Circulation: Cardiovascular Genetics最新文献

{"title":"α-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease.","authors":"Daniel Oder,&nbsp;Dan Liu,&nbsp;Kai Hu,&nbsp;Nurcan Üçeyler,&nbsp;Tim Salinger,&nbsp;Jonas Müntze,&nbsp;Kristina Lorenz,&nbsp;Reinhard Kandolf,&nbsp;Hermann-Josef Gröne,&nbsp;Claudia Sommer,&nbsp;Georg Ertl,&nbsp;Christoph Wanner,&nbsp;Peter Nordbeck","doi":"10.1161/CIRCGENETICS.116.001691","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001691","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy is the most common type of cardiomyopathy, but many patients lack sarcomeric/myofilament mutations. We studied whether cardio-specific α-galactosidase A gene variants are misinterpreted as hypertrophic cardiomyopathy because of the lack of extracardiac organ involvement.</p><p><strong>Methods and results: </strong>All subjects who tested positive for the N215S genotype (n=26, 13 females, mean age 49±17 [range, 14-74] years) were characterized in this prospective monocentric longitudinal cohort study to determine genotype-specific clinical characteristics of the N215S (c.644A>G [p.Asn215Ser]) α-galactosidase A gene variant. All subjects were initially referred with suspicion of genetically determined hypertrophic cardiomyopathy. Cardiac hypertrophy (interventricular septum, 12±4 [7-23] mm; left ventricular posterior wall, 11±4 [7-21] mm; left ventricular mass, 86±41 [46-195] g/m²) was progressive, systolic function mainly preserved (cardiac index 2.8±0.6 [1.9-3.9] L/min per m²), and diastolic function mildly abnormal. Cardiac magnetic resonance imaging revealed replacement fibrosis in <i>loco typico</i> (18/26, 69%), particularly in subjects >50 years. Elderly subjects had advanced heart failure, and 6 (23%) were suggested for implantable cardioverter-defibrillator therapy. Leukocyte α-galactosidase A enzyme activity was mildly reduced in 19 subjects and lyso-globotriaosylceramide slightly elevated (median, 4.9; interquartile range, 1.3-9.1 ng/mL). Neurological and renal impairments (serum creatinine, 0.87±0.20; median, 0.80; interquartile range, 0.70-1.01 mg/dL; glomerular filtration rate, 102±23; median, 106; interquartile range, 84-113 mL/min) were discreet. Only 2 subjects developed clinically relevant proteinuria.</p><p><strong>Conclusions: </strong>α-Galactosidase A genotype N215S does not lead to the development of a classical Fabry phenotype but induces a specific cardiac variant of Fabry disease mimicking nonobstructive hypertrophic cardiomyopathy. The lack of prominent noncardiac impairment leads to a significant delay in diagnosis and Fabry-specific therapy.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001691","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35501398","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}

{"title":"Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the <i>GPR98</i> Locus on 5q14.3.","authors":"Tingwei Guo, Gabriela M Repetto, Donna M McDonald McGinn, Jonathan H Chung, Hiroko Nomaru, Christopher L Campbell, Anna Blonska, Anne S Bassett, Eva W C Chow, Elisabeth E Mlynarski, Ann Swillen, Joris Vermeesch, Koen Devriendt, Doron Gothelf, Miri Carmel, Elena Michaelovsky, Maude Schneider, Stephan Eliez, Stylianos E Antonarakis, Karlene Coleman, Aoy Tomita-Mitchell, Michael E Mitchell, M Cristina Digilio, Bruno Dallapiccola, Bruno Marino, Nicole Philip, Tiffany Busa, Leila Kushan-Wells, Carrie E Bearden, Małgorzata Piotrowicz, Wanda Hawuła, Amy E Roberts, Flora Tassone, Tony J Simon, Esther D A van Duin, Thérèse A van Amelsvoort, Wendy R Kates, Elaine Zackai, H Richard Johnston, David J Cutler, A J Agopian, Elizabeth Goldmuntz, Laura E Mitchell, Tao Wang, Beverly S Emanuel, Bernice E Morrow","doi":"10.1161/CIRCGENETICS.116.001690","DOIUrl":"10.1161/CIRCGENETICS.116.001690","url":null,"abstract":"<p><strong>Background: </strong>The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort.</p><p><strong>Methods and results: </strong>To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, <i>P</i>=2.98×10^-⁸) in an intron of the adhesion <i>GPR98</i> (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with <i>GPR98</i>, including <i>MEF2C</i> (Myocyte-specific enhancer factor 2C). <i>MEF2C</i> is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS.</p><p><strong>Conclusions: </strong>In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/30/a5/hcg-10-e001690.PMC5647121.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35601883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients.","authors":"Allison L Cirino,&nbsp;Neal K Lakdawala,&nbsp;Barbara McDonough,&nbsp;Lauren Conner,&nbsp;Dale Adler,&nbsp;Mark Weinfeld,&nbsp;Patrick O'Gara,&nbsp;Heidi L Rehm,&nbsp;Kalotina Machini,&nbsp;Matthew Lebo,&nbsp;Carrie Blout,&nbsp;Robert C Green,&nbsp;Calum A MacRae,&nbsp;Christine E Seidman,&nbsp;Carolyn Y Ho","doi":"10.1161/CIRCGENETICS.117.001768","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001768","url":null,"abstract":"<p><strong>Background: </strong>As DNA sequencing costs decline, genetic testing options have expanded. Whole exome sequencing and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multigene panels that have been the cornerstone of genetic testing.