Circulation: Cardiovascular Genetics最新文献

{"title":"Identity-by-Descent Mapping Identifies Major Locus for Serum Triglycerides in Amerindians Largely Explained by an <i>APOC3</i> Founder Mutation.","authors":"Wen-Chi Hsueh,&nbsp;Anup K Nair,&nbsp;Sayuko Kobes,&nbsp;Peng Chen,&nbsp;Harald H H Göring,&nbsp;Toni I Pollin,&nbsp;Alka Malhotra,&nbsp;William C Knowler,&nbsp;Leslie J Baier,&nbsp;Robert L Hanson","doi":"10.1161/CIRCGENETICS.117.001809","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001809","url":null,"abstract":"<p><strong>Background: </strong>Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization.</p><p><strong>Methods and results: </strong>Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; <i>P</i>=3.5×10^-11 on chromosome 11q). In subsequent fine-mapping and replication association studies in ≈7500 Amerindians, we determined that this signal reflects effects of a loss-of-function Ala43Thr substitution in <i>APOC3</i> (rs147210663) and 3 established functional SNPs in <i>APOA5</i>. The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower triglycerides (β=-0.92±0.059 SD unit; <i>P</i>=9.6×10^-55 in 4668 Pimas and 2793 Southwest Amerindians combined). The Thr allele is extremely rare in most global populations but has a frequency of 2.5% in Pimas. We further demonstrated that 3 <i>APOA5</i> SNPs with established functional impact could explain the association with the most well-replicated SNP (rs964184) for triglycerides identified by genome-wide association studies. Collectively, these 4 SNPs account for 6.9% of variation in triglycerides in Pimas (and 4.1% in Southwest Amerindians), and their inclusion in the original linkage model reduced the linkage signal to virtually null.</p><p><strong>Conclusions: </strong><i>APOC3/APOA5</i> constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants.</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.117.001809","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653865","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":"Harnessing the Power of Pharmacometabolomics: The Metabolic Footprint of Statins.","authors":"Jennifer E Ho","doi":"10.1161/CIRCGENETICS.117.002014","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.002014","url":null,"abstract":"It has been 30 years since the approval of lovastatin, the first commercially available statin by the US Food and Drug Administration. Since that time, the uptake in statin use has been remarkable, with over 1 in 4 United States adults now taking statins for hyperlipidemia and cardiovascular disease, and nearly half of adults estimated to be statin eligible based on the 2013 ACC/AHA cholesterol treatment guidelines.1,2 Clearly, the cardioprotective effects of statins are linearly related to LDL-C (low-density lipoprotein cholesterol) lowering.3 However, despite the widespread use of statins, the extent to which event reduction is directly related to LDL lowering, versus effects on other lipid subclass or even pleiotropic effects remains unclear.\u0000\u0000See Article by Kofink et al \u0000\u0000The emerging use of metabolomic platforms to interrogate metabolites broadly representative of human metabolism has the potential to unravel on- and off-target effects and lend new insights into drug responses, referred to as pharmacometabolomics.4 In this issue, Kofink et al5 illustrate the power of pharmacometabolomics, by …","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.117.002014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653864","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":"Familial Ebstein Anomaly: Whole Exome Sequencing Identifies Novel Phenotype Associated With <i>FLNA</i>.","authors":"Catherine L Mercer,&nbsp;Gaia Andreoletti,&nbsp;Aisling Carroll,&nbsp;Anthony P Salmon,&nbsp;I Karen Temple,&nbsp;Sarah Ennis","doi":"10.1161/CIRCGENETICS.116.001683","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001683","url":null,"abstract":"<p><strong>Background: </strong>Familial Ebstein anomaly is a rare form of congenital heart disease. We report 7 individuals among 2 generations of 1 family with Ebstein anomaly. This family was first reported in 1991 by Balaji et al in which family members were also reported to have a mild skeletal phenotype. The most likely mechanism of inheritance was concluded to be autosomal dominant. We sought to identify the genetic pathogenesis in this family using a next generation sequencing approach.