Skovgaard Asmus Cosmos, Nejad Afsaneh M, Beck Hans Christian, Tan Qihua, Soerensen Mette
The Danish Twin Registry and the Research Unit for Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark.
Hypertens Res. 2025 Apr;48(4):1599-1612. doi: 10.1038/s41440-025-02164-5. Epub 2025 Feb 19.
Hypertension is the most frequent health-related condition worldwide and is a primary risk factor for renal and cardiovascular diseases. However, the underlying molecular mechanisms are still poorly understood. To uncover these mechanisms, multi-omics studies have significant potential, but such studies are challenged by genetic and environmental confounding - an issue that can be effectively reduced by studying intra-pair differences in twins. Here, we coupled data on hypertension diagnoses from the nationwide Danish Patient Registry to a study population of 740 twins for whom genome-wide DNA methylation and gene expression data were available together with measurements of systolic and diastolic blood pressure. We investigated five phenotypes: incident hypertension cases, systolic blood pressure, diastolic blood pressure, hypertension (140/90 mmHg), and hypertension (130/80 mmHg). Statistical analyses were performed using Cox (incident cases) or linear (remaining) regression analyses at both the individual-level and twin pair-level. Significant genes (p < 0.05) at both levels and in both types of biological data were investigated by bioinformatic analyses, including gene set enrichment analysis and interaction network analysis. Overall, most of the identified pathways related to the immune system, particularly inflammation, and biology of vascular smooth muscle cell. Of specific genes, lysine methyltransferase 2 A (KMT2A) was found to be central for incident hypertension, ataxia-telangiectasia mutated (ATM) for systolic blood pressure, and beta-actin (ACTB) for diastolic blood pressure. Noteworthy, lysine methyltransferase 2A (KMT2A) was also identified in the systolic and diastolic blood pressure analyses. Here, we present novel biomarkers for hypertension. This study design is surprisingly rare in the field of hypertension. We identified biological pathways related to vascular smooth muscle cells and the immune system, particular inflammation, to be associated with hypertension and blood pressure. Of specific genes, we identified KMT2A (lysine methyltransferase 2A) to be central for blood pressure and hypertension development. ACTB beta-actin, ATM ataxiatelangiectasia mutated, BP blood pressure, EWAS epigenome-wide association studies, KMT2A lysine methyltransferase 2A, LMER linear mixed effect regression, LR linear regression, TWAS transcriptome-wide association studies.
高血压是全球范围内与健康相关的最常见病症，也是肾脏和心血管疾病的主要危险因素。然而，其潜在的分子机制仍知之甚少。为了揭示这些机制，多组学研究具有巨大潜力，但此类研究受到遗传和环境混杂因素的挑战——通过研究双胞胎对内差异可有效减少这一问题。在此，我们将来自丹麦全国患者登记处的高血压诊断数据与740对双胞胎的研究人群相结合，这些双胞胎可获取全基因组DNA甲基化和基因表达数据以及收缩压和舒张压测量值。我们研究了五种表型：新发高血压病例、收缩压、舒张压、高血压（140/90 mmHg）和高血压（130/80 mmHg）。使用Cox（新发病例）或线性（其余）回归分析在个体水平和双胞胎对水平上进行统计分析。通过生物信息学分析，包括基因集富集分析和相互作用网络分析，研究了两种生物数据在两个水平上的显著基因（p < 0.05）。总体而言，大多数鉴定出的途径与免疫系统有关，特别是炎症以及血管平滑肌细胞生物学。在特定基因中，发现赖氨酸甲基转移酶2A（KMT2A）对新发高血压至关重要，共济失调毛细血管扩张症突变基因（ATM）对收缩压至关重要，β-肌动蛋白（ACTB）对舒张压至关重要。值得注意的是，在收缩压和舒张压分析中也鉴定出了赖氨酸甲基转移酶2A（KMT2A）。在此，我们提出了高血压的新型生物标志物。这种研究设计在高血压领域出人意料地罕见。我们确定与血管平滑肌细胞和免疫系统（特别是炎症）相关的生物途径与高血压和血压有关。在特定基因中，我们确定赖氨酸甲基转移酶2A（KMT2A）对血压和高血压发展至关重要。ACTB为β-肌动蛋白，ATM为共济失调毛细血管扩张症突变基因，BP为血压，EWAS为全表观基因组关联研究，KMT2A为赖氨酸甲基转移酶2A，LMER为线性混合效应回归，LR为线性回归，TWAS为全转录组关联研究。