</p><p><strong>Methods and results: </strong>Forty-one patients with hypertrophic cardiomyopathy who had undergone targeted hypertrophic cardiomyopathy genetic testing (either multigene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS. Results from panel genetic testing and WGS were compared. In 20 of 41 participants, panel genetic testing identified variants classified as pathogenic, likely pathogenic, or uncertain significance. WGS identified 19 of these 20 variants, but the variant detection algorithm missed a pathogenic 18 bp duplication in myosin binding protein C (<i>MYBPC3</i>) because of low coverage. In 3 individuals, WGS identified variants in genes implicated in cardiomyopathy but not included in prior panel testing: a pathogenic protein tyrosine phosphatase, non-receptor type 11 (<i>PTPN11</i>) variant and variants of uncertain significance in integrin-linked kinase (<i>ILK</i>) and filamin-C (<i>FLNC</i>). WGS also identified 84 secondary findings (mean=2 per person, range=0-6), which mostly defined carrier status for recessive conditions.</p><p><strong>Conclusions: </strong>WGS detected nearly all variants identified on panel testing, provided 1 new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical use and numerous secondary genetic findings were also identified. Whereas panel testing and WGS provided similar diagnostic yield, WGS offers the advantage of reanalysis over time to incorporate advances in knowledge, but requires expertise in genomic interpretation to appropriately incorporate WGS into clinical care.</p><p><strong>Clinical trial registration: </strong>URL: https://clinicaltrials.gov. Unique identifier: NCT01736566.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001768","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35449485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic Triangulation in Sudden Unexplained Death in the Young: The Way to Go?","authors":"Emil Daniel Bartels,&nbsp;Jacob Tfelt-Hansen,&nbsp;Bo Gregers Winkel","doi":"10.1161/CIRCGENETICS.117.001915","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001915","url":null,"abstract":"The use of next-generation sequencing techniques in the exploration of monogenic causes of disease has greatly increased in the recent years, and it is now possible to cover the whole exome with great precision and at low cost within days. The implementation of the next-generation sequencing techniques and target gene panels in clinical laboratories has not only improved the screening for genetic causes in patients with a distinct disease associated phenotype but also opened up for unraveling the causes of sudden unexplained death in the young. In this group, whole-exome sequencing used as molecular autopsy can be a supplement to especially negative or inconclusive autopsies. In several studies, either targeted gene panels focusing on channelopathies or whole-exome sequencing has been used to …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001915","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35479279","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}

{"title":"Reduced Cardiac <i>Calcineurin</i> Expression Mimics Long-Term Hypoxia-Induced Heart Defects in <i>Drosophila</i>.","authors":"Rachel Zarndt, Stanley M Walls, Karen Ocorr, Rolf Bodmer","doi":"10.1161/CIRCGENETICS.117.001706","DOIUrl":"10.1161/CIRCGENETICS.117.001706","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia is often associated with cardiopulmonary diseases, which represent some of the leading causes of mortality worldwide. Long-term hypoxia exposures, whether from disease or environmental condition, can cause cardiomyopathy and lead to heart failure. Indeed, hypoxia-induced heart failure is a hallmark feature of chronic mountain sickness in maladapted populations living at high altitude. In a previously established <i>Drosophila</i> heart model for long-term hypoxia exposure, we found that hypoxia caused heart dysfunction. Calcineurin is known to be critical in cardiac hypertrophy under normoxia, but its role in the heart under hypoxia is poorly understood.</p><p><strong>Methods and results: </strong>In the present study, we explore the function of <i>calcineurin</i>, a gene candidate we found downregulated in the <i>Drosophila</i> heart after lifetime and multigenerational hypoxia exposure. We examined the roles of 2 homologs of Calcineurin A, CanA14F, and Pp2B in the <i>Drosophila</i> cardiac response to long-term hypoxia. We found that knockdown of these calcineurin catalytic subunits caused cardiac restriction under normoxia that are further aggravated under hypoxia. Conversely, cardiac overexpression of Pp2B under hypoxia was lethal, suggesting that a hypertrophic signal in the presence of insufficient oxygen supply is deleterious.</p><p><strong>Conclusions: </strong>Our results suggest a key role for calcineurin in cardiac remodeling during long-term hypoxia with implications for diseases of chronic hypoxia, and it likely contributes to mechanisms underlying these disease states.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669044/pdf/nihms912716.