Circulation: Cardiovascular Genetics最新文献

{"title":"Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study.","authors":"Daniel D Kinnamon, Ana Morales, Deborah J Bowen, Wylie Burke, Ray E Hershberger","doi":"10.1161/CIRCGENETICS.117.001826","DOIUrl":"10.1161/CIRCGENETICS.117.001826","url":null,"abstract":"<p><strong>Background: </strong>The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality.</p><p><strong>Methods: </strong>On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity-ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of <i>Family Heart Talk</i>, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives.</p><p><strong>Conclusions: </strong>We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives.</p><p><strong>Clinical trial registration: </strong>URL: http://www.clinicaltrials.gov. Unique identifier: NCT03037632.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842914/pdf/nihms918523.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653866","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":"Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease.","authors":"Christian Paludan-Müller,&nbsp;Gustav Ahlberg,&nbsp;Jonas Ghouse,&nbsp;Jesper H Svendsen,&nbsp;Stig Haunsø,&nbsp;Morten S Olesen","doi":"10.1161/CIRCGENETICS.117.001878","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001878","url":null,"abstract":"<p><strong>Background: </strong>De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database.</p><p><strong>Methods and results: </strong>We performed a literature search for previous publications on de novo variants associated with severe arrhythmias and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706). We identified monogenic variants in single case reports and smaller studies (≤200 subjects) and variants considered to increase susceptibility of disease in 3 larger trio studies (>1000 subjects). Of the monogenic variants, 11% (23/211) were present in ExAC, whereas 26% (802/3050) variants believed to increase susceptibility of disease were identified in ExAC. Monogenic de novo variants in ExAC had a total allele count of 109 and with ≈844 expected cases in ExAC, these variants would account for 13% of all cases in the studied diseases if truly monogenetic.</p><p><strong>Conclusions: </strong>We observed numerous de novo variants associated with cardiac disease as standing variation in ExAC, thus these variants are less likely monogenetic causes or major risk contributors for cardiac disease. This highlights the importance of investigating the pathogenicity of de novo variants because they are not as exclusive and pathogenically evident as presumed previously.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001878","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653274","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":"Does Computer Simulation Help Facilitate Personalized Precision Medicine for the Use of Warfarin?","authors":"Shinichi Goto,&nbsp;Shinya Goto","doi":"10.1161/CIRCGENETICS.117.001969","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001969","url":null,"abstract":"In this issue of Circulation: Cardiovascular Genetics , Ravvaz et al1 presented an interesting report on the evaluation of warfarin dosing protocols among patients with atrial fibrillation with various different clinical backgrounds. This article is unique in reporting a new method using a computer simulation–based approach.\u0000\u0000See Article by Ravvaz et al \u0000\u0000To date, anticoagulation effects of warfarin are monitored by prothrombin time international normalized ratio (PT-INR).2 The appropriate warfarin dose to achieve the target PT-INR is affected by various factors, including age, sex, comorbidity, concomitant drug,3 and genetic polymorphisms of specific enzymes related to warfarin metabolism, such as vitamin K epoxide reductase complex and CYP2C9 .4 After clarification of warfarin metabolism, the impact of genetics on the PT-INR control with warfarin was of particular interest. Conflicting results have been published to date on the improvement of PT-INR control using genotype-guided warfarin dosing.5–8 Despite speculated impacts of the 2 enzymes directly related to warfarin metabolism, prediction of appropriate warfarin dose in individual patients using genotype information had less impact than expected. Furthermore, the impact of genotype-guided warfarin dose adjustment strategy on the clinical outcome rather than achieving target PT-INR is difficult to prove because clinical outcomes are influenced by multiple factors including those that could not be monitored by PT-INR control. Randomized clinical trials give us strong scientific evidences but require substantial numbers of real patients who agree to participate into the trials. Constructive …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001969","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653276","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":"Metabolic Profiling of Adiponectin Levels in Adults: Mendelian Randomization Analysis.","authors":"Maria Carolina Borges, Aluísio J D Barros, Diana L Santos Ferreira, Juan Pablo Casas, Bernardo Lessa Horta, Mika Kivimaki, Meena Kumari, Usha Menon, Tom R Gaunt, Yoav Ben-Shlomo, Deise F Freitas, Isabel O Oliveira, Aleksandra Gentry-Maharaj, Evangelia Fourkala, Debbie A Lawlor, Aroon D Hingorani","doi":"10.1161/CIRCGENETICS.117.001837","DOIUrl":"10.1161/CIRCGENETICS.117.001837","url":null,"abstract":"<p><strong>Background: </strong>Adiponectin, a circulating adipocyte-derived protein, has insulin-sensitizing, anti-inflammatory, antiatherogenic, and cardiomyocyte-protective properties in animal models. However, the systemic effects of adiponectin in humans are unknown. Our aims were to define the metabolic profile associated with higher blood adiponectin concentration and investigate whether variation in adiponectin concentration affects the systemic metabolic profile.