Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease.
Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease.
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DOI：
10.1161/circgenetics.115.001145
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
Bossé Y
中科院分区：
文献类型：
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作者：
Guauque-Olarte S;Messika-Zeitoun D;Droit A;Lamontagne M;Tremblay-Marchand J;Lavoie-Charland E;Gaudreault N;Arsenault BJ;Dubé MP;Tardif JC;Body SC;Seidman JG;Boileau C;Mathieu P;Pibarot P;Bossé Y
钙化性主动脉瓣狭窄(AS)是一种威胁生命的疾病，目前尚无药物治疗。AS的基因结构仍然难以捉摸。本研究结合全基因组关联研究、基因表达和人类瓣膜组织中表达的数量性状基因座定位，以确定AS的易感基因。Meta分析结合了来自魁北克市(加拿大)和巴黎(法国)的两个全基因组相关性研究的结果，分别对474和486个病例进行了分析。相应的对照由2988名和1864名来自欧洲血统的人组成，这些人来自于基因和表型数据库。应用RNA测序技术检测9例钙化主动脉瓣和8例正常主动脉瓣组织中mRNA的表达水平。结果与22例AS患者的瓣膜表达数量性状基因座数据相结合。在全基因组关联研究的Meta分析中，有25个单核苷酸多态具有P<；5×10−6。钙信号通路是被定位为中度AS相关单核苷酸多态的基因的最高基因组。该途径中的基因在有无AS的瓣膜中有差异表达。编码成骨转录因子的RUNX2(矮小相关转录因子2)上的两个单核苷酸多态与AS有关(全基因组关联研究P=5.33×10−5)。RUNX2在钙化瓣膜中表达上调，并与eQTL-SNPs相关。编码电压依赖性钙通道亚单位的CACNA1C在钙化瓣膜中上调。位于CACNA1C的与AS关联最显著的eQTL-SNP与该基因的高表达相关。这一整合的基因组研究证实了RUNX2是AS的潜在驱动基因，并发现了一个新的AS易感基因CACNA1C，该基因属于钙信号通路。
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. 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. 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.