遗传关联分析突出了、和作为导致钙化性主动脉瓣狭窄的 3 个新的易感基因。

Genetic Association Analyses Highlight , , and As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.

机构信息

Institut universitaire de cardiologie et de pneumologie de Québec (S.T., R.C., N.G., Z.L., M.L., M.-A.C., B.J.A., P.P., P.M., Y.B.), Laval University, Quebec City, Canada.

Department of Molecular Biology, Medical Biochemistry and Pathology (S.T.), Laval University, Quebec City, Canada.

出版信息

Circ Genom Precis Med. 2019 Oct;12(10):e002617. doi: 10.1161/CIRCGEN.119.002617. Epub 2019 Oct 15.

DOI:10.1161/CIRCGEN.119.002617

PMID:32141789

Abstract

BACKGROUND

Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, and , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS.

METHODS

A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits.

RESULTS

In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: (interleukin 6) on 7p15.3 and (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the locus. The signal identified colocalizes with the expression of the RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors.

CONCLUSIONS

Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.

摘要

背景

钙化性主动脉瓣狭窄（CAVS）是一种常见且危及生命的心血管疾病，目前尚无有效的治疗方法。迄今为止，仅有 2 个基因，和，被确定为 CAVS 的致病基因。我们旨在鉴定 CAVS 的其他易感基因。

方法

对 4 个队列进行了 GWAS（全基因组关联研究）荟萃分析，共纳入 5115 例病例和 354072 例欧洲血统对照。完成了 TWAS（转录组全基因组关联研究），整合了 233 个人主动脉瓣的转录组数据。进行了一系列 GWAS 后分析，包括精细映射、共定位、表型全基因组关联研究、途径和组织富集以及与心血管特征的遗传相关性。

结果

在 GWAS 荟萃分析中，有 4 个位点达到全基因组显著水平，包括 2 个新位点：位于 7p15.3 的（白细胞介素 6）和位于 1p36.12 的（碱性磷酸酶）。整合 233 个人主动脉瓣转录组数据的 TWAS 鉴定出 1q32.1 上的（神经导航器 1）作为新的候选致病基因。CAVS 风险等位基因与瓣膜组织中基因的高 mRNA 表达相关。精细映射确定 rs1800795 为位点最可能的因果变异。该信号与各种组织中 RNA 反义的表达共定位。在 UK Biobank 中的表型全基因组关联分析显示，位于先导变异的风险等位基因与嗜酸性粒细胞计数、脉压、收缩压和颈动脉手术的升高存在共定位关联，提示 IL6 途径的调节。位于先导变异的风险等位基因与脉压升高和颈动脉狭窄患病率升高共定位。全基因组关联分析结果表明，CAVS、冠心病和心血管危险因素之间存在遗传相关性。