</p><p><strong>Methods and results: </strong>We applied multivariable regression in ≤5909 adults and Mendelian randomization (using <i>cis</i>-acting genetic variants in the vicinity of the adiponectin gene as instrumental variables) for analyzing the causal effect of adiponectin in the metabolic profile of ≤37 545 adults. Participants were largely European from 6 longitudinal studies and 1 genome-wide association consortium. In the multivariable regression analyses, higher circulating adiponectin was associated with higher high-density lipoprotein lipids and lower very-low-density lipoprotein lipids, glucose levels, branched-chain amino acids, and inflammatory markers. However, these findings were not supported by Mendelian randomization analyses for most metabolites. Findings were consistent between sexes and after excluding high-risk groups (defined by age and occurrence of previous cardiovascular event) and 1 study with admixed population.</p><p><strong>Conclusions: </strong>Our findings indicate that blood adiponectin concentration is more likely to be an epiphenomenon in the context of metabolic disease than a key determinant.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653867","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":"Genetic Variants Contributing to Circulating Matrix Metalloproteinase 8 Levels and Their Association With Cardiovascular Diseases: A Genome-Wide Analysis.","authors":"Aino Salminen,&nbsp;Efthymia Vlachopoulou,&nbsp;Aki S Havulinna,&nbsp;Taina Tervahartiala,&nbsp;Wolfgang Sattler,&nbsp;Marja-Liisa Lokki,&nbsp;Markku S Nieminen,&nbsp;Markus Perola,&nbsp;Veikko Salomaa,&nbsp;Juha Sinisalo,&nbsp;Seppo Meri,&nbsp;Timo Sorsa,&nbsp;Pirkko J Pussinen","doi":"10.1161/CIRCGENETICS.117.001731","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001731","url":null,"abstract":"<p><strong>Background: </strong>Matrix metalloproteinase 8 (MMP-8) is a proinflammatory enzyme expressed mainly by neutrophils. Elevated serum and plasma concentrations of MMP-8 are associated with the risk for and outcome of cardiovascular diseases (CVDs). The origin of circulating MMP-8 is not completely clear.</p><p><strong>Methods and results: </strong>We performed a genome-wide association study of serum MMP-8 levels in 2 populations comprising altogether 6049 individuals. Moreover, we studied whether MMP-8-associated variants are linked to increased risk of CVDs and overall mortality in >20 000 subjects. The strongest association with serum MMP-8 was found in locus 1q31.3, containing the gene for complement factor H (lead single nucleotide polymorphism: rs800292; <i>P</i>=2.4×10^-35). In functional experiments, activation of the alternative pathway of complement in the carriers of rs800292 minor allele (Ile62 in factor H) led to decreased release of MMP-8 from neutrophils compared with the major allele (Val62 in factor H). Another association was detected in 1q21.3, containing genes <i>S100A8</i>, <i>S100A9</i>, and <i>S100A12</i> (strongest association: rs1560833; <i>P</i>=5.3×10^-15). The minor allele of rs1560833 was inversely associated with CVD (odds ratio [95% confidence interval]: 0.90 [0.82-0.99]; <i>P</i>=0.032) and the time to incident CVD event (hazard ratio [95% confidence interval]: 0.91 [0.84-0.99]; <i>P</i>=0.032) in men but not in women.</p><p><strong>Conclusions: </strong>According to our results, the activation of the alternative pathway of the complement system strongly contributes to serum MMP-8 concentration. Genetic polymorphism in <i>S100A9-S100A12-S100A8</i> locus affects serum and plasma MMP-8 and shows a suggestive association with the risk of CVDs. Our results show that genetic variation determines a significant portion of circulating MMP-8 concentrations.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001731","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35318158","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":"Is Left Ventricular Noncompaction a Trait, Phenotype, or Disease? The Evidence Points to Phenotype.","authors":"Ray E Hershberger,&nbsp;Ana Morales,&nbsp;Jason Cowan","doi":"10.1161/CIRCGENETICS.117.001968","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001968","url":null,"abstract":"The question is is left ventricular noncompaction (LVNC) a trait, phenotype, or disease? By trait, we refer to a discrete and measurable characteristic like eye color. The term phenotype expands this definition to include multiple observable traits derived from diverse genetic factors (genotype) and to recognize additional roles for the environment in shaping visible expression of a genetically defined trait. Pathological phenotypes, with their myriad signs, symptoms, diagnoses, and prognoses, are recognized as diseases and are most often associated with adverse clinical manifestations or need for medical or surgical intervention.\u0000\u0000See Article by Miller et al \u0000\u0000So where in this conceptual framework do we place LVNC? This is a well-debated topic1,2 and one that has been recently systematically and expertly reviewed in much greater depth than afforded by this editorial.1–4 Although LVNC has increasingly been recognized as a cardiomyopathy5—itself a term with clear disease connotations—mounting evidence now points to reclassification of LVNC as a distinct but not necessarily pathological phenotype. More specifically, the degree of compacted to noncompacted (NC) myocardium, by itself alone, does not seem to cause disease.