Unveiling blood pressure-associated genes in aortic cells through integrative analysis of GWAS and RNA modification-associated variants

Q1 Medicine

Chronic Diseases and Translational Medicine Pub Date : 2024-04-30 DOI:10.1002/cdt3.124

Huan Zhang, Yuxi Chen, Peng Xu, Dan Liu, Naqiong Wu, Laiyuan Wang, Xingbo Mo

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引用次数: 0

Abstract

Background

Genome-wide association studies (GWAS) have identified more than a thousand loci for blood pressure (BP). Functional genes in these loci are cell-type specific. The aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification-associated single-nucleotide polymorphisms (RNAm-SNPs).

Methods

Utilizing large-scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium, we identified associations between RNAm-SNPs and BP. The association between RNAm-SNPs, gene expression, and BP were examined.

Results

A total of 355 RNAm-SNPs related to m⁶A, m¹A, m⁵C, m⁷G, and A-to-I modification were associated with BP. The related genes were enriched in the pancreatic secretion pathway and renin secretion pathway. The BP GWAS signals were significantly enriched with m⁶A-SNPs, highlighting the potential functional relevance of m⁶A in physiological processes influencing BP. Notably, m⁶A-SNPs in CYP11B1, PDE3B, HDAC7, ACE, SLC4A7, PDE1A, FRK, MTHFR, NPPA, CACNA1D, and HDAC9 were identified. Differential methylation and differential expression of the BP genes in FTO-overexpression and METTL14-knockdown vascular smooth muscle cells were detected. RNAm-SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection (AD) cases and controls. In scRNA-seq study, we identified ARID5A, HLA-DPB1, HLA-DRA, IRF1, LINC01091, MCL1, MLF1, MLXIPL, NAA16, NADK, RERG, SRM, and USP53 as differential expression genes for AD in aortic cells.

Conclusion

The present study identified RNAm-SNPs in BP loci and elucidated the associations between the RNAm-SNPs, gene expression, and BP. The identified BP-associated genes in aortic cells were associated with AD.

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通过 GWAS 和 RNA 修饰相关变异的综合分析，揭示主动脉细胞中的血压相关基因

背景全基因组关联研究（GWAS）发现了一千多个血压（BP）基因位点。这些位点中的功能基因具有细胞类型特异性。本研究旨在通过利用 RNA 修饰相关单核苷酸多态性（RNAm-SNPs），阐明与主动脉血压相关的潜在功能基因。方法我们利用英国生物库和国际血压联盟（International Consortium of Blood Pressure consortium）的 757,601 人的大规模基因数据，确定了 RNAm-SNPs 与血压之间的关联。我们还研究了 RNAm-SNPs、基因表达和血压之间的关联。结果共有355个与m6A、m1A、m5C、m7G和A-to-I修饰相关的RNAm-SNPs与血压有关。相关基因富集于胰腺分泌途径和肾素分泌途径。血压 GWAS 信号与 m6A-SNPs 显著富集，突出了 m6A 在影响血压的生理过程中的潜在功能相关性。值得注意的是，在 CYP11B1、PDE3B、HDAC7、ACE、SLC4A7、PDE1A、FRK、MTHFR、NPPA、CACNA1D 和 HDAC9 中发现了 m6A-SNPs。在 FTO 高表达和 METTL14 敲除的血管平滑肌细胞中，检测到了 BP 基因的差异甲基化和差异表达。RNAm-SNPs与升主动脉和降主动脉直径相关，主动脉夹层（AD）病例和对照组之间的基因甲基化存在差异。在 scRNA-seq 研究中，我们发现 ARID5A、HLA-DPB1、HLA-DRA、IRF1、LINC01091、MCL1、MLF1、MLXIPL、NAA16、NADK、RERG、SRM 和 USP53 是主动脉细胞中 AD 的差异表达基因。结论本研究发现了血压基因座中的 RNAm-SNPs，并阐明了 RNAm-SNPs、基因表达和血压之间的关联。在主动脉细胞中鉴定出的血压相关基因与 AD 相关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chronic Diseases and Translational Medicine Medicine-General Medicine

CiteScore

6.70

自引率

0.00%

发文量

195

审稿时长

35 weeks

期刊介绍： This journal aims to promote progress from basic research to clinical practice and to provide a forum for communication among basic, translational, and clinical research practitioners and physicians from all relevant disciplines. Chronic diseases such as cardiovascular diseases, cancer, diabetes, stroke, chronic respiratory diseases (such as asthma and COPD), chronic kidney diseases, and related translational research. Topics of interest for Chronic Diseases and Translational Medicine include Research and commentary on models of chronic diseases with significant implications for disease diagnosis and treatment Investigative studies of human biology with an emphasis on disease Perspectives and reviews on research topics that discuss the implications of findings from the viewpoints of basic science and clinical practic.