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35479275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of a Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for the Study of Variant Pathogenicity: Validation of a <i>KCNJ2</i> Mutation.","authors":"Roselle Gélinas,&nbsp;Nabil El Khoury,&nbsp;Marie-A Chaix,&nbsp;Claudine Beauchamp,&nbsp;Azadeh Alikashani,&nbsp;Nathalie Ethier,&nbsp;Gabrielle Boucher,&nbsp;Louis Villeneuve,&nbsp;Laura Robb,&nbsp;Frédéric Latour,&nbsp;Blandine Mondesert,&nbsp;Lena Rivard,&nbsp;Philippe Goyette,&nbsp;Mario Talajic,&nbsp;Céline Fiset,&nbsp;John David Rioux","doi":"10.1161/CIRCGENETICS.117.001755","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001755","url":null,"abstract":"<p><strong>Background: </strong>Long-QT syndrome is a potentially fatal condition for which 30% of patients are without a genetically confirmed diagnosis. Rapid identification of causal mutations is thus a priority to avoid at-risk situations that can lead to fatal cardiac events. Massively parallel sequencing technologies are useful for the identification of sequence variants; however, electrophysiological testing of newly identified variants is crucial to demonstrate causality. Long-QT syndrome could, therefore, benefit from having a standardized platform for functional characterization of candidate variants in the physiological context of human cardiomyocytes.</p><p><strong>Methods and results: </strong>Using a variant in Kir2.1 (Gly52Val) revealed by whole-exome sequencing in a patient presenting with symptoms of long-QT syndrome as a proof of principle, we demonstrated that commercially available human induced pluripotent stem cell-derived cardiomyocytes are a powerful model for screening variants involved in genetic cardiac diseases. Immunohistochemistry experiments and whole-cell current recordings in human embryonic kidney cells expressing the wild-type or the mutant Kir2.1 demonstrated that Kir2.1-52V alters channel cellular trafficking and fails to form a functional channel. Using human induced pluripotent stem cell-derived cardiomyocytes, we not only confirmed these results but also further demonstrated that Kir2.1-52V is associated with a dramatic prolongation of action potential duration with evidence of arrhythmic activity, parameters which could not have been studied using human embryonic kidney cells.</p><p><strong>Conclusions: </strong>Our study confirms the pathogenicity of Kir2.1-52V in 1 patient with long-QT syndrome and also supports the use of isogenic human induced pluripotent stem cell-derived cardiomyocytes as a physiologically relevant model for the screening of variants of unknown function.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001755","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35597825","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}

{"title":"Machine Learning and Rare Variant Adjudication in Type 1 Long QT Syndrome.","authors":"John R Giudicessi","doi":"10.1161/CIRCGENETICS.117.001944","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001944","url":null,"abstract":"Long QT syndrome (LQTS) is a clinically and genetically heterogenous disorder of myocardial repolarization that often manifests clinically as heart rate–corrected QT interval (QTc) prolongation on 12-lead ECG and increased risk of syncope and sudden cardiac death.1,2 Among phenotypically robust nonsyndromic LQTS cases (ie, persistent QTc prolongation ≥480 ms or Schwartz diagnostic score ≥3.5), ≈75% are anticipated to harbor a heterozygous pathogenic variant in 1 of the 3 major LQTS-susceptibility genes ( KCNQ1 /LQT1, ≈35%; KCNH2 /LQT2, ≈30%; and SCN5A /LQT3, ≈10%).2–4 As a result of established genotype-phenotype correlations, the identification of a putative pathogenic KCNQ1 , KCNH2 , or SCN5A genetic variant often enables use of genotype-guided approaches to risk stratification and clinical management.5 As such, current Heart Rhythm Society/European Heart Rhythm Association guidelines consider LQTS-specific genetic testing for individuals with a strong clinical suspicion of LQTS based on clinical/family history and electrocardiographic phenotype as a class I recommendation.6\u0000\u0000See Article by Li et al \u0000\u0000However, even when potentially LQTS-causative rare variants are unearthed, the presence of a ≈3% to 8% background rate of rare KCNQ1 , KCNH2 , and SCN5A nonsynonymous variants in public exomes/genomes can make assignment of causation problematic.7–9 When coupled with the increased utilization of genetic testing to probe weak or nonexistent clinical phenotypes, whether out of concern for the marked incomplete penetrance and variable expressivity observed in most sudden cardiac death-predisposing genetic heart disorders10 or a failure to recognize the probablistic rather than binary nature of genetic testing, the net result has been a surge …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001944","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35597827","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}