</p><p><strong>Methods and results: </strong>Whole exome sequencing was performed in 2 cousins in this family using the Agilent SureSelect Human all Exon 51 Mb version 5 capture kit. Data were processed through an analytic in-house pipeline. Whole exome sequencing identified a missense mutation in <i>FLNA</i> (Filamin A), an actin-binding protein located at Xq28, mutations in which are associated with the skeletal phenotypes Frontometaphyseal dysplasia, Otopalatodigital, and Melnick-Needles syndrome, with X-linked periventricular nodular heterotopia and FG syndrome (Omim, 305450). Review of the phenotypes of those with the mutation in this family shows increased severity of the cardiac phenotype and associated skeletal features in affected males, consistent with X-linked inheritance.</p><p><strong>Conclusions: </strong>Although congenital heart disease is reported in families with mutations in <i>FLNA</i>, this is the first report of individuals being affected by Ebstein anomaly because of a mutation in this gene and details the concurrent skeletal phenotype observed in this family.</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.116.001683","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653931","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 Mutation in <i>FLNC</i> (Filamin C) Causes Familial Restrictive Cardiomyopathy.","authors":"Nathan R Tucker,&nbsp;Micheal A McLellan,&nbsp;Dongjian Hu,&nbsp;Jiangchuan Ye,&nbsp;Victoria A Parsons,&nbsp;Robert W Mills,&nbsp;Sebastian Clauss,&nbsp;Elena Dolmatova,&nbsp;Marisa A Shea,&nbsp;David J Milan,&nbsp;Nandita S Scott,&nbsp;Mark Lindsay,&nbsp;Steven A Lubitz,&nbsp;Ibrahim J Domian,&nbsp;James R Stone,&nbsp;Honghuang Lin,&nbsp;Patrick T Ellinor","doi":"10.1161/CIRCGENETICS.117.001780","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001780","url":null,"abstract":"<p><strong>Background: </strong>Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported, and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes.</p><p><strong>Methods and results: </strong>We evaluated 8 family members across 4 generations by history, physical examination, electrocardiography, and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (filamin C; p.V2297M). <i>FLNC</i> encodes filamin C-a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of FLNC localization in cardiac tissue from an affected family member revealed a diminished localization at the z disk, whereas traditional localization at the intercalated disk was preserved. Stem cell-derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared with controls.</p><p><strong>Conclusion: </strong>We have identified a novel variant in <i>FLNC</i> as pathogenic variant for familial RCM-a finding that further expands on the genetic basis of this rare and morbid cardiomyopathy.</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.117.001780","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35318160","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":"Correction.","authors":"","doi":"10.1161/HCG.0000000000000040","DOIUrl":"https://doi.org/10.1161/HCG.0000000000000040","url":null,"abstract":"","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":"e000040"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/HCG.0000000000000040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36849921","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":"Cardiovascular Risk and Matrix Metalloproteinase Polymorphisms: Not Just a Simple Substitution.","authors":"Francis G Spinale,&nbsp;Ashley A Sapp","doi":"10.1161/CIRCGENETICS.117.001958","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001958","url":null,"abstract":"Cardiovascular remodeling is a process by which structural changes occur within the vascular compartment and the myocardium and are hallmark events in the development and progression of cardiovascular disease. This remodeling process is multifactorial entailing biological shifts in molecular, cellular, and extracellular matrix (ECM) structure and function. The ECM, for example, plays a critical role in maintaining normal vascular and myocardial architecture, and proteolytic turnover of the ECM, driven in large part by the induction and activation of matrix metalloproteinases (MMPs), is a major determinant of ECM structure and function. The MMPs are tightly regulated by transcriptional, post-transcriptional, and post-translational checkpoints. Transcriptional regulation of MMPs is primarily determined by upstream gene promoter activity, whereby several intracellular signaling factors bind to specific sequences within the MMP promoter sequence. As such, there has been considerable interest in nucleic acid substitutions (ie, polymorphisms) that occur within the MMP