\u0000\u0000Why phenotype rather than trait? Traits are considered to be genetically driven and not malleable by the environment. As defined above, genetics interacting with environment are best labeled as phenotype. Left ventricular (LV) morphology is not fixed for certain characteristics, including LV wall thickness or LV size. The former is well known to increase with severe hypertension or aortic stenosis, and the latter increases with volume overload from aortic insufficiency. With medical or surgical therapy, both conditions will regress. A similar paradigm has been observed with dilated cardiomyopathy—a disease phenotype associated with heart failure and arrhythmia for which the dilated or remodeled left ventricle will reverse remodel with appropriate medical therapy. Characteristics such …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001968","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35318162","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":"Correction.","authors":"","doi":"10.1161/HCG.0000000000000042","DOIUrl":"https://doi.org/10.1161/HCG.0000000000000042","url":null,"abstract":"","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":"e000042"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/HCG.0000000000000042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36849923","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":"Diminished <i>PRRX1</i> Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.","authors":"Nathan R Tucker,&nbsp;Elena V Dolmatova,&nbsp;Honghuang Lin,&nbsp;Rebecca R Cooper,&nbsp;Jiangchuan Ye,&nbsp;William J Hucker,&nbsp;Heather S Jameson,&nbsp;Victoria A Parsons,&nbsp;Lu-Chen Weng,&nbsp;Robert W Mills,&nbsp;Moritz F Sinner,&nbsp;Maxim Imakaev,&nbsp;Jordan Leyton-Mange,&nbsp;Gus Vlahakes,&nbsp;Emelia J Benjamin,&nbsp;Kathryn L Lunetta,&nbsp;Steven A Lubitz,&nbsp;Leonid Mirny,&nbsp;David J Milan,&nbsp;Patrick T Ellinor","doi":"10.1161/CIRCGENETICS.117.001902","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001902","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor <i>PRRX1</i> could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility.</p><p><strong>Methods and results: </strong>We sequenced a ≈158 kb region encompassing <i>PRRX1</i> in 962 individuals with and without AF. We identified a broad region of association with AF at the 1q24 locus. Using in silico prediction and functional validation, we identified an enhancer that interacts with the promoter of <i>PRRX1</i> in cells of cardiac lineage. Within this enhancer, we identified a single-nucleotide polymorphism, rs577676, which alters enhancer activity in a mouse atrial cell line and in embryonic zebrafish and differentially regulates <i>PRRX1</i> expression in human left atria. We found that suppression of <i>PRRX1</i> in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF.</p><p><strong>Conclusions: </strong>We have identified a functional genetic variant that alters <i>PRRX1</i> expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.</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.117.001902","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35569342","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":"One Size Does Not Fit All: Genetic Prediction of Kawasaki Disease Treatment Response in Diverse Populations.","authors":"Michael A Portman, Sadeep Shrestha","doi":"10.1161/CIRCGENETICS.117.001917","DOIUrl":"10.1161/CIRCGENETICS.117.001917","url":null,"abstract":"","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/PMC5661947/pdf/nihms903256.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35601882","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":"Transcriptome and Functional Profile of Cardiac Myocytes Is Influenced by Biological Sex.","authors":"Christa L Trexler, Aaron T Odell, Mark Y Jeong, Robin D Dowell, Leslie A Leinwand","doi":"10.1161/CIRCGENETICS.117.001770","DOIUrl":"10.1161/CIRCGENETICS.117.001770","url":null,"abstract":"<p><strong>Background: </strong>Although cardiovascular disease is the primary killer of women in the United States, women and female animals have traditionally been omitted from research studies. In reports that do include both sexes, significant sexual dimorphisms have been demonstrated in development, presentation, and outcome of cardiovascular disease. However, there is little understanding of the mechanisms underlying these observations. A more thorough understanding of sex-specific cardiovascular differences both at baseline and in disease is required to effectively consider and treat all patients with cardiovascular disease.</p><p><strong>Methods and results: </strong>We analyzed contractility in the whole rat heart, adult rat ventricular myocytes (ARVMs), and myofibrils from both sexes of rats and observed functional sex differences at all levels. Hearts and ARVMs from female rats displayed greater fractional shortening than males, and female ARVMs and myofibrils took longer to relax. To define factors underlying these functional differences, we performed an RNA sequencing experiment on ARVMs from male and female rats and identified ≈600 genes were expressed in a sexually dimorphic manner. Further analysis revealed sex-specific enrichment of signaling pathways and key regulators. At the protein level, female ARVMs exhibited higher protein kinase A activity, consistent with pathway enrichment identified through RNA sequencing. In addition, activating the protein kinase A pathway diminished the contractile sexual dimorphisms previously observed.</p><p><strong>Conclusions: </strong>These data support the notion that sex-specific gene expression differences at baseline influence cardiac function, particularly through the protein kinase A pathway, and could potentially be responsible for differences in cardiovascular disease presentation and outcomes.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679409/pdf/nihms905671.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9344678","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}