Circulation-Cardiovascular Genetics最新文献

{"title":"Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta","authors":"M. Sanchez‐Castro, Hadja Eldjouzi, Eric Charpentier, P. Busson, Q. Hauet, P. Lindenbaum, Béatrice Delasalle-Guyomarch, Adrien Baudry, Olivier Pichon, Cécile Pascal, B. Lefort, F. Bajolle, P. Pezard, J. Schott, C. Dina, R. Redon, V. Gournay, D. Bonnet, C. Le Caignec","doi":"10.1161/CIRCGENETICS.115.001213","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001213","url":null,"abstract":"Background—Congenital heart defects are the most frequent malformations among newborns and a frequent cause of morbidity and mortality. Although genetic variation contributes to congenital heart defects, their precise molecular bases remain unknown in the majority of patients. Methods and Results—We analyzed, by high-resolution array comparative genomic hybridization, 316 children with sporadic, nonsyndromic congenital heart defects, including 76 coarctation of the aorta, 159 transposition of the great arteries, and 81 tetralogy of Fallot, as well as their unaffected parents. We identified by array comparative genomic hybridization, and validated by quantitative real-time polymerase chain reaction, 71 rare de novo (n=8) or inherited (n=63) copy-number variants (CNVs; 50 duplications and 21 deletions) in patients. We identified 113 candidate genes for congenital heart defects within these CNVs, including BTRC, CHRNB3, CSRP2BP, ERBB2, ERMARD, GLIS3, PLN, PTPRJ, RLN3, and TCTE3. No de novo CNVs were identified in patients with transposition of the great arteries in contrast to coarctation of the aorta and tetralogy of Fallot (P=0.002; Fisher exact test). A search for transcription factor binding sites showed that 93% of the rare CNVs identified in patients with coarctation of the aorta contained at least 1 gene with FOXC1-binding sites. This significant enrichment (P<0.0001; permutation test) was not observed for the CNVs identified in patients with transposition of the great arteries and tetralogy of Fallot. We hypothesize that these CNVs may alter the expression of genes regulated by FOXC1. Foxc1 belongs to the forkhead transcription factors family, which plays a critical role in cardiovascular development in mice. Conclusions—These data suggest that deregulation of FOXC1 or its downstream genes play a major role in the pathogenesis of coarctation of the aorta in humans.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"86–94"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396701","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 6p21.3 Risk Haplotype Predisposes to Acute Coronary Syndrome","authors":"J. Sinisalo, E. Vlachopoulou, M. Marchesani, J. Nokelainen, M. Mäyränpää, J. Lappalainen, R. Paakkanen, A. Wennerström, K. Salli, H. J. Niemi, S. Männistö, P. Salo, J. Junttila, M. Eskola, K. Nikus, T. Arstila, M. Perola, H. Huikuri, P. Karhunen, P. Kovanen, A. Palotie, A. Havulinna, C. Lluís-Ganella, J. Marrugat, R. Elosúa, V. Salomaa, M. Nieminen, M. Lokki","doi":"10.1161/CIRCGENETICS.115.001226","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001226","url":null,"abstract":"Background—The HLA-DRB1*01 allele of the human leukocyte antigen has been associated with acute coronary syndrome. Genome-wide association studies have revealed associations with human leukocyte antigen and non–human leukocyte antigen genes of 3 major histocompatibility complex gene classes but not at allelic level. Methods and Results—We conducted a large-scale genetic analysis on a case–control cohort comprising 5376 acute coronary syndrome cases and 4852 unrelated controls from 4 populations of 2 European countries. We analyzed the risk candidate allele of HLA-DRB1*01 by genomic real-time polymerase chain reaction together with high-density single nucleotide polymorphisms of the major histocompatibility complex to precisely identify risk loci for acute coronary syndrome with effective clinical implications. We found a risk haplotype for the disease containing single nucleotide polymorphisms from BTNL2 and HLA-DRA genes and the HLA-DRB1*01 allele. The association of the haplotype appeared in 3 of the 4 populations, and the direction of the effect was consistent in the fourth. Coronary samples from subjects homozygous for the disease-associated haplotype showed higher BTNL2 mRNA levels (r=0.760; P<0.00001).We localized, with immunofluorescence staining, BTNL2 in CD68-positive macrophages of the coronary artery plaques. In homozygous cases, BTNL2 blocking, in T-cell stimulation assays, enhanced CD4+FOXP3+ regulatory T cell proliferation significantly (blocking versus nonblocking; P<0.05). Conclusions—In cases with the risk haplotype for acute coronary syndrome, these results suggest involvement of enhanced immune reactions. BTNL2 may have an inhibitory effect on FOXP3+ T cell proliferation, especially in patients homozygous for the risk alleles. Clinical Trial Registration—https://www.clinicaltrials.gov; Unique Identifier: NCT00417534.