Circulation-Cardiovascular Genetics最新文献

{"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}

{"title":"Response by Crotti et al to Letter Regarding Article, \"Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?\"","authors":"L. Crotti, Annukka M. Lahtinen, C. Spazzolini, E. Mastantuono, Maria Cristina Monti, Caterina Morassutto, G. Parati, M. Heradien, A. Goosen, P. Lichtner, T. Meitinger, P. Brink, K. Kontula, H. Swan, P. Schwartz","doi":"10.1161/CIRCGENETICS.116.001635","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001635","url":null,"abstract":"We welcome the opportunity to respond to the expected comments by Amin et al regarding our article on the modifying role of 3′ untranslated region (3′UTR) single-nucleotide polymorphisms (SNPs) in type 1 long-QT syndrome patients.1\u0000\u0000In the original cohort studied by Amin et al,2 the analysis of 3 small families supported the modifying role of 3′UTR SNPs. Amin et al now propose, as a possible reason for the different results, the predominance of haploinsufficient type 1 long-QT syndrome–causative mutations in our population. However, in our 3 founder families, 2 ( KCNQ1 A341V and also KCNQ1 IVS7-2A>G) of the 3 mutations have a dominant-negative effect,3,4 and only 1 ( KCNQ1 -G589D) reduces the ability of the mutated proteins to form functional tetramers leading to haploinsufficiency.5 This is exactly the same pattern of their 3 families: 2 have a dominant-negative effect …","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397542","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":"Letter by Amin et al Regarding Article, \"Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?\"","authors":"A. Amin, Y. Pinto, M. Ackerman, A. Wilde","doi":"10.1161/CIRCGENETICS.116.001629","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001629","url":null,"abstract":"In their article, Crotti et al1 aimed to replicate our earlier discovery that single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′UTR) of KCNQ1 can suppress gene expression and thereby alter disease expressivity in patients with type 1 long-QT syndrome (LQT1).2 To do this, they studied the association between 3 3′UTR SNPs and the clinical phenotype in 3 LQT1 founder populations. They found that the 3′UTR SNPs were not associated with QTc or symptoms in these 3 populations. However, when the 3 groups were combined, the derived SNP haplotype located on the mutated allele did associate with shorter QTc and less cardiac events, which is fully in line with our earlier discovery. Despite this clear congruency with our findings, the authors still conclude that they could not replicate our findings. They base this on additional statistical analysis because when they …","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001629","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397914","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":"Homozygous Familial Hypercholesterolemia in SpainCLINICAL PERSPECTIVE","authors":"R. Sánchez-Hernández, F. Civeira, M. Stef, S. Pérez-Calahorra, F. Almagro, N. Plana, F. Nóvoa, Pedro Sáenz-Aranzubía, D. Mosquera, C. Soler, F. Fuentes, Y. Brito-Casillas, J. Real, F. Blanco-Vaca, J. Ascaso, M. Pocovi","doi":"10.1161/CIRCGENETICS.116.001545","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001545","url":null,"abstract":"Background— Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor ( LDLR ), apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and LDL protein receptor adaptor 1 ( LDLRAP1 ). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain.\u0000\u0000Methods and Results— Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH—of whom, 47 were true homozygous (1 for APOB , 5 for LDLRAP1 , and 41 for LDLR ), 45 compound heterozygous for LDLR , 3 double heterozygous for LDLR and PSCK9 , and 2 double heterozygous for LDLR and APOB . No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events.\u0000\u0000Conclusions— HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"504-510"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001545","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397825","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":"Defining a Contemporary Ischemic Heart Disease Genetic Risk Profile Using Historical Data.","authors":"Jonathan D Mosley, Sara L van Driest, Quinn S Wells, Christian M Shaffer, Todd L Edwards, Lisa Bastarache, Catherine A McCarty, Will Thompson, Christopher G Chute, Gail P Jarvik, David R Crosslin, Eric B Larson, Iftikhar J Kullo, Jennifer A Pacheco, Peggy L Peissig, Murray H Brilliant, James G Linneman, Josh C Denny, Dan M Roden","doi":"10.1161/CIRCGENETICS.116.001530","DOIUrl":"10.1161/CIRCGENETICS.116.001530","url":null,"abstract":"<p><strong>Background: </strong>Continued reductions in morbidity and mortality attributable to ischemic heart disease (IHD) require an understanding of the changing epidemiology of this disease. We hypothesized that we could use genetic correlations, which quantify the shared genetic architectures of phenotype pairs and extant risk factors from a historical prospective study to define the risk profile of a contemporary IHD phenotype.