{"title":"Connecting the Dots in Atrial Fibrillation.","authors":"Sylvia T Nurnberg","doi":"10.1161/CIRCGENETICS.117.001908","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001908","url":null,"abstract":"Atrial fibrillation is a common cardiac arrhythmia displaying a large heritable component,1 with twin studies estimating the genetic heritability at ≈60%.2 Several genome-wide association studies have been performed to identify common DNA variation associated with risk for disease and have to date identified 23 genomic loci with genome-wide significance.3 Each of these loci contains several common single-nucleotide polymorphisms (SNPs) that are significantly associated with disease risk, lie almost exclusively in nonprotein-coding regions of the human genome, and whose potential effects on surrounding protein-coding genes are largely unknown. The biggest challenge in postgenomic studies therefore lies in the functional annotation of those SNPs and the identification of the downstream target genes.\u0000\u0000See Article by Tucker and Dolmatova et al \u0000\u0000In this issue of Circulation: Cardiovascular Genetics , Tucker et al4 elegantly link noncoding variation via enhancer function with a disease phenotype (Figure) at …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001908","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35412732","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}

{"title":"Sex Determines Cardiac Myocyte Stretch and Relaxation.","authors":"Michael J Coronado,&nbsp;DeLisa Fairweather,&nbsp;Katelyn A Bruno","doi":"10.1161/CIRCGENETICS.117.001950","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001950","url":null,"abstract":"Trexler et al1 show for the first time that biological sex differences in isolated rat cardiomyocytes and myofibrils affect myocyte function. In addition, they discovered sex-specific cardiomyocyte gene expression profiles, like the protein kinase A pathway, that could provide insight into sex differences in cardiovascular diseases (CVDs). This study reports sex differences in gene profiles of isolated cardiomyocytes using high-quality RNAseq data, which allows a more detailed look at gene differences than previously published gene expression studies that typically used microarray of whole hearts (a combination of myocytes, fibroblasts, endothelial, and resident immune cells, for example).2,3 A major finding of Trexler et al1 is that healthy female rats have increased fractional shortening in both whole hearts and in paced cardiomyocytes. Female cardiac myocytes and myofibrils also take longer to relax after contraction, which may contribute to cardiac dysfunction in women after cardiac injury or disease.\u0000\u0000See Article by Trexler et al \u0000\u0000CVD is the leading cause of death in men and women worldwide.4 Before age 60, men are at an increased risk of death because of heart failure, whereas women develop some forms of heart disease, like stroke and hypertension, more frequently after menopause.4,5 Historically, women have been underrepresented in cardiovascular clinical trials.6 This led to the National Institutes of Health requirement to include women in clinical trials with the unexpected outcome that the data were in most cases not being analyzed according to sex. Controlling for sex or examining only one sex is not sufficient to understand the reason for sex (biological) and gender (social) differences in CVD and other chronic diseases.7 …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001950","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35449459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biases in Genetic Association of Coronary Heart Disease Events May Be Less Likely Than Suspected: Here Is When to Check for Them.","authors":"Jennifer R Dungan","doi":"10.1161/CIRCGENETICS.117.001912","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001912","url":null,"abstract":"Investigating lethal diseases like coronary heart disease (CHD) and major adverse events like myocardial infarction (MI) and death can sometimes seem a bit macabre. We are interested in understanding the events with the hope of preventing them; yet, to demonstrate effects, it is essential for a high rate of such unfortunate events to occur and to be observed. Fortunately, the increasing availability of big [event] data supports an unprecedented ability and power to explore genetic influences on primary and subsequent CHD events. Tempering the enthusiasm around this opportunity is the concern for biases that threaten the internal and external validity of such investigations.\u0000\u0000See Article by Hu and Schmidt et al \u0000\u0000In particular, selection and survival biases are of concern to the context of CHD events. When subjects are nonrandomly selected or tend to be systematically included based on the presence of a related risk profile, diagnosis, or event, this is deemed selection bias (also known as index event bias). Survival bias occurs when sampling is dependent on an individual’s likelihood of surviving an event in the first place, or when attrition or study closure prevents complete observation of time to censoring. These types of bias can systematically distort variance and lead to spurious outcomes.\u0000\u0000Selection bias has been a well-acknowledged concern in genetic association.1 …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001912","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35479278","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}