| Title: | The shared genetic architecture underlying the autoimmune and cardiovascular disease: a multivariate genome-wide analysis |
| Journal: | Cardiovascular Diabetology |
| Published: | 11 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41673668/ |
| DOI: | https://doi.org/10.1186/s12933-025-03041-8 |
Publication 18308
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Abstract
BackgroundEpidemiological studies have established that autoimmune diseases (AD) increase cardiovascular disease (CVD) risk. We aimed to elucidate their shared genetic architecture and clinical implications.MethodsWe conducted a cross-trait multivariate genome-wide association study (GWAS) for three autoimmune diseases (type 1 diabetes, systemic lupus erythematosus, and rheumatoid arthritis) and four cardiovascular diseases (coronary artery disease, heart failure, stroke, and peripheral artery disease). We performed both genome-wide and locus-based analysis including fine-mapping, functional annotation, enrichment analyses, transcriptome-wide association studies (TWAS), and proteome-wide and drug-repurposing Mendelian randomization (MR). We constructed a polygenic risk score (PRS) and explored its pleiotropic effects beyond AD and CVD in the UK Biobank population.ResultsIn the multivariate GWAS, we identified 259 genome-wide significant association signals that were enriched primarily in arterial tissues and lipid metabolism pathways. Through convergent evidence from TWAS and MR analyses, we prioritized 15 therapeutic targets including TGFB1 and IL6R, and identified histone deacetylase inhibitors as candidate drugs. The polygenic risk score showed discriminative ability in cardiovascular risk stratification among autoimmune patients, with individuals in the highest PRS decile exhibiting significantly elevated CVD risk compared to those in the 2nd-9th deciles (hazard ratios: 1.60 [95% CI: 1.19-2.15] for type 1 diabetes, 2.28 [95% CI: 1.14-4.56] for systemic lupus erythematosus, and 2.33 [95% CI: 1.94-2.80] for rheumatoid arthritis). Additionally, the PRS revealed pleiotropic associations with risk of various health conditions, including polyneuropathy, chronic renal failure, and depressive episodes.ConclusionOur study unveils the shared genetic architecture between autoimmune and cardiovascular diseases, providing insights for therapeutic development and risk stratification.Graphical abstractIn this multivariate genome-wide association study, we derived a shared genetic factor (Faid_cvd) using seven autoimmune and cardiovascular diseases: rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, coronary artery disease, heart failure, stroke, and peripheral artery disease to describe the shared genetic liability of autoimmune and cardiovascular diseases. We identified the genomic loci, cells, tissues and pathways associated with Faid-cvd, and 15 potential therapeutic target genes or drug repurposing opportunities. We examined the clinical risk stratification performance of the Faid-cvd PRS in individuals of European ancestry in UK biobank. Additionally, we examined the association between Faid-cvd PRS and various health outcomes. PRS, polygenic risk score. MR, Mendelian randomization. transcriptome-wide association studies, TWAS.Graphical abstract</p>
19 Keywords
- Arthritis, Rheumatoid
- Autoimmune Diseases
- Autoimmunity
- Cardiovascular Diseases
- Diabetes Mellitus, Type 1
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Heart Disease Risk Factors
- Humans
- Lupus Erythematosus, Systemic
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Multifactorial Inheritance
- Phenotype
- Polymorphism, Single Nucleotide
- Risk Assessment
- Risk Factors
5 Authors
- Jie Zhang
- Xinyu Fang
- Qianling Ye
- Xianyong Yin
- Dongqing Ye
1 Application
| Application ID | Title |
|---|---|
| 62663 | Evaluation of causal risk factors for autoimmune diseases: evidence from epidemiological studies, phenome-wide Mendelian randomisation study |
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