promoter regions and relation to overall MMP levels, and most importantly, relation to cardiovascular outcomes.1,2\u0000\u0000See Article by Salminen et al \u0000\u0000There have been several MMP polymorphisms identified in key MMP types, which include the collagenases (MMP-1, -8), the gelatinases (MMP-2, MMP-9), and stromelysins (MMP-3). A brief synopsis of MMP polymorphisms with respect to cardiovascular remodeling processes and selected citations is provided in Table.2–19 This summary table is by no means exhaustive but underscores the fact that several polymorphisms, primarily within the MMP promoter regions, have been identified and associated with subsets of patients at risk for cardiovascular events. Several of the …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":"e001958"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001958","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35318163","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":"Searching for the Causal Variants of the Association Between Hypertriglyceridemia and the Genome-Wide Association Studies-Derived Signals? Take a Look in the Native American Populations.","authors":"Carlos A Aguilar-Salinas,&nbsp;Magdalena Del Rocío Sevilla González,&nbsp;María Teresa Tusie-Luna","doi":"10.1161/CIRCGENETICS.117.002010","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.002010","url":null,"abstract":"Genome-wide association studies (GWAS) have made possible the identification of >175 loci that affect plasma lipid levels. Its results have been crucial to identify roles of new players in lipid metabolism (ie, apolipoprotein A5) or even to postulate potential treatment targets (ie, apolipoprotein C-III). However, a large proportion of the GWAS results has not been translated in clinically useful information because a large proportion of responsible single nucleotide polymorphisms (SNPs) are located either in noncoding regions or in genes without an obvious participation in any metabolic pathway.1 This is the case of the association between rs964184 and plasma triglycerides concentrations. This highly significant association has been a constant finding in the GWAS reports, regardless the sample size or the study sample composition.2 The frequency of the risk allele (G) varies between populations from 12% in whites to 27% in Mexicans. Also, it is common in Japanese (31%) and in Native American communities located in Central Mexico (≈50%). This SNP is nearby the 3′ untranslated region of the zinc finger gene ( ZPR1 ) and close to APOA5 . However, the identification of the functional variant that explains the association has not been possible.\u0000\u0000See Article by Hsueh et al \u0000\u0000The study of ethnic groups not included in the discovery cohorts, some methodological approaches (ie, admixture mapping or inception by descent [IBD] mapping), and deep genotyping are among the potential approaches to identify the variants responsible for a GWAS signal.3 The study of the Native American populations is an option because this group has not included in the majority of the lipids-related GWAS. The greater susceptibility of the populations derived from the Native American founding groups for having hypertriglyceridemia is well documented.4 These groups include the Amerindian communities living in Canada and the United States, mestizos living in the …","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.117.002010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653280","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":"Pathogenicity of De Novo Rare Variants: Challenges and Opportunities.","authors":"Arya Mani","doi":"10.1161/CIRCGENETICS.117.002013","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.002013","url":null,"abstract":"Human molecular genetics has played a critical role in the discovery of novel disease pathways and identification of new targets for therapeutic development. The most significant advantage of this scientific field is its unique potentials to establish causal links between germline mutations and human diseases. This in turn has led to the identification of most relevant targets in humans for development of potent therapeutics. This general concept pertains mainly to single gene or so-called Mendelian disorders, which are largely caused by mutations that alter a protein structure or function and have sufficient power to independently cause disease. Before the advent of high-throughput sequencing, these variants were largely identified by positional cloning. Regardless of the tools used for their discovery, disease causality