic Testing in Familial Dilated Cardiomyopathy","authors":"Matthew J. Wolf, Dagny Noeth, C. Rammohan, Svati H. Shah","doi":"10.1161/CIRCGENETICS.115.001157","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001157","url":null,"abstract":"A 59-year-old female with a personal and family history of dilated cardiomyopathy (DCM) was referred by her cardiologist for genetic testing and counseling. The patient was initially diagnosed with DCM after presenting with dyspnea and fatigue. Her symptoms also included mild bilateral pedal edema, but she denied orthopnea, paroxysmal nocturnal dyspnea, palpitations, presyncope, or syncope. An electrocardiogram showed sinus rhythm and a left bundle branch block morphology (Figure 1). She underwent a gadolinium-enhanced cardiac magnetic resonance imaging that showed an enlarged left ventricle (LV; internal diameter at end diastole and systole were 6.5 cm and 5.4 cm, respectively), and the LV ejection fraction was ≈25%. Abnormal septal wall motion consistent with a bundle branch block was noted. All other walls of the LV were diffusely hypokinetic. Mild midmyocardial hyperenhancement suggestive of idiopathic DCM was present. The right ventricle was normal in size and function. There were no valvular abnormalities. Left heart catheterization showed no significant epicardial coronary artery disease. She was treated with a β-adrenergic antagonist, an angiotensinogen inhibitor, a mineralocorticoid antagonist, and a loop diuretic. Her symptoms improved; however, the LV remained enlarged and had poor systolic function with an ejection fraction of ≈30%. She subsequently underwent biventricular implantable cardioverter-defibrillator implantation.\u0000\u0000\u0000\u0000Figure 1. \u0000ECG of proband. Heart rate (HR) in bpm, P–R interval (PR) in milliseconds (ms), QRS duration (QRS) in ms, Q–T interval (QT) in ms, and corrected Q–T interval using Bazett formula (QTc) in ms are shown. aVF indicates augmented vector foot; aVL, augmented vector left; and aVR, augmented vector right.\u0000\u0000\u0000\u0000At the time of her initial diagnosis, the patient’s family history was notable for a 86-year-old mother who had atrial fibrillation and valvular heart disease; a father who died at the age of 89 years with coronary artery disease; a 59-year-old sister who had hypertension; a 50-year-old brother …","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"95–99"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-02-01DOI: 10.1161/CIRCGENETICS.115.001142
R. Jensen, X. Sim, A. Smith, Xiaohui Li, J. Jakobsdóttir, Ching-Yu Cheng, Jennifer A. Brody, M. Cotch, B. McKnight, R. Klein, Jie-Jin Wang, A. Kifley, T. Harris, L. Launer, K. Taylor, B. Klein, L. Raffel, Xiang Li, M. Ikram, C. Klaver, S. J. van der Lee, U. Mutlu, A. Hofman, A. Uitterlinden, Chunyu Liu, A. Kraja, P. Mitchell, V. Gudnason, J. Rotter, E. Boerwinkle, C. V. van Duijn, B. Psaty, T. Wong
Background—There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size. Methods and Results—This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10−11; minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10−9; minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10−10; minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10−8; minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10−12). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10−04). Conclusions—Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.
