Causal Relationship Between Psoriatic Arthritis and Coronary Heart Disease: A Mendelian Randomization and...

Psoriatic arthritis (PsA) often coexists with coronary heart disease (CHD). We integrated Mendelian randomization (MR), bioinformatics and reverse network pharmacology to dissect their causality, biomarkers, candidate therapeutics and transcription factors (TFs).

With PsA and CHD GWAS statistics, five MR methods including inverse variance weighted (IVW), weighted mode, weighted median, simple mode, MR Egger were used to assess causality, followed by sensitivity analyses. We analyzed the differentially expressed genes (DEGs) from the PsA and CHD GEO datasets and identified co-DEGs through intersection. GO, KEGG and GeneMANIA analyses elucidated their functions and pathways. We screened therapeutic candidates through DSigDB and reverse network pharmacology, and mined co-DEGs-related TFs from TRRUST.

The MR analysis revealed genetically predicted PsA confers increased CHD risk (IVW, OR = 1.098, 95% CI 1.016, 1.187, p = 0.018), whereas reverse MR showed no causal effect of CHD on PsA. Our study revealed 71 DEGs from GSE61281 (PsA) and 1116 DEGs from GSE66360 (CHD). The seven intersecting co-DEGs participated in immune recruitment, migration, and inflammatory activation, linked to NF-κB, TLR, and CLR pathways. The drug prediction analysis indicated that prednisone, tretinoin, fumaric acid, adenosine, fenofibrate, and herbal medicines including Salvia miltiorrhiza Bunge, Conioselinum anthriscoides "Chuanxiong", Achyranthes bidentata Blume, along with herbