Circulation: Cardiovascular Genetics最新文献

{"title":"<i>PCSK9</i> Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.","authors":"Shia T Kent, Robert S Rosenson, Christy L Avery, Yii-Der I Chen, Adolfo Correa, Steven R Cummings, L Adrienne Cupples, Mary Cushman, Daniel S Evans, Vilmundur Gudnason, Tamara B Harris, George Howard, Marguerite R Irvin, Suzanne E Judd, J Wouter Jukema, Leslie Lange, Emily B Levitan, Xiaohui Li, Yongmei Liu, Wendy S Post, Iris Postmus, Bruce M Psaty, Jerome I Rotter, Monika M Safford, Colleen M Sitlani, Albert V Smith, James D Stewart, Stella Trompet, Fangui Sun, Ramachandran S Vasan, J Michael Woolley, Eric A Whitsel, Kerri L Wiggins, James G Wilson, Paul Muntner","doi":"10.1161/CIRCGENETICS.116.001632","DOIUrl":"10.1161/CIRCGENETICS.116.001632","url":null,"abstract":"<p><strong>Background: </strong><i>PCSK9</i> loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of <i>PCSK9</i> LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.</p><p><strong>Methods and results: </strong>These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between <i>PCSK9</i> LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, <i>PCSK9</i> LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. <i>PCSK9</i> LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. <i>PCSK9</i> LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites).</p><p><strong>Conclusions: </strong><i>PCSK9</i> LOF variants were associated with lower LDL-C and coronary heart disease incidence. <i>PCSK9</i> LOF variants were not associated with stroke risk.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":"e001632"},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729040/pdf/nihms889818.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35284645","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":"CKing Precision in the Interpretation of Diagnostic Biomarkers.","authors":"Simon de Denus,&nbsp;Jean-Claude Tardif,&nbsp;Marie-Pierre Dubé","doi":"10.1161/CIRCGENETICS.117.001874","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001874","url":null,"abstract":"Creatine kinase (CK) is a dimeric globular protein that includes 2 subunits.1 The different combinations of the 2 subunits of the CK dimer, CK-M and CK-B, lead to 3 isoforms of the cytoplasmic enzyme.2 CK-MM is primarily expressed in skeletal muscles and represents the greater part of serum CK. Two isoenzymes also exist in mitochondria.1 From a physiological perspective, CK is vital to catalyze the reversible exchange of high-energy phosphate bonds, which is crucial for energy buffering in tissues with variable energy demand, such as skeletal muscles.1 From a clinical perspective, the measurement of CK, a biomarker of muscle damage,3 is a routine part of the assessment of patients with several conditions.\u0000\u0000See Article by Siddiqui et al \u0000\u0000A frequent use of CK as a biomarker is in the assessment of patients with muscle pain or weakness while being treated with a statin, which is now broadly referred to as statin-associated muscle symptoms (SAMS).4,5 Because muscle aches and pains are unspecific, subjective, and frequently observed with multiple common conditions, CK measurement is a key component in the evaluation of patients reporting SAMS to identify those at risk of more severe muscle problems, such as myopathy or rhabdomyolysis (severe myopathy in the presence of myoglobinemia or myoglobinuria and renal impairment/failure).5 Fortunately, severe SAMS accompanied with CK elevation >10× the upper reference limit (URL) are extremely rare, occurring in 1 per 1000 to 1 per 10 000 patients per year.5\u0000\u0000For the clinician, muscle symptoms in the presence of no or only minor to modest CK elevations represent a particular challenge to discriminate SAMS from other secondary causes (hypothyroidism, other drugs). In the case the former is suspected, this often leads to a laborious exercise, for both the patient and the clinician, that …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001874","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35393655","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":"Carotid Plaque Rupture Is Accompanied by an Increase in the Ratio of Serum circR-284 to miR-221 Levels.","authors":"Hernan A Bazan,&nbsp;Samuel A Hatfield,&nbsp;Aaron Brug,&nbsp;Ashton J Brooks,&nbsp;Daniel J Lightell,&nbsp;T Cooper Woods","doi":"10.1161/CIRCGENETICS.117.001720","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001720","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerotic plaque rupture is accompanied by an acute decrease in the carotid plaque expression of micro-RNAs (miRs)-221 and miR-222. Circular RNA (circR)-284 is a potential inhibitor of miR-221/miR-222 activity. We aimed to determine whether changes in the serum levels of these noncoding RNAs are observed in patients with asymptomatic high-grade carotid disease versus patients with acutely symptomatic carotid disease and recent ischemic stroke. Additionally, we tested the use of functionally related noncoding RNA pairs to enhance the discriminatory power of noncoding RNAs as circulating biomarkers.