{"title":"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","authors":"Xiaojian Li, Zhangren Yan, Hongrong Lan, Yanyu Wu, Shiyu Chen, Guirong Qiu, Yunbo Wu","doi":"10.1111/exd.70158","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>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 (<i>p</i> < 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.</p>\n </div>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 8","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genetic Comorbidity of Psoriasis and Four Cardiovascular Diseases: Uncovering Shared Mechanisms and Potential Therapeutic Targets\",\"authors\":\"Xiaojian Li, Zhangren Yan, Hongrong Lan, Yanyu Wu, Shiyu Chen, Guirong Qiu, Yunbo Wu\",\"doi\":\"10.1111/exd.70158\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>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 (<i>p</i> < 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.</p>\\n </div>\",\"PeriodicalId\":12243,\"journal\":{\"name\":\"Experimental Dermatology\",\"volume\":\"34 8\",\"pages\":\"\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2025-08-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Dermatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/exd.70158\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"DERMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Dermatology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/exd.70158","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"DERMATOLOGY","Score":null,"Total":0}
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.
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.