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"55–63"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396879","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 Susceptibility to Lipid Levels and Lipid Change Over Time and Risk of Incident Hyperlipidemia in Chinese Populations","authors":"Xiangfeng Lu, Jianfeng Huang, Z. Mo, Jiang He, Laiyuan Wang, Xueli Yang, Aihua Tan, Aihua Tan, Shufeng Chen, Jingping Chen, C. Gu, Jichun Chen, Jichun Chen, Y. Li, Liancheng Zhao, Hongfan Li, Yongchen Hao, Jianxin Li, J. Hixson, Yunzhi Li, Yunzhi Li, Min Cheng, Min Cheng, Xiaoli Liu, Jie Cao, Fangcao Liu, Fangcao Liu, Chen Huang, Chong Shen, Jinjin Shen, Lin Yu, Li-hua Xu, J. Mu, Xianping Wu, Xianping Wu, X. Ji, D. Guo, Zheng-yuan Zhou, Zili Yang, Renping Wang, Jun Yang, Weili Yan, Xiaozhong Peng, D. Gu","doi":"10.1161/CIRCGENETICS.115.001096","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001096","url":null,"abstract":"Background—Multiple genetic loci associated with lipid levels have been identified predominantly in Europeans, and the issue of to what extent these genetic loci can predict blood lipid levels increases over time and the incidence of future hyperlipidemia remains largely unknown. Methods and Results—We conducted a meta-analysis of genome-wide association studies of lipid levels in 8344 subjects followed by replication studies including 14 739 additional individuals. We replicated 17 previously reported loci. We also newly identified 3 Chinese-specific variants in previous regions (HLA-C, LIPG, and LDLR) with genome-wide significance. Almost all the variants contributed to lipid levels change and incident hyperlipidemia >8.1-year follow-up among 6428 individuals of a prospective cohort study. The strongest associations for lipid levels change were detected at LPL, TRIB1, APOA1-C3-A4-A5, LIPC, CETP, and LDLR (P range from 4.84×10−4 to 4.62×10−18), whereas LPL, TRIB1, ABCA1, APOA1-C3-A4-A5, CETP, and APOE displayed significant strongest associations for incident hyperlipidemia (P range from 1.20×10−3 to 4.67×10−16). The 4 lipids genetic risk scores were independently associated with linear increases in their corresponding lipid levels and risk of incident hyperlipidemia. A C-statistics analysis showed significant improvement in the prediction of incident hyperlipidemia on top of traditional risk factors including the baseline lipid levels. Conclusions—These findings identified some evidence for allelic heterogeneity in Chinese when compared with Europeans in relation to lipid associations. The individual variants and those cumulative effects were independent risk factors for lipids increase and incident hyperlipidemia.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"10 1","pages":"37–44"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396978","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":"Endothelial Cell Bioenergetics and Mitochondrial DNA Damage Differ in Humans Having African or West Eurasian Maternal Ancestry","authors":"D. Krzywanski, D. Moellering, D. Westbrook, Kimberly J. Dunham-Snary, Jamelle A. Brown, Alexander W. Bray, Kyle P. Feeley, Melissa J. Sammy, Matthew R. Smith, T. Schurr, J. Vita, N. Ambalavanan, David Calhoun, Louis A. Dell’Italia, S. Ballinger","doi":"10.1161/CIRCGENETICS.115.001308","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001308","url":null,"abstract":"Background—We hypothesized that endothelial cells having distinct mitochondrial genetic backgrounds would show variation in mitochondrial function and oxidative stress markers concordant with known differential cardiovascular disease susceptibilities. To test this hypothesis, mitochondrial bioenergetics were determined in endothelial cells from healthy individuals with African versus European maternal ancestries. Methods and Results—Bioenergetics and mitochondrial DNA (mtDNA) damage were assessed in single-donor human umbilical vein endothelial cells belonging to mtDNA haplogroups H and L, representing West Eurasian and African maternal ancestries, respectively. Human