{"title":"Novel Genetic Loci Associated With Retinal Microvascular Diameter","authors":"R. Jensen, X. Sim, A. Smith, Xiaohui Li, J. Jakobsdóttir, Ching-Yu Cheng, Jennifer A. Brody, M. Cotch, B. McKnight, R. Klein, Jie-Jin Wang, A. Kifley, T. Harris, L. Launer, K. Taylor, B. Klein, L. Raffel, Xiang Li, M. Ikram, C. Klaver, S. J. van der Lee, U. Mutlu, A. Hofman, A. Uitterlinden, Chunyu Liu, A. Kraja, P. Mitchell, V. Gudnason, J. Rotter, E. Boerwinkle, C. V. van Duijn, B. Psaty, T. Wong","doi":"10.1161/CIRCGENETICS.115.001142","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001142","url":null,"abstract":"Background—There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size. Methods and Results—This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10−11; minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10−9; minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10−10; minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10−8; minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10−12). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10−04). Conclusions—Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"45–54"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001142","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-02-01DOI: 10.1161/CIRCGENETICS.115.001322
S. Wens, G. Schaaf, M. Michels, M. Kruijshaar, T. J. van Gestel, Stijn L. M. in ’t Groen, J. Pijnenburg, D. Dekkers, Jeroen A. A. Demmers, L. Verdijk, E. Brusse, R. V. van Schaik, A. T. van der Ploeg, P. V. van Doorn, W. Pijnappel
Background—Elevated plasma cardiac troponin T (cTnT) levels in patients with neuromuscular disorders may erroneously lead to the diagnosis of acute myocardial infarction or myocardial injury. Methods and Results—In 122 patients with Pompe disease, the relationship between cTnT, cardiac troponin I, creatine kinase (CK), CK-myocardial band levels, and skeletal muscle damage was assessed. ECG and echocardiography were used to evaluate possible cardiac disease. Patients were divided into classic infantile, childhood-onset, and adult-onset patients. cTnT levels were elevated in 82% of patients (median 27 ng/L, normal values <14 ng/L). Cardiac troponin I levels were normal in all patients, whereas CK-myocardial band levels were increased in 59% of patients. cTnT levels correlated with CK levels in all 3 subgroups (P<0.001). None of the abnormal ECGs recorded in 21 patients were indicative of acute myocardial infarction, and there were no differences in cTnT levels between patients with and without (n=90) abnormalities on ECG (median 28 ng/L in both groups). The median left ventricular mass index measured with echocardiography was normal in all the 3 subgroups. cTnT mRNA expression in skeletal muscle was not detectable in controls but was strongly induced in patients with Pompe disease. cTnT protein was identified by mass spectrometry in patient-derived skeletal muscle tissue. Conclusions—Elevated plasma cTnT levels in patients with Pompe disease are associated with skeletal muscle damage, rather than acute myocardial injury. Increased cTnT levels in Pompe disease and likely other neuromuscular disorders should be interpreted with caution to avoid unnecessary cardiac interventions.
{"title":"Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle Damage in Pompe Disease","authors":"S. Wens, G. Schaaf, M. Michels, M. Kruijshaar, T. J. van Gestel, Stijn L. M. in ’t Groen, J. Pijnenburg, D. Dekkers, Jeroen A. A. Demmers, L. Verdijk, E. Brusse, R. V. van Schaik, A. T. van der Ploeg, P. V. van Doorn, W. Pijnappel","doi":"10.1161/CIRCGENETICS.115.001322","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001322","url":null,"abstract":"Background—Elevated plasma cardiac troponin T (cTnT) levels in patients with neuromuscular disorders may erroneously lead to the diagnosis of acute myocardial infarction or myocardial injury. Methods and Results—In 122 patients with Pompe disease, the relationship between cTnT, cardiac troponin I, creatine kinase (CK), CK-myocardial band levels, and skeletal muscle damage was assessed. ECG and echocardiography were used to evaluate possible cardiac disease. Patients were divided into classic infantile, childhood-onset, and adult-onset patients. cTnT levels were elevated in 82% of patients (median 27 ng/L, normal values <14 ng/L). Cardiac troponin I levels were normal in all patients, whereas CK-myocardial band levels were increased in 59% of patients. cTnT levels correlated with CK levels in all 3 subgroups (P<0.001). None of the abnormal ECGs recorded in 21 patients were indicative of acute myocardial infarction, and there were no differences in cTnT levels between patients with and without (n=90) abnormalities on ECG (median 28 ng/L in both groups). The median left ventricular mass index measured with echocardiography was normal in all the 3 subgroups. cTnT mRNA expression in skeletal muscle was not detectable in controls but was strongly induced in patients with Pompe disease. cTnT protein was identified by mass spectrometry in patient-derived skeletal muscle tissue. Conclusions—Elevated plasma cTnT levels in patients with Pompe disease are associated with skeletal muscle damage, rather than acute myocardial injury. Increased cTnT levels in Pompe disease and likely other neuromuscular disorders should be interpreted with caution to avoid unnecessary cardiac interventions.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"6–13"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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