Circulation-Cardiovascular Genetics最新文献

{"title":"Genetic Insurance Discrimination in Sudden Arrhythmia Death Syndromes: Empirical Evidence From a Cross-Sectional Survey in North America.","authors":"Saira S. Mohammed, Zaneta Lim, Paige H. Dean, J. Potts, Jessica Tang, S. Etheridge, Alice Lara, P. Husband, E. Sherwin, M. Ackerman, S. Sanatani","doi":"10.1161/CIRCGENETICS.116.001442","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001442","url":null,"abstract":"BACKGROUND\u0000There is virtually no information assessing the insurability of families affected with Sudden Arrhythmia Death Syndromes (SADS) for the determination of the nonclinical implications of genetic screening. It is important to identify the barriers and challenges faced by families as a result of genetic screening for SADS to enable equitable access to insurance coverage.\u0000\u0000\u0000METHODS AND RESULTS\u0000To explore the insurance coverage experiences of SADS-affected families, we administered a cross-sectional online survey across North America from April 28, 2012 to November 13, 2013. Participants included individuals with a SADS diagnosis and their relatives who have applied for insurance (health, life, travel, and disability) or have existing insurance coverage. Of 202 participants, 92% had a SADS diagnosis (92%) as either a proband (50%) or an affected relative (42%); 8% of participants were unaffected family members of a proband; and genetic confirmation was reported by 73%. Of the 54% of SADS respondents who applied for insurance, 60% were rejected by insurers. The preexisting SADS diagnosis was the major reason reported for rejection (57%). Most respondents (80%) had insurance coverage through a spouse/parent plan at the time of diagnosis; 14% experienced a subsequent negative effect on coverage. Thirty-nine percent of affected SADS respondents reported an increase in insurance premium rates.\u0000\u0000\u0000CONCLUSIONS\u0000Increased genetic testing has negatively impacted insurability for SADS patients and affected family members. The challenges in obtaining life and health insurance are mainly because of the preexisting condition, even in the presence of protective laws in the United States.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397198","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":"Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults","authors":"S. Seidelmann, Emily Smith, L. Subrahmanyan, Daniel J. Dykas, M. A. Abou Ziki, Bani M Azari, Fady Hannah-Shmouni, Yuexin Jiang, J. Akar, M. Marieb, D. Jacoby, A. Bale, R. Lifton, A. Mani","doi":"10.1161/CIRCGENETICS.116.001573","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001573","url":null,"abstract":"Background— With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. Methods and Results— We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. Conclusions— Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"10 1","pages":"e001573"},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001573","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45891872","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":"Inflammatory Biomarkers Predict Heart Failure Severity and Prognosis in Patients With Heart Failure With Preserved Ejection Fraction: A Holistic Proteomic Approach","authors":"C. Hage, E. Michaëlsson, C. Linde, E. Donal, J. Daubert, L. Gan, L. Lund","doi":"10.1161/CIRCGENETICS.116.001633","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001633","url":null,"abstract":"Background— Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis. Methods and Results— In 86 stable patients with HF and EF ≥45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay. Orthogonal projection to latent structures by partial least square analysis was performed on 87 biomarkers and 240 clinical variables, ranking biomarkers associated with New York Heart Association (NYHA) Functional class and the composite outcome (all-cause mortality and HF hospitalization). Biomarkers significantly correlated with outcome were analyzed by multivariable Cox regression and correlations with echocardiographic measurements performed. The orthogonal partial least square outcome-predicting biomarker pattern was run against the Ingenuity Pathway Analysis (IPA) database, containing annotated data from the public domain. The orthogonal partial least square analyses identified 32 biomarkers correlated with NYHA class and 28 predicting outcomes. Among outcome-predicting biomarkers, growth/differentiation factor-15 was the strongest and an additional 7 were also significant in Cox regression analyses when adjusted for age, sex, and N-terminal probrain natriuretic peptide: adrenomedullin (hazard ratio per log increase 2.53), agouti-related protein; (1.48), chitinase-3–like protein 1 (1.35), C–C motif chemokine 20 (1.35), fatty acid–binding protein (1.33), tumor necrosis factor receptor 1 (2.29), and TNF-related apoptosis-inducing ligand (0.34). Twenty-three of them correlated with diastolic dysfunction (E/e′) and 5 with left atrial volume index. The IPA suggested that increased inflammation, immune activation with decreased necrosis and apoptosis preceded poor outcome. Conclusions— In HF with preserved ejection fraction, novel biomarkers of inflammation predict HF severity and prognosis that may complement or even outperform traditional markers, such as N-terminal probrain natriuretic peptide. These findings lend support to a hypothesis implicating global systemic inflammation in HF with preserved ejection fraction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov; Unique identifier: NCT00774709.