</p><p><strong>Methods and results: </strong>We used 37 phenotypes measured in the ARIC study (Atherosclerosis Risk in Communities; n=7716, European ancestry subjects) and clinical diagnoses from an electronic health record (EHR) data set (n=19 093). All subjects had genome-wide single-nucleotide polymorphism genotyping. We measured pairwise genetic correlations (rG) between the ARIC and EHR phenotypes using linear mixed models. The genetic correlation estimates between the ARIC risk factors and the EHR IHD were modestly linearly correlated with hazards ratio estimates for incident IHD in ARIC (Pearson correlation [r]=0.62), indicating that the 2 IHD phenotypes had differing risk profiles. For comparison, this correlation was 0.80 when comparing EHR and ARIC type 2 diabetes mellitus phenotypes. The EHR IHD phenotype was most strongly correlated with ARIC metabolic phenotypes, including total:high-density lipoprotein cholesterol ratio (rG=-0.44, P=0.005), high-density lipoprotein (rG=-0.48, P=0.005), systolic blood pressure (rG=0.44, P=0.02), and triglycerides (rG=0.38, P=0.02). EHR phenotypes related to type 2 diabetes mellitus, atherosclerotic, and hypertensive diseases were also genetically correlated with these ARIC risk factors.</p><p><strong>Conclusions: </strong>The EHR IHD risk profile differed from ARIC and indicates that treatment and prevention efforts in this population should target hypertensive and metabolic disease.</p>","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"521-530"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397784","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":"International Registry of Patients Carrying TGFBR1 or TGFBR2 MutationsCLINICAL PERSPECTIVE","authors":"G. Jondeau, J. Ropers, Ellen S. Regalado, A. Braverman, A. Evangelista, Guisela Teixedo, J. Backer, L. Muiño-Mosquera, S. Naudion, C. Zordan, T. Morisaki, H. Morisaki, Y. Kodolitsch, S. Dupuis-Girod, S. Morris, R. Jeremy, S. Odent, L. C. Adès, Madhura Bakshi, K. Holman, S. Lemaire, O. Milleron, M. Langeois, M. Spentchian, M. Aubart, C. Boileau, R. Pyeritz, D. Milewicz","doi":"10.1161/CIRCGENETICS.116.001485","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001485","url":null,"abstract":"Background— The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive.\u0000\u0000Methods and Results— The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2 . Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies.\u0000\u0000Conclusions— Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"548-558"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001485","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397157","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":"Letter by Finsterer and Zarrouk-Mahjoub Regarding Article, \"Combination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction\".","authors":"J. Finsterer, S. Zarrouk-Mahjoub","doi":"10.1161/CIRCGENETICS.116.001630","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001630","url":null,"abstract":"With interest, we read the article by Hastings et al1 about a 3-generation family in whom 7 members carried the titin mutation p.A178D , and 5 (3 on echocardiography and 2 on cardiac magnetic resonance imaging [MRI]) had left ventricular hypertrabeculation/noncompaction (LVHT). We have the following comments and concerns.\u0000\u0000To date, a causal relation between mutations in any of the >40 genes and many chromosomal defects associated with LVHT and LVHT has never been proven. Arguments against a causal relation are that only a small number of patients with a certain mutation in any of these genes regarded as causative truly develop LVHT; …","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001630","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397938","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":"Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.","authors":"Pradeep Natarajan, Joshua C Bis, Lawrence F Bielak, Amanda J Cox, Marcus Dörr, Mary F Feitosa, Nora Franceschini, Xiuqing Guo, Shih-Jen Hwang, Aaron Isaacs, Min A Jhun, Maryam Kavousi, Ruifang Li-Gao, Leo-Pekka Lyytikäinen, Riccardo E Marioni, Ulf Schminke, Nathan O Stitziel, Hayato Tada, Jessica van Setten, Albert V Smith, Dina Vojinovic, Lisa R Yanek, Jie Yao, Laura M Yerges-Armstrong, Najaf Amin, Usman Baber, Ingrid B Borecki, J Jeffrey Carr, Yii-Der Ida Chen, L Adrienne Cupples, Pim A de Jong, Harry de Koning, Bob D de Vos, Ayse Demirkan, Valentin Fuster, Oscar H Franco, Mark O Goodarzi, Tamara B Harris, Susan R Heckbert, Gerardo Heiss, Udo Hoffmann, Albert Hofman, Ivana Išgum, J Wouter Jukema, Mika Kähönen, Sharon L R Kardia, Brian G Kral, Lenore J Launer, Joe Massaro, Roxana Mehran, Braxton D Mitchell, Thomas H Mosley, Renée de Mutsert, Anne B Newman, Khanh-Dung Nguyen, Kari E North, Jeffrey R O'Connell, Matthijs Oudkerk, James S Pankow, Gina M Peloso, Wendy Post, Michael A Province, Laura M Raffield, Olli T Raitakari, Dermot F Reilly, Fernando Rivadeneira, Frits Rosendaal, Samantha Sartori, Kent D Taylor, Alexander Teumer, Stella Trompet, Stephen T Turner, Andre G Uitterlinden, Dhananjay Vaidya, Aad van der Lugt, Uwe Völker, Joanna M Wardlaw, Christina L Wassel, Stefan Weiss, Mary K Wojczynski, Diane M Becker, Lewis C Becker, Eric Boerwinkle, Donald W Bowden, Ian J Deary, Abbas Dehghan, Stephan B Felix, Vilmundur Gudnason, Terho Lehtimäki, Rasika Mathias, Dennis O Mook-Kanamori, Bruce M Psaty, Daniel J Rader, Jerome I Rotter, James G Wilson, Cornelia M van Duijn, Henry Völzke, Sekar Kathiresan, Patricia A Peyser, Christopher J O'Donnell","doi":"10.1161/CIRCGENETICS.116.001572","DOIUrl":"10.1161/CIRCGENETICS.116.001572","url":null,"abstract":"<p><strong>Background: </strong>The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.