</p><p><strong>Methods and results: </strong>Serum levels of miR-221, miR-222, miR-145, and circR-284 were measured in 24 asymptomatic (asymptomatic) and 17 acutely symptomatic patients ([urgent] ischemic cerebrovascular event within the previous 5 days) undergoing carotid endarterectomy. miR-221 was significantly lower, whereas circR-284 was elevated in the serum of the urgent compared with the asymptomatic group. The ratio of serum circR-284:miR-221 was significantly elevated in the urgent group (<i>P</i>=0.0002) and exhibited favorable characteristics as a biomarker indicative of carotid plaque rupture and stroke. A validation study in 112 patients (47 asymptomatic, 41 urgent, and 24 patients with a cerebrovascular event between 5 and 180 days of the carotid endarterectomy [symptomatic]) confirmed elevation of serum circR-284:miR-221 uniquely in the urgent group (<i>P</i><0.001) and favorable sensitivity and specificity for detecting plaque rupture and stroke.</p><p><strong>Conclusions: </strong>Serum circR-284:miR-221 has potential as a diagnostic biomarker of carotid plaque rupture and stroke. Moreover, we demonstrate the use of functionally related pairs of circulating noncoding RNAs as biomarkers in cardiovascular disease.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35384204","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":"Previously Unreported in Women <i>Galactosidase Alpha</i> Pro409Ser Variant Is Associated With Fabry Disease.","authors":"Sushil Allen Luis,&nbsp;Joseph J Maleszewski,&nbsp;Phillip M Young,&nbsp;Hartzell V Schaff,&nbsp;Naveen L Pereira","doi":"10.1161/CIRCGENETICS.116.001661","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001661","url":null,"abstract":"Fabry disease is a rare X-linked lysosomal storage disorder involving a deficiency in α- galactosidase A. This condition results in an impaired ability to metabolize globotriaosylceramide in the glycosphingolipid metabolic pathway, which accumulates within tissues throughout the body. Fabry disease affects 1 in 40 000 to 117 000 men with an unknown prevalence in women.1 Clinical presentations can be variable, ultimately resulting in potentially severe end-organ damage. In light of the variability in clinical presentation and rarity of the disease, initial misdiagnosis is common with a mean delay to diagnosis of between 13.7 and 16.3 years from symptom onset.1 Typical manifestations can include cutaneous lesions (angiokeratoma corporis), peripheral neuropathy, cerebrovascular accidents, proteinuria, renal insufficiency, and cardiac dysfunction.2,3 Cardiac manifestations include increased ventricular wall thickness, heart failure, valvular thickening and dysfunction, and coronary artery disease.2,3 Accurate and early diagnosis is imperative because early treatment with agalsidase β had been demonstrated to reduce the incidence of major adverse outcomes, including renal failure, stroke, cardiac events, and death.2\u0000\u0000A 50-year-old woman presented to our institution with a recent onset of worsening exertional shortness of breath, fatigue, and chest tightness on a background of a presumptive diagnosis of hypertrophic cardiomyopathy made 10 years before. Her family history was significant for ischemic heart disease in her father and brother and valvular disease in her sister, but there was no known family history of hypertrophic cardiomyopathy. There were no other systemic symptoms, and clinical examination revealed a holosystolic murmur without other features of systemic disease, including cornea verticillata. Baseline renal function was normal with a creatinine of 0.8 mg/dL. Echocardiography (Figure 1A and 1B) demonstrated severe concentric increase in left ventricular wall thickness with systolic anterior motion of the mitral valve leaflets resulting in severe left ventricular outflow tract …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":"e001661"},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001661","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35284644","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 Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.","authors":"Karol Miszalski-Jamka,&nbsp;John L Jefferies,&nbsp;Wojciech Mazur,&nbsp;Jan Głowacki,&nbsp;Jianhong Hu,&nbsp;Monika Lazar,&nbsp;Richard A Gibbs,&nbsp;Jacek Liczko,&nbsp;Jan Kłyś,&nbsp;Eric Venner,&nbsp;Donna M Muzny,&nbsp;Jarosław Rycaj,&nbsp;Jacek Białkowski,&nbsp;Ewa Kluczewska,&nbsp;Zbigniew Kalarus,&nbsp;Shalini Jhangiani,&nbsp;Hussein Al-Khalidi,&nbsp;Tomasz Kukulski,&nbsp;James R Lupski,&nbsp;William J Craigen,&nbsp;Matthew N Bainbridge","doi":"10.1161/CIRCGENETICS.117.001763","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001763","url":null,"abstract":"<p><strong>Background: </strong>Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous disease and, although increasingly recognized in clinical practice, there is a lack of widely accepted diagnostic criteria. We sought to identify novel genetic causes of LVNC and describe genotype-phenotype correlations.</p><p><strong>Methods and results: </strong>A total of 190 patients from 174 families with left ventricular hypertrabeculation (LVHT) or LVNC were referred for cardiac magnetic resonance and whole-exome sequencing. A total of 425 control individuals were included to identify variants of interest (VOIs). We found an excess of 138 VOIs in 102 (59%) unrelated patients in 54 previously identified LVNC or other known cardiomyopathy genes. VOIs were found in 68 of 90 probands with LVNC and 34 of 84 probands with LVHT (76% and 40%, respectively; <i>P</i><0.001). We identified 0, 1, and ≥2 VOIs in 72, 74, and 28 probands, respectively. We found increasing number of VOIs in a patient strongly correlated with several markers of disease severity, including ratio of noncompacted to compacted myocardium (<i>P</i><0.001) and left ventricular ejection fraction (<i>P</i>=0.01). The presence of sarcomeric gene mutations was associated with increased occurrence of late gadolinium enhancement (<i>P</i>=0.004).</p><p><strong>Conclusions: </strong>LVHT and LVNC likely represent a continuum of genotypic disease with differences in severity and variable phenotype explained, in part, by the number of VOIs and whether mutations are present in sarcomeric or nonsarcomeric genes. Presence of VOIs is common in patients with LVHT. Our findings expand the current clinical and genetic diagnostic approaches for patients with LVHT and LVNC.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001763","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35401815","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":"Genetics of Congenital Heart Disease: Is the Glass Now Half-Full?","authors":"Linda Leatherbury,&nbsp;Charles I Berul","doi":"10.1161/CIRCGENETICS.117.001746","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001746","url":null,"abstract":"Congenital heart defects are present in 1% of all live births and are a significant burden on the parents and family, healthcare system, and overall community. Congenital heart defects (CHD) are also identified in 10% of still births and are presumed to be a substantial cause of early fetal demise. With advances in prenatal diagnosis, corrective strategies, and longitudinal care, infant mortality has substantially declined. Today >75% of CHD children who survive the first year of live will enter into adulthood. Elucidating the cause of an offspring’s CHD is greatly valued by parents, providing comfort that the defect was because of genetic randomness beyond their control and that certain problems arise from the same underlying genetic issue and not from preventable errors.1 As Helen Taussig stated 50 years ago “Our next great step forward will come in the field of cause and prevention of malformations.”2 Causes of CHD are often divided into genetic and nongenetic influences. The advantage of contemporary genomic technologies including single-nucleotide polymorphism (SNP) arrays, next-generation sequencing, and copy-number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these tools enable the study of sporadic cases, the most common presentation of CHD. A review article summarizing this field entitled the “Genetics of Congenital Heart Disease: The Glass Half-Empty” previously highlighted the limitations of genetic technologies for assigning causality.3 Articles such as the present one in this journal entitled “Genome-Wide Association Studies and Meta-analysis for Congenital Heart Defects”4 are important studies performed using distinct patient cohorts from multiple sites. We are now looking for the complex multigenetic explanations for CHD in a multifactorial scheme, including epigenetic and environmental factors. There is renewed optimism in the field such that today we would see the genetics of CHD but hopefully now with the …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 3","pages":"e001746"},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001746","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34963958","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 Anthropology: Selection Pressure Shapes Fatty Acid Metabolism in Greenlandic Inuit Populations.","authors":"Robert W McGarrah","doi":"10.1161/CIRCGENETICS.117.001802","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001802","url":null,"abstract":"By shaping the genomes of ancient populations, selection pressure allowed individuals to adapt to local environments and stressors.1 Well-known examples include thalassemia and sickle cell disease, which offered protection against malaria in Mediterranean and African populations, respectively. More recently, variations in the lactase gene have been identified among populations with a long history of cattle herding and milk consumption to maintain the ability to metabolize lactose into adulthood.2 Indeed, many of the ancient genetic variations shaped by selection pressure explain the phenotypic and physiological variation across geographically diverse populations that exist today. As is the case with sickle cell disease, however, the benefits of certain genetic variants can disappear, or worse, the variants can become detrimental in environments different from which they were derived.\u0000\u0000See Article by Skotte et al \u0000\u0000Whereas early investigations in molecular anthropology studied population genetics in relation to anthropometric or physiological characteristics, advances in ‘omics technology now allow the integration of genetic variation with additional molecular data to provide a more granular and mechanistic view of evolutionary adaptation. However, although this integrative molecular approach has been used within populations to characterize the genetic architecture of certain disease states,3–5 its application in unraveling the implications of genetic variation between populations has been limited. As populations …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001802","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35085782","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":"Familial Analysis of Epistatic and Sex-Dependent Association of Genes of the Renin-Angiotensin-Aldosterone System and Blood Pressure.","authors":"Katrina J Scurrah,&nbsp;Angela Lamantia,&nbsp;Justine A Ellis,&nbsp;Stephen B Harrap","doi":"10.1161/CIRCGENETICS.116.001595","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001595","url":null,"abstract":"<p><strong>Background: </strong>Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis).</p><p><strong>Methods and results: </strong>We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (<i>REN</i>), angiotensinogen (<i>AGT</i>), angiotensin-converting enzyme (<i>ACE</i>), angiotensin II type 1 receptor (<i>AGTR1</i>), and aldosterone synthase (<i>CYP11B2</i>), including sex-SNP or SNP-SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at <i>ACE</i> and rs12721297 at <i>AGTR1</i>) were individually associated with lower systolic blood pressure with significant (<i>P</i><0.00076) effect sizes ≈1.7 to 2.5 mm Hg. Sex-specific associations were seen for 3 SNPs in men (rs2468523 and rs2478544 at <i>AGT</i> and rs11658531 at <i>ACE</i>) and 1 SNP in women (rs12451328 at <i>ACE</i>). SNP-SNP interaction was suggested (<i>P</i><0.005) for 14 SNP pairs, none of which had shown individual association with systolic blood pressure. Four SNP pairs were at the same gene (2 for <i>REN</i>, 1 for <i>AGT</i>, and 1 for <i>AGTR1</i>). The SNP rs3097 at <i>CYP11B2</i> was represented in 5 separate pairs.</p><p><strong>Conclusions: </strong>SNPs at key renin-angiotensin-aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001595","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34997221","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":"Repeats and Survival in Myotonic Dystrophy Type 1.","authors":"Matthew T Wheeler","doi":"10.1161/CIRCGENETICS.117.001783","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001783","url":null,"abstract":"The myotonic dystrophies are multisystem disorders characterized by progressive skeletal muscle weakness, myotonia, cataracts, endocrine abnormalities, cognitive impairment, and cardiomyopathy. Myotonic dystrophy type 1 (DM1) is the most common of the myotonic dystrophies. The cardiac-specific phenotypes of DM1 include progressive atrioventricular conduction delay, atrial and ventricular arrhythmias, impaired left ventricular diastolic and systolic dysfunction, impaired contractile reserve, and mesocardial fibrosis. Cardiac conduction abnormalities in patients with DM1 range from asymptomatic preclinical conduction system disease to complete heart block or ventricular arrhythmias leading to sudden death. In addition, DM1 patients are at increased risk for left ventricular dysfunction, ranging from impaired global longitudinal strain and impaired contractile reserve with preserved resting ejection fraction to overt left ventricular systolic dysfunction leading to overt heart failure.\u0000\u0000See Article by Chong-Nguyen et al \u0000\u0000Much concerning the pathogenesis of DM1 has been elucidated. Abnormal repeat expansion of a CTG triplet repeat in the 3′ untranslated region of the DMPK gene (dystrophia myotonica protein kinase)1 leads to accumulation of mutant transcripts in the nuclei of cells that in turn lead to dysregulated splicing and altered transcription.2,3 Sequestration of RNA-binding proteins including MBNL1 by DMPK mRNA CUG repeats and compensatory upregulation and activation of CUGBP1 (CUG-binding protein) lead to altered splicing of multiple transcripts.4–6 In addition to splicing defects, reduction of the DM protein kinase itself may contribute to the cardiac conduction defect seen in patients with DM1.7,8 Aberrant differential splicing of the SCN5A mRNA, with switching of exon 6 from the adult exon 6B to fetal 6A, is likely contributory to reductions in cardiomyocyte excitability and increased atrioventricular conduction delay.9\u0000\u0000There is extensive evidence of a relationship between age-dependent neuromuscular dysfunction and DMPK CTG repeat length in DM1. Indeed, clinical phenotypes of late-adult-onset, classical-adult-onset, childhood-onset, …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001783","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35086934","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":"Multiancestry Study of Gene-Lifestyle Interactions for Cardiovascular Traits in 610 475 Individuals From 124 Cohorts: Design and Rationale.","authors":"D C Rao,&nbsp;Yun J Sung,&nbsp;Thomas W Winkler,&nbsp;Karen Schwander,&nbsp;Ingrid Borecki,&nbsp;L Adrienne Cupples,&nbsp;W James Gauderman,&nbsp;Kenneth Rice,&nbsp;Patricia B Munroe,&nbsp;Bruce M Psaty","doi":"10.1161/CIRCGENETICS.116.001649","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001649","url":null,"abstract":"Background— Several consortia have pursued genome-wide association studies for identifying novel genetic loci for blood pressure, lipids, hypertension, etc. They demonstrated the power of collaborative research through meta-analysis of study-specific results. Methods and Results— The Gene-Lifestyle Interactions Working Group was formed to facilitate the first large, concerted, multiancestry study to systematically evaluate gene–lifestyle interactions. In stage 1, genome-wide interaction analysis is performed in 53 cohorts with a total of 149 684 individuals from multiple ancestries. In stage 2 involving an additional 71 cohorts with 460 791 individuals from multiple ancestries, focused analysis is performed for a subset of the most promising variants from stage 1. In all, the study involves up to 610 475 individuals. Current focus is on cardiovascular traits including blood pressure and lipids, and lifestyle factors including smoking, alcohol, education (as a surrogate for socioeconomic status), physical activity, psychosocial variables, and sleep. The total sample sizes vary among projects because of missing data. Large-scale gene–lifestyle or more generally gene–environment interaction (G×E) meta-analysis studies can be cumbersome and challenging. This article describes the design and some of the approaches pursued in the interaction projects. Conclusions— The Gene-Lifestyle Interactions Working Group provides an excellent framework for understanding the lifestyle context of genetic effects and to identify novel trait loci through analysis of interactions. An important and novel feature of our study is that the gene–lifestyle interaction (G×E) results may improve our knowledge about the underlying mechanisms for novel and already known trait loci.","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001649","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35093485","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}