umbilical vein endothelial cells from haplogroup L used less oxygen for ATP production and had increased levels of mtDNA damage compared with those in haplogroup H. Differences in bioenergetic capacity were also observed in that human umbilical vein endothelial cells belonging to haplogroup L had decreased maximal bioenergetic capacities compared with haplogroup H. Analysis of peripheral blood mononuclear cells from age-matched healthy controls with West Eurasian or African maternal ancestries showed that haplogroups sharing an A to G mtDNA mutation at nucleotide pair 10398 had increased mtDNA damage compared with those lacking this mutation. Further study of angiographically proven patients with coronary artery disease and age-matched healthy controls revealed that mtDNA damage was associated with vascular function and remodeling and that age of disease onset was later in individuals from haplogroups lacking the A to G mutation at nucleotide pair 10398. Conclusions—Differences in mitochondrial bioenergetics and mtDNA damage associated with maternal ancestry may contribute to endothelial dysfunction and vascular disease.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"26–36"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001308","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397382","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":"Interaction of Hereditary Thrombophilia and Traditional Cardiovascular Risk Factors on the Risk of Arterial Thromboembolism: Pooled Analysis of Four Family Cohort Studies","authors":"B. Mahmoodi, N. Veeger, S. Middeldorp, W. Lijfering, J. Brouwer, J. T. ten Berg, K. Hamulyák, K. Meijer","doi":"10.1161/CIRCGENETICS.115.001211","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001211","url":null,"abstract":"Background—Hereditary thrombophilia is associated with a slightly increased risk of arterial thromboembolism (ATE). Whether hereditary thrombophilia interacts with traditional cardiovascular risk factors on the risk of ATE has yet to be established. Methods and Results—A total of 1891 individuals belonging to 4 family cohorts from the Netherlands were included in the analyses. Five hereditary thrombophilic defects, including factor V Leiden, prothrombin G20210A defect, and deficiencies of the natural anticoagulants (ie, antithrombin, protein C, and protein S), were assessed, and data on risk factors and previous ATE were collected. Thrombophilia was associated with elevated risk of ATE (hazard ratio =1.74, 95% confidence interval, 1.18–2.58; P=0.005). Overall, the association of thrombophilia with ATE tended to be stronger in the presence of traditional cardiovascular risk factors, especially the synergistic effect of thrombophilia with diabetes mellitus was striking (hazard ratio of thrombophilia–ATE association was 1.41 in nondiabetics versus 8.11 in diabetics). Moreover, the association of thrombophilia with ATE tended to be stronger in females and before the age of 55 years as compared with males and individuals >55 years of age, respectively. Conclusions—Thrombophilia is associated with ATE. This association may be stronger in the presence of traditional cardiovascular risk factors in particular in individuals with diabetes mellitus. Future studies on thrombophilia–ATE risk should focus on high-risk populations with high prevalence of traditional cardiovascular risk factors.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"4 1","pages":"79–85"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396685","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":"CD36 Is a Matrix Metalloproteinase-9 Substrate That Stimulates Neutrophil Apoptosis and Removal During Cardiac Remodeling","authors":"K. DeLeon-Pennell, Yuan Tian, Bai Zhang, Courtney A. Cates, R. Iyer, Presley L. Cannon, Punit Shah, P. Aiyetan, G. Halade, Yonggang Ma, Elizabeth R. Flynn, Zhen Zhang, Yu-Fang Jin, Hui Zhang, M. Lindsey","doi":"10.1161/CIRCGENETICS.115.001249","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001249","url":null,"abstract":"Background—After myocardial infarction, the left ventricle undergoes a wound healing response that includes the robust infiltration of neutrophils and macrophages to facilitate removal of dead myocytes as well as turnover of the extracellular matrix. Matrix metalloproteinase (MMP)-9 is a key enzyme that regulates post-myocardial infarction left ventricular remodeling. Methods and Results—Infarct regions from wild-type and MMP-9 null mice (n=8 per group) analyzed