of Mendelian variants is primarily established by close to perfect segregation of the disease alleles with the trait in family-based studies. A major benefit of family-based studies is the common genetic background of the studied subjects, which allows circumventing the problem of population stratification. Selective pressures in direct relationship to the effect size and severity of disease alleles determine the allele frequencies. For instance, fitness-related traits are highly subjected to natural selection and are caused by variants with much lower allele frequencies compared with those that underlie late-onset diseases.1 In general, disease allele frequencies of Mendelian traits are low and at a fraction of their prevalence. With the advent of high-throughput sequencing, the ability to identify rare Mendelian variants has dramatically increased. The reducing cost of sequencing and its increased throughput have turned whole-exome sequencing and whole-genome sequencing to increasingly attractive genetic tools for Mendelian traits. The modern tools of whole-exome sequencing or whole-genome sequencing have facilitated discovery of novel rare variants for Mendelian disorders with previously unknown genetic causes. These, in turn, have led to the discovery …","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.117.002013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653863","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":"Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study.","authors":"Daniel D Kinnamon,&nbsp;Ana Morales,&nbsp;Deborah J Bowen,&nbsp;Wylie Burke,&nbsp;Ray E Hershberger","doi":"10.1161/CIRCGENETICS.117.001826","DOIUrl":"https://doi.org/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://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001826","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":"Genome-Wide Association Study Implicates Atrial Natriuretic Peptide Rather Than B-Type Natriuretic Peptide in the Regulation of Blood Pressure in the General Population.","authors":"Perttu P Salo,&nbsp;Aki S Havulinna,&nbsp;Taru Tukiainen,&nbsp;Olli Raitakari,&nbsp;Terho Lehtimäki,&nbsp;Mika Kähönen,&nbsp;Johannes Kettunen,&nbsp;Minna Männikkö,&nbsp;Johan G Eriksson,&nbsp;Antti Jula,&nbsp;Stefan Blankenberg,&nbsp;Tanja Zeller,&nbsp;Veikko Salomaa,&nbsp;Kati Kristiansson,&nbsp;Markus Perola","doi":"10.1161/CIRCGENETICS.117.001713","DOIUrl":"10.1161/CIRCGENETICS.117.001713","url":null,"abstract":"<p><strong>Background: </strong>Cardiomyocytes secrete atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in response to mechanical stretching, making them useful clinical biomarkers of cardiac stress. Both human and animal studies indicate a role for ANP as a regulator of blood pressure with conflicting results for BNP.</p><p><strong>Methods and results: </strong>We used genome-wide association analysis (n=6296) to study the effects of genetic variants on circulating natriuretic peptide concentrations and compared the impact of natriuretic peptide-associated genetic variants on blood pressure (n=27 059). Eight independent genetic variants in 2 known (<i>NPPA-NPPB</i> and <i>POC1B-GALNT4</i>) and 1 novel locus (<i>PPP3CC</i>) associated with midregional proANP (MR-proANP), BNP, aminoterminal proBNP (NT-proBNP), or BNP:NT-proBNP ratio. The <i>NPPA-NPPB</i> locus containing the adjacent genes encoding ANP and BNP harbored 4 independent <i>cis</i> variants with effects specific to either midregional proANP or BNP and a rare missense single nucleotide polymorphism in NT-proBNP seriously altering its measurement. Variants near the calcineurin catalytic subunit gamma gene <i>PPP3CC</i> and the polypeptide N-acetylgalactosaminyltransferase 4 gene <i>GALNT4</i> associated with BNP:NT-proBNP ratio but not with BNP or midregional proANP, suggesting effects on the post-translational regulation of proBNP. Out of the 8 individual variants, only those correlated with midregional proANP had a statistically significant albeit weak impact on blood pressure. The combined effect of these 3 single nucleotide polymorphisms also associated with hypertension risk (<i>P</i>=8.2×10^-⁴).</p><p><strong>Conclusions: </strong>Common genetic differences affecting the circulating concentration of ANP associated with blood pressure, whereas those affecting BNP did not, highlighting the blood pressure-lowering effect of ANP in the general population.</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.117.001713","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653932","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}