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"10 1","pages":"e001633"},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001633","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47246560","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":"The Long Noncoding RNA Landscape of the Ischemic Human Left Ventricle","authors":"L. Saddic, M. Sigurdsson, Tzuu-Wang Chang, Erica Mazaika, M. Heydarpour, S. Shernan, C. Seidman, J. Seidman, S. Aranki, S. Body, J. Muehlschlegel","doi":"10.1161/CIRCGENETICS.116.001534","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001534","url":null,"abstract":"Background— The discovery of functional classes of long noncoding RNAs (lncRNAs) has expanded our understanding of the variety of RNA species that exist in cells. In the heart, lncRNAs have been implicated in the regulation of development, ischemic and dilated cardiomyopathy, and myocardial infarction. Nevertheless, there is a limited description of expression profiles for these transcripts in human subjects. Methods and Results— We obtained left ventricular tissue from human patients undergoing cardiac surgery and used RNA sequencing to describe an lncRNA profile. We then identified a list of lncRNAs that were differentially expressed between pairs of samples before and after the ischemic insult of cardiopulmonary bypass. The expression of some of these lncRNAs correlates with ischemic time. Coding genes in close proximity to differentially expressed lncRNAs and coding genes that have coordinated expression with these lncRNAs are enriched in functional categories related to myocardial infarction, including heart function, metabolism, the stress response, and the immune system. Conclusions— We describe a list of lncRNAs that are differentially expressed after ischemia in the human heart. These genes are predicted to function in pathways consistent with myocardial injury. As a result, lncRNAs may serve as novel diagnostic and therapeutic targets for ischemic heart disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00985049.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"10 1","pages":"e001534"},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001534","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44134107","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":"Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome","authors":"L. A. Swayne, Nathaniel P. Murphy, Sirisha Asuri, Lena Chen, Xiaoxue Xu, Sarah McIntosh, Chao Wang, P. Lancione, Jason D. Roberts, Charles R. Kerr, S. Sanatani, E. Sherwin, C. F. Kline, Mingjie Zhang, P. Mohler, L. Arbour","doi":"10.1161/CIRCGENETICS.116.001537","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001537","url":null,"abstract":"Background— Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is ≈15× more common in First Nations of Northern British Columbia largely because of a known mutation in KCNQ1. However, 2 large multigenerational families were affected, but negative for the known mutation. Methods and Results— Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novel ANK2 c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (±40). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant. Conclusions— We identify the first disease-causing ANK2 variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role of ANK2 in targeting and stabilization of key structural and signaling molecules in cardiac cells.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"10 1","pages":"e001537"},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001537","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44853617","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":"Effect of Metformin on Metabolites and Relation With Myocardial Infarct Size and Left Ventricular Ejection Fraction After Myocardial Infarction","authors":"R. N. Eppinga, D. Kofink, R. Dullaart, G. Dalmeijer, E. Lipšic, D. V. van Veldhuisen, I. V. D. van der Horst, F. Asselbergs, P. van der Harst","doi":"10.1161/CIRCGENETICS.116.001564","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001564","url":null,"abstract":"Background— Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term survival after myocardial infarction (MI). However, little is known about the biochemical pathways driving LV dysfunction after MI. To identify novel biomarkers predicting post-MI LVEF and ISZ, we performed metabolic profiling in the GIPS-III randomized clinical trial (Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction). We also investigated the metabolic footprint of metformin, a drug associated with improved post-MI LV function in experimental studies. Methods