Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sjögren’s disease for cardiovascular disease
Abstract Objectives This study aims to clarify the genetic associations between Sjögren’s Disease (SD) and cardiovascular disease (CVD) outcomes, and to conduct an in-depth exploration of specific pleiotropic susceptibility genes. Methods We performed two-sample and multivariable Mendelian randomiza...
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BMC
2025-05-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06568-2 |
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| author | Xinglin Yi Erxiong Liu Yong Wang |
| author_facet | Xinglin Yi Erxiong Liu Yong Wang |
| author_sort | Xinglin Yi |
| collection | DOAJ |
| description | Abstract Objectives This study aims to clarify the genetic associations between Sjögren’s Disease (SD) and cardiovascular disease (CVD) outcomes, and to conduct an in-depth exploration of specific pleiotropic susceptibility genes. Methods We performed two-sample and multivariable Mendelian randomization (MR) analysis to investigate the association between SD and the risk of ischemic heart disease (IHD) and stroke. Linkage disequilibrium score regression (LDSC) and Bayesian co-localization analyses were employed to assess the genetic associations between traits. Cross-phenotype analyses were employed to identify shared variants and genes, followed by a Transcriptome-Wide Association Study (TWAS) and Multi-marker Analysis of Genomic Annotation (MAGMA) based on Multi-Trait Analysis of GWAS (MTAG) results. To validate the pleiotropic genes, we further analyzed tissue-specific differentially expressed genes (DEGs) related to SD using RNA sequencing data. Results The two-sample and multivariable MR analyses revealed that SD confers a genetic vulnerability to IHD and stroke. LDSC and co-localization analyses indicated a strong genetic linkage between SD and CVDs. Cross-phenotype analyses identified 38 and 37 pleiotropic single nucleotide polymorphisms (SNPs) for SD-Stroke and SD-IHD, respectively, primarily located within the MHC class region on 6p21.32:33 loci. Additionally, TWAS and MAGMA analyses identified pleiotropic genes located outside the MHC regions—seven associated with stroke (UHRF1BP1, SNRPC, BLK, FAM167A, ARHGAP27, C8orf12, and PLEKHM1) and two associated with IHD (UHRF1BP1 and SNRPC). Proxy variants within these genes in SD suggested an increased causal risk for stroke or IHD. Co-localization analysis further reinforced that SD and stroke share significant SNPs within the loci of FAM167A, BLK, C8orf12, SNRPC, and UHRF1BP1. DEG analysis revealed a significant up-regulation of the identified genes in SD-specific tissues. Conclusions SD appears genetically predisposed to an increased risk of CVDs. Moreover, this research not only identified pleiotropic genes shared between SD and CVDs, but also, for the first time, detected key gene expressions that elevate CVD risk in SD patients—findings that may offer promising therapeutic targets for patient management. |
| format | Article |
| id | doaj-art-cfc103e4cf1f465d884c18067bca03c5 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-cfc103e4cf1f465d884c18067bca03c52025-08-20T03:48:02ZengBMCJournal of Translational Medicine1479-58762025-05-0123111810.1186/s12967-025-06568-2Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sjögren’s disease for cardiovascular diseaseXinglin Yi0Erxiong Liu1Yong Wang2Department of Respiratory and Critical Care Medicine, Southwest Hospital, Army Medical University (the Third Military Medical University)Department of Rheumatology and Immunology, Southwest Hospital, Army Medical University (the Third Military Medical University)Department of Rheumatology and Immunology, Southwest Hospital, Army Medical University (the Third Military Medical University)Abstract Objectives This study aims to clarify the genetic associations between Sjögren’s Disease (SD) and cardiovascular disease (CVD) outcomes, and to conduct an in-depth exploration of specific pleiotropic susceptibility genes. Methods We performed two-sample and multivariable Mendelian randomization (MR) analysis to investigate the association between SD and the risk of ischemic heart disease (IHD) and stroke. Linkage disequilibrium score regression (LDSC) and Bayesian co-localization analyses were employed to assess the genetic associations between traits. Cross-phenotype analyses were employed to identify shared variants and genes, followed by a Transcriptome-Wide Association Study (TWAS) and Multi-marker Analysis of Genomic Annotation (MAGMA) based on Multi-Trait Analysis of GWAS (MTAG) results. To validate the pleiotropic genes, we further analyzed tissue-specific differentially expressed genes (DEGs) related to SD using RNA sequencing data. Results The two-sample and multivariable MR analyses revealed that SD confers a genetic vulnerability to IHD and stroke. LDSC and co-localization analyses indicated a strong genetic linkage between SD and CVDs. Cross-phenotype analyses identified 38 and 37 pleiotropic single nucleotide polymorphisms (SNPs) for SD-Stroke and SD-IHD, respectively, primarily located within the MHC class region on 6p21.32:33 loci. Additionally, TWAS and MAGMA analyses identified pleiotropic genes located outside the MHC regions—seven associated with stroke (UHRF1BP1, SNRPC, BLK, FAM167A, ARHGAP27, C8orf12, and PLEKHM1) and two associated with IHD (UHRF1BP1 and SNRPC). Proxy variants within these genes in SD suggested an increased causal risk for stroke or IHD. Co-localization analysis further reinforced that SD and stroke share significant SNPs within the loci of FAM167A, BLK, C8orf12, SNRPC, and UHRF1BP1. DEG analysis revealed a significant up-regulation of the identified genes in SD-specific tissues. Conclusions SD appears genetically predisposed to an increased risk of CVDs. Moreover, this research not only identified pleiotropic genes shared between SD and CVDs, but also, for the first time, detected key gene expressions that elevate CVD risk in SD patients—findings that may offer promising therapeutic targets for patient management.https://doi.org/10.1186/s12967-025-06568-2Sjögren’s diseaseCardiovascular diseaseGenome-wide association studyMendelian randomization |
| spellingShingle | Xinglin Yi Erxiong Liu Yong Wang Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sjögren’s disease for cardiovascular disease Journal of Translational Medicine Sjögren’s disease Cardiovascular disease Genome-wide association study Mendelian randomization |
| title | Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sjögren’s disease for cardiovascular disease |
| title_full | Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sjögren’s disease for cardiovascular disease |
| title_fullStr | Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sjögren’s disease for cardiovascular disease |
| title_full_unstemmed | Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sjögren’s disease for cardiovascular disease |
| title_short | Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sjögren’s disease for cardiovascular disease |
| title_sort | post genome wide association study dissects genetic vulnerability and risk gene expression of sjogren s disease for cardiovascular disease |
| topic | Sjögren’s disease Cardiovascular disease Genome-wide association study Mendelian randomization |
| url | https://doi.org/10.1186/s12967-025-06568-2 |
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