Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease

Q Medicine

Circulation-Cardiovascular Genetics Pub Date : 2015-12-01 DOI:10.1161/CIRCGENETICS.115.001145

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

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引用次数: 53

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.

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钙信号通路基因RUNX2和CACNA1C与钙化性主动脉瓣病相关

背景:钙化性主动脉瓣狭窄(AS)是一种危及生命的疾病，没有药物治疗。AS的遗传结构仍然难以捉摸。本研究结合人瓣膜组织全基因组关联研究、基因表达和表达数量性状位点定位来鉴定AS的易感基因。方法与结果:对来自加拿大魁北克市和法国巴黎的474例和486例患者的2项全基因组关联研究结果进行meta分析。相应的对照包括2988和1864个来自基因型和表型数据库的欧洲血统个体。采用RNA测序法测定9例钙化主动脉瓣和8例正常主动脉瓣mRNA表达水平。结果与22例AS患者的瓣膜表达数量性状位点数据相结合。在全基因组关联研究荟萃分析中，25个单核苷酸多态性P<5×10−6。钙信号通路是与中度as相关的单核苷酸多态性基因富集的顶级基因集。该途径的基因在有和没有AS的瓣膜中存在差异表达。两个位于RUNX2(矮子相关转录因子2)的单核苷酸多态性，编码成骨转录因子，与AS有一定的关联(全基因组关联研究P=5.33×10−5)。RUNX2 mRNA表达水平在钙化瓣膜中上调，并与eqtl - snp相关。编码电压依赖性钙通道亚基的CACNA1C在钙化瓣膜中上调。位于CACNA1C中与AS相关性最显著的eQTL-SNP与该基因的高表达相关。结论:这项整合基因组研究证实了RUNX2作为as的潜在驱动因素的作用，并发现了一个新的as易感基因CACNA1C，属于钙信号通路。

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来源期刊

Circulation-Cardiovascular Genetics CARDIAC & CARDIOVASCULAR SYSTEMS-GENETICS & HEREDITY

CiteScore

3.95

自引率

0.00%

发文量

期刊介绍： Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease. Manuscripts are examined by the editorial staff and usually evaluated by expert reviewers assigned by the editors. Both clinical and basic articles will also be subject to statistical review, when appropriate. Provisional or final acceptance is based on originality, scientific content, and topical balance of the journal. Decisions are communicated by email, generally within six weeks. The editors will not discuss a decision about a manuscript over the phone. All rebuttals must be submitted in writing to the editorial office.