</p><p><strong>Methods and results: </strong>We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10^-¹⁰). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10^-¹²) and 1.4% reduced carotid intima-media thickness (P=4×10^-¹⁴) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10^-¹¹).</p><p><strong>Conclusions: </strong>Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.</p>","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"511-520"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397871","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":"Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial)","authors":"Yunpeng Ding, E. Pedersen, G. Svingen, Ø. Helgeland, J. Gregory, K. Løland, K. Meyer, G. Tell, P. Ueland, O. Nygård","doi":"10.1161/CIRCGENETICS.116.001483","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001483","url":null,"abstract":"Background—Serine and glycine interconversion and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)–mediated 1-carbon transfer are the major sources of methyl groups for 1-carbon metabolism. Recently, plasma glycine and a common polymorphism in MTHFD1 have been associated with risk of acute myocardial infarction (AMI). It is, therefore, of interest to explore if these 2 pathways interact in relation to AMI. Methods and Results—A total of 2571 participants in the WENBIT (Western Norway B Vitamin Intervention Trial) undergoing coronary angiography for stable angina pectoris were studied. Associations of plasma serine and glycine concentrations with risk of AMI across 2 common and functional MTHFD1 polymorphisms (rs2236225 and rs1076991) were explored in Cox regression models. During a median follow-up of 4.7 years, 212 patients (8.2%) experienced an AMI. In age- and sex-adjusted analyses, plasma glycine (P<0.01), but not serine (P=0.52), showed an overall association with AMI. However, interactions of MTHFD1 rs2236225 polymorphism with both plasma serine and glycine were observed (Pinteraction=0.03 for both). Low plasma serine and glycine were associated with an increased risk of AMI among patients carrying the rs2236225 minor A allele. Similarly, low plasma glycine showed stronger risk relationship with AMI in the rs1076991 CC genotype carriers but weaker associations in patients carrying the minor T allele (Pinteraction=0.02). Conclusions—Our results showed that 2 common and functional polymorphisms in the MTHFD1 gene modulate the risk associations of plasma serine and glycine with AMI. These findings emphasize the possible role of the MTHFD1 in regulating serine and glycine metabolism in relation to atherosclerotic complications. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00354081.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"541–547"},"PeriodicalIF":0.0,"publicationDate":"2016-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001483","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397343","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":"Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated With Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities","authors":"C. Shimizu, H. Eleftherohorinou, V. Wright, Jihoon Kim, M. Alphonse, J. Perry, R. Cimaz, D. Burgner, N. Dahdah, L. Hoang, C. Khor, A. Salgado, A. Tremoulet, S. Davila, T. Kuijpers, M. Hibberd, Todd A. Johnson, A. Takahashi, T. Tsunoda, M. Kubo, Toshihiro Tanaka, Y. Onouchi, R. Yeung, L. Coin, M. Levin, J. Burns","doi":"10.1161/CIRCGENETICS.116.001533","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001533","url":null,"abstract":"Background—Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility. Methods and Results—To search for additional functional genetic variation, we performed pathway and gene stability analysis on a genome-wide association study data set. Pathway analysis using European genome-wide association study data identified 100 significantly associated pathways (P<5×10−4). Gene stability selection identified 116 single nucleotide polymorphisms in 26 genes that were responsible for driving the pathway associations, and gene ontology analysis demonstrated enrichment for calcium transport (P=1.05×10−4). Three single nucleotide polymorphisms in solute carrier family 8, member 1 (SLC8A1), a sodium/calcium exchanger encoding NCX1, were validated in an independent Japanese genome-wide association study data set (meta-analysis P=0.0001). Patients homozygous for the A (risk) allele of rs13017968 had higher rates of coronary artery abnormalities (P=0.029). NCX1, the protein encoded by SLC8A1, was expressed in spindle-shaped and inflammatory cells in the aneurysm wall. Increased intracellular calcium mobilization was observed in B cell lines from healthy controls carrying the risk allele. Conclusions—Pathway-based association analysis followed by gene stability selection proved to be a valuable tool for identifying risk alleles in a rare disease with complex genetics. The role of SLC8A1 polymorphisms in altering calcium flux in cells that mediate coronary artery damage in KD suggests that this pathway may be a therapeutic target and supports the study of calcineurin inhibitors in acute KD.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"559–568"},"PeriodicalIF":0.0,"publicationDate":"2016-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001533","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397816","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}