银屑病与四种心血管疾病的遗传共病:揭示共同机制和潜在治疗靶点

IF 3.1 3区 医学 Q1 DERMATOLOGY
Xiaojian Li, Zhangren Yan, Hongrong Lan, Yanyu Wu, Shiyu Chen, Guirong Qiu, Yunbo Wu
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引用次数: 0

摘要

银屑病(PSO)是一种慢性、全身性免疫介导的炎症性疾病,已越来越多地被认为与各种心血管疾病(cvd)共病。然而,潜在的共享遗传结构和连接这些条件的生物机制在很大程度上仍然不清楚。本研究旨在系统评估PSO与四种主要心血管疾病(高血压、冠心病、冠状动脉粥样硬化和心力衰竭)之间的遗传相关性,并确定共享的遗传位点、功能基因和免疫介导的途径,这些基因可能作为合并症干预的潜在靶点。我们整合了多个大规模公开的全基因组关联研究数据集,并采用了多维遗传分析框架。这包括连锁不平衡评分回归(LDSC)、高清晰度似然(HDL)、分层LDSC (S-LDSC)、多维基因集浓缩(MAGMA)、复合零假设下的多效性分析(PLACO)和基于汇总数据的孟德尔随机化(SMR)。这些方法被用来阐明共享的遗传结构,并功能性地注释PSO-CVD合并症的生物学机制。LDSC和HDL分析显示PSO与所有四种cvd之间存在显著的正遗传相关性(p < 0.05)。PLACO共鉴定出653个多效性snp,富集于12q24.12(如SH2B3、BRAP)和5q31.1(如IL3、C5orf56)等关键基因组位点。S-LDSC结果显示,这些共同信号在疾病相关组织中显著富集,包括主动脉、冠状动脉、外周血和脾脏。免疫共定位分析进一步强调了T细胞、单核/巨噬细胞和NK细胞参与PSO和cvd的遗传共病。结合MAGMA、SMR和FUMA的综合分析发现了多个潜在的治疗靶点,如APOE、IL13和C5orf56,这些靶点可能在这两种疾病的发病机制中发挥关键作用。本研究首次对PSO和cvd的合并症进行了全面的遗传解剖。我们提出了一个“遗传-免疫-组织”的调节模型,其基础是共同的病理生理。我们的研究结果为PSO作为一种全身性疾病可能影响心血管病理生理提供了潜在的证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genetic Comorbidity of Psoriasis and Four Cardiovascular Diseases: Uncovering Shared Mechanisms and Potential Therapeutic Targets

Psoriasis (PSO) is a chronic, systemic immune-mediated inflammatory disease that has been increasingly recognised as being significantly comorbid with various cardiovascular diseases (CVDs). However, the underlying shared genetic architecture and biological mechanisms connecting these conditions remain largely unclear. This study aimed to systematically evaluate the genetic correlations between PSO and four major CVDs—hypertension, coronary heart disease, coronary atherosclerosis, and heart failure—and to identify shared genetic loci, functional genes, and immune-mediated pathways that may serve as potential targets for comorbidity intervention. We integrated multiple large-scale publicly available genome-wide association study datasets and employed a multidimensional genetic analysis framework. This included linkage disequilibrium score regression (LDSC), high-definition likelihood (HDL), stratified LDSC (S-LDSC), multi-dimensional gene-set enrichment (MAGMA), pleiotropy analysis under the composite null hypothesis (PLACO), and summary-data-based Mendelian randomisation (SMR). These approaches were used to elucidate the shared genetic architecture and to functionally annotate the biological mechanisms underlying PSO–CVD comorbidity. LDSC and HDL analyses revealed significant positive genetic correlations between PSO and all four CVDs (p < 0.05). PLACO identified a total of 653 pleiotropic SNPs, enriched in key genomic loci such as 12q24.12 (e.g., SH2B3, BRAP) and 5q31.1 (e.g., IL3, C5orf56). S-LDSC results demonstrated significant enrichment of these shared signals in disease-relevant tissues including the aorta, coronary arteries, peripheral blood, and spleen. Immune colocalization analysis further highlighted the involvement of T cells, monocytes/macrophages, and NK cells in the genetic comorbidity between PSO and CVDs. Integrative analyses combining MAGMA, SMR, and FUMA identified multiple potential therapeutic targets, such as APOE, IL13, and C5orf56, that may play key roles in the pathogenesis of both diseases. This study provides the first comprehensive genetic dissection of the comorbidity between PSO and CVDs. We propose a “genetics–immunity–tissue” regulatory model underlying the shared pathophysiology. Our findings provide potential evidence that PSO, as a systemic condition, may influence cardiovascular pathophysiology.

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来源期刊
Experimental Dermatology
Experimental Dermatology 医学-皮肤病学
CiteScore
6.70
自引率
5.60%
发文量
201
审稿时长
2 months
期刊介绍: Experimental Dermatology provides a vehicle for the rapid publication of innovative and definitive reports, letters to the editor and review articles covering all aspects of experimental dermatology. Preference is given to papers of immediate importance to other investigators, either by virtue of their new methodology, experimental data or new ideas. The essential criteria for publication are clarity, experimental soundness and novelty. Letters to the editor related to published reports may also be accepted, provided that they are short and scientifically relevant to the reports mentioned, in order to provide a continuing forum for discussion. Review articles represent a state-of-the-art overview and are invited by the editors.
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