by glycoproteomics showed that of 541 N-glycosylated proteins quantified, 45 proteins were at least 2-fold upregulated or downregulated with MMP-9 deletion (all P<0.05). Cartilage intermediate layer protein and platelet glycoprotein 4 (CD36) were identified as having the highest fold increase in MMP-9 null mice. By immunoblotting, CD36 but not cartilage intermediate layer protein decreased steadily during the time course post-myocardial infarction, which identified CD36 as a candidate MMP-9 substrate. MMP-9 was confirmed in vitro and in vivo to proteolytically degrade CD36. In vitro stimulation of day 7 post-myocardial infarction macrophages with MMP-9 or a CD36-blocking peptide reduced phagocytic capacity. Dual immunofluorescence revealed concomitant accumulation of apoptotic neutrophils in the MMP-9 null group compared with wild-type group. In vitro stimulation of isolated neutrophils with MMP-9 decreased neutrophil apoptosis, indicated by reduced caspase-9 expression. Conclusions—Our data reveal a new cell-signaling role for MMP-9 through CD36 degradation to regulate macrophage phagocytosis and neutrophil apoptosis.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"9 1","pages":"14–25"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397218","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":"Editorial Board.","authors":"","doi":"10.1161/HCG.0000000000000028","DOIUrl":"https://doi.org/10.1161/HCG.0000000000000028","url":null,"abstract":"","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/HCG.0000000000000028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64429122","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":"Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy–Associated Mutation in Human Cardiac Troponin I (K206I)","authors":"C. Warren, Chehade N. Karam, B. Wolska, Tomoyoshi Kobayashi, Pieter P. de Tombe, G. Arteaga, J. Bos, Michael J. Ackerman, R. J. Solaro","doi":"10.1161/CIRCGENETICS.115.001234","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001234","url":null,"abstract":"Background—Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease characterized by thickening of ventricular walls and decreased left ventricular chamber volume. The majority of HCM-associated mutations are found in genes encoding sarcomere proteins. Herein, we set out to functionally characterize a novel HCM-associated mutation (K206I-TNNI3) and elucidate the mechanism of dysfunction at the level of myofilament proteins. Methods and Results—The male index case was diagnosed with HCM after an out-of-hospital cardiac arrest, which was followed by comprehensive clinical evaluation, transthoracic echocardiography, and clinical genetic testing. To determine molecular mechanism(s) of the mutant human cardiac troponin I (K206I), we tested the Ca2+ dependence of thin filament–activated myosin-S1–ATPase activity in a reconstituted, regulated, actomyosin system comparing wild-type human troponin complex, 50% mix of K206I/wildtype, or 100% K206I. We also exchanged native troponin detergent extracted fibers with reconstituted troponin containing either wildtype or a 65% mix of K206I/wildtype and measured force generation. The Ca2+ sensitivity of the myofilaments containing the K206I variant was significantly increased, and when treated with 20 µmol/L (-)-epigallocatechin gallate (green tea) was restored back to wild-type levels in ATPase and force measurements. The K206I mutation impairs the ability of the troponin I to inhibit ATPase activity in the absence of calcium-bound human cardiac troponin C. The ability of calcium-bound human cardiac troponin C to neutralize the inhibition of K206I was greater than with wild-type TnI. Conclusions—Compromised interactions of K206I with actin and hcTnC may lead to impaired relaxation and HCM.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"117 1","pages":"765–773"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001234","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Genetic Testing in Hypertrophic Cardiomyopathy for Preclinical Disease Detection","authors":"J. Ingles, C. Burns, A. Barratt, C. Semsarian","doi":"10.1161/CIRCGENETICS.115.001093","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001093","url":null,"abstract":"Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular diseases, with a prevalence of at least 1 in 500 in the general population.1,2 HCM is characterized by left ventricular hypertrophy, in the absence of other loading conditions, such as hypertension.3 The hallmark feature of HCM is significant clinical heterogeneity in presentation, ranging from asymptomatic patients to those who have the most serious outcomes of heart failure and sudden cardiac death.