and Results— Participants were patients with ST-segment–elevated MI who were randomly assigned to receive metformin or placebo for 4 months. Blood samples were obtained on admission, 24 hours post-MI, and 4 months post-MI. A total of 233 metabolite measures were quantified using nuclear magnetic resonance spectrometry. LVEF and ISZ were assessed 4 months post-MI. Twenty-four hours post-MI measurements of high-density lipoprotein (HDL) triglycerides (HDL-TG) predicted LVEF (&bgr;=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P=6.4×10−4) and ISZ (&bgr;=−0.41 [95% CI, −0.60 to −0.21]; P=3.2×10−5). In addition, 24 hours post-MI measurements of medium HDL-TG (&bgr;=−0.40 [95% CI, −0.60 to −0.20]; P=6.4×2×10−5), small HDL-TG (&bgr;=−0.34 [95% CI, −0.53 to −0.14]; P=7.3×10−4), and the triglyceride content of very large HDL (&bgr;=−0.38 [95% CI, −0.58 to −0.18]; P=2.7×10−4) were associated with ISZ. After the 4-month treatment, the phospholipid content of very large HDL was lower in metformin than in placebo-treated patients (28.89% versus 38.79%; P=7.5×10−5); alanine levels were higher in the metformin group (0.46 versus 0.44 mmol/L; P=2.4×10−4). Conclusions— HDL triglyceride concentrations predict post-MI LVEF and ISZ. Metformin increases alanine levels and reduces the phospholipid content in very large HDL particles. Clinical Trial Registration— URL: https://clinicaltrials.gov/ct2/show/NCT01217307. Unique Identifier: NCT01217307.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"10 1","pages":"e001564"},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001564","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42843079","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":"Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin &agr;v&bgr;3/FAK/AKT Pathway Suppression","authors":"Daile Jia, Qian Zhu, Huan Liu, C. Zuo, Yuhu He, Guilin Chen, Ankang Lu","doi":"10.1161/CIRCGENETICS.116.001591","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001591","url":null,"abstract":"Background— Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity. Methods and Results— Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416– and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416–induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin &agr;v&bgr;3 to elicit downstream focal adhesion kinase and AKT pathway activation. Conclusions— Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"10 1","pages":"e001591"},"PeriodicalIF":0.0,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001591","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43039381","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 Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response","authors":"Mohamed H. Shahin, A. C. Sá, A. Webb, Y. Gong, T. Langaee, C. McDonough, A. Riva, Amber L Beitleshees, A. Chapman, J. Gums, S. Turner, E. Boerwinkle, S. Scherer, W. Sadee, R. Cooper-DeHoff, Julie A. Johnson","doi":"10.1161/CIRCGENETICS.116.001404","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001404","url":null,"abstract":"Background— Thiazide diuretics are among the most commonly prescribed antihypertensives. However, <50% of thiazide-treated patients achieve blood pressure (BP) control. Herein, we used different omics (genomics and transcriptomics) to identify novel biomarkers of thiazide diuretics BP response. Methods and Results— Genome-wide analysis included 228 white hypertensives with BP determined at baseline and after 9 weeks of hydrochlorothiazide. Single-nucleotide polymorphisms with P <5×10−5 were prioritized according to their biological function, using RegulomeDB, haploreg, and Genome-Wide Annotation of Variants. The results from the prioritization approach revealed rs10995 as the most likely functional single-nucleotide polymorphism, among single-nucleotide polymorphisms tested, that has been associated with hydrochlorothiazide BP response. The rs10995 G-allele was associated with better BP response to hydrochlorothiazide versus noncarriers (&Dgr; systolic BP/&Dgr; diastolic BP: −12.3/−8.2 versus −6.8/−3.5 mm Hg, respectively, &Dgr; systolic BP P=3×10−4, &Dgr; diastolic BP P=5×10−5). This association was replicated in independent participants treated with chlorthalidone. In addition, rs10995 G-allele was associated with increased mRNA expression of VASP (vasodilator-stimulated phosphoprotein). Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good responders to hydrochlorothiazide compared with 25 poor responders (P=0.01). This finding was replicated in independent participants treated with chlorthalidone (P=0.04). Last, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a single-nucleotide polymorphism in high linkage disequilibrium (r2=0.7) with rs10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression. Conclusions— This study highlights the strength of using different omics to identify novel biomarkers of drug response and suggests VASP as a potential determinant of thiazide diuretics BP response. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"10 1","pages":"e001404"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397139","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":"Functional Validation of a Common Nonsynonymous Coding Variant in ZC3HC1 Associated With Protection From Coronary Artery Disease","authors":"Tara Linseman, S. Soubeyrand, Amy Martinuk, M. Nikpay, P. Lau, R. McPherson","doi":"10.1161/CIRCGENETICS.116.001498","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001498","url":null,"abstract":"Background— Although virtually all coronary artery disease associated single-nucleotide polymorphisms identified by genome-wide association studies (GWAS) are in noncoding regions of the genome, a common polymorphism in ZC3HC1 (rs11556924), resulting in an arginine (Arg) to histidine (His) substitution in its encoded protein, NIPA (Nuclear Interacting Partner of Anaplastic Lyphoma Kinase) is linked to a protection from coronary artery disease. NIPA plays a role in cell cycle progression, but the functional consequences of this polymorphism have not been established. Methods and Results— Here we demonstrate that total ZC3HC1 expression in whole blood is similar across genotypes, despite expression being slightly biased toward the risk allele in heterozygotes. At the protein level, the protective His363 NIPA variant exhibits increased phosphorylation of a critical serine residue (Ser354) and higher protein expression as compared with the Arg363 variant. Binding experiments indicate that neither SKP1 (S-phase kinase-associated protein 1) nor CCNB1 binding were affected by the polymorphism. Despite similar nuclear distribution, NIPA His363 exhibits greater nuclear mobility. NIPA suppression results in a modest reduction of proliferation in vascular smooth muscle cells, but given low proliferative capacity, a significant effect of the variant was not noted. By contrast, we demonstrate that the protective variant reduces cell proliferation in HeLa cells. Conclusions— These findings extend the genetic association between rs11556924 and coronary artery disease risk by characterizing its effects on the encoded protein, NIPA. The resulting amino acid change Arg363His is associated with increased expression and nuclear mobility, as well as lower rates of cell growth in HeLa cells, further supporting a role for cell proliferation in atherosclerosis and its clinical consequences.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"72 1","pages":"e001498"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001498","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397662","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":"New Insights Into the Genetic Basis of Inherited Arrhythmia Syndromes","authors":"B. Gray, E. Behr","doi":"10.1161/CIRCGENETICS.116.001571","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001571","url":null,"abstract":"Inherited arrhythmia syndromes encompass several different diseases, including long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), and progressive cardiac conduction system disease (PCCD).1 The heart is typically structurally normal with no evidence of disease macroscopically. They are an important cause for sudden cardiac death in the young, and an autopsy is typically negative.2,3\u0000\u0000Ventricular arrhythmias are caused by mutations of ion channels and their interacting proteins, predominantly involving potassium, sodium, and calcium handling.4 Genetic studies have identified the specific genetic abnormalities that underpin these diseases, even permitting diagnosis in the deceased using postmortem genetic testing (the molecular autopsy).3 Most arrhythmia syndromes are inherited in an autosomal dominant manner, such that first-degree family members have a 50% chance of inheriting the disease. Identification of the mutation allows for predictive genetic testing in other living family members.4 Variable penetrance is common in all arrhythmia syndromes, the same mutation in the same family causing wide variation in phenotype.4 This suggests that other factors such as genetic modifiers and environmental factors may influence the phenotype.\u0000\u0000This review will highlight the latest developments in understanding the genetic basis of inherited arrhythmia syndromes and discusses the new opportunities and challenges faced with evolving genetic technologies including determining pathogenicity and the utility of large genetic databases. Finally, we will discuss newly described entities that continue the evolving theme of genetic syndromes with phenotypic overlap. Early views that a single genotype associates with a particular phenotype continue to be challenged by our greater understanding of the genotype–phenotype relationship.\u0000\u0000### Long QT Syndrome\u0000\u0000Congenital LQTS is diagnosed in the presence of a prolonged corrected QT (QTc) interval after secondary causes (eg, QT-prolonging medications or electrolyte abnormalities) are excluded.1 The 2013 Heart Rhythm …","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"569–577"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001571","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397833","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}