\u0000\u0000Over 1500 mutations in at least 15 sarcomere-encoding genes have been identified.4–7 The significance of cardiac genetic testing in clinical practice is 2-fold. For the proband, identification of the underlying genetic cause in some cases can clarify the cause of hypertrophy, for example, clarifying phenocopies, such as PRKAG2-glycogen storage disease and Fabry disease. The greatest utility, however, is in cascade genetic testing of asymptomatic relatives, with clear benefits either for confirming a borderline clinical diagnosis, or suspicious clinical changes suggestive of early disease, or most importantly ruling out the disease in those who test gene-negative. Identification of a silent gene carrier will guide cascade testing of additional family members, in effect clarifying their risk status. Of most benefit, a negative genetic result can reassure offspring that they are not at risk of HCM.\u0000\u0000The escalation in our understanding of the genetic basis of HCM has been catalyzed by the implementation of next generation sequencing technologies. In response to faster and more affordable testing, commercial genetic testing for HCM now often comprises vast cardiac gene chips (ie, 50–200 or more genes). This approach, although comprehensive, also draws into sharp focus the limitations of our current knowledge. The challenges of cardiac genetic testing are increasingly documented, such as identification of variants of uncertain significance (VUS), incidental genetic findings,8 reclassification of variants,9 increased need …","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"8 1","pages":"852–859"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396933","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":"Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease","authors":"Sandra Guauque-Olarte, D. Messika‐Zeitoun, A. Droit, M. Lamontagne, Joël Tremblay-Marchand, Emilie Lavoie-Charland, N. Gaudreault, B. Arsenault, M. Dubé, J. Tardif, S. Body, J. Seidman, C. Boileau, P. Mathieu, P. Pibarot, Y. Bossé","doi":"10.1161/CIRCGENETICS.115.001145","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001145","url":null,"abstract":"Background—Calcific aortic valve stenosis (AS) is a life-threatening disease with no medical therapy. The genetic architecture of AS remains elusive. This study combines genome-wide association studies, gene expression, and expression quantitative trait loci mapping in human valve tissues to identify susceptibility genes of AS. Methods and Results—A meta-analysis was performed combining the results of 2 genome-wide association studies in 474 and 486 cases from Quebec City (Canada) and Paris (France), respectively. Corresponding controls consisted of 2988 and 1864 individuals with European ancestry from the database of genotypes and phenotypes. mRNA expression levels were evaluated in 9 calcified and 8 normal aortic valves by RNA sequencing. The results were integrated with valve expression quantitative trait loci data obtained from 22 AS patients. Twenty-five single-nucleotide polymorphisms had P<5×10−6 in the genome-wide association studies meta-analysis. The calcium signaling pathway was the top gene set enriched for genes mapped to moderately AS-associated single-nucleotide polymorphisms. Genes in this pathway were found differentially expressed in valves with and without AS. Two single-nucleotide polymorphisms located in RUNX2 (runt-related transcription factor 2), encoding an osteogenic transcription factor, demonstrated some association with AS (genome-wide association studies P=5.33×10−5). The mRNA expression levels of RUNX2 were upregulated in calcified valves and associated with eQTL-SNPs. CACNA1C encoding a subunit of a voltage-dependent calcium channel was upregulated in calcified valves. The eQTL-SNP with the most significant association with AS located in CACNA1C was associated with higher expression of the gene. Conclusions—This integrative genomic study confirmed the role of RUNX2 as a potential driver of AS and identified a new AS susceptibility gene, CACNA1C, belonging to the calcium signaling pathway.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":"53 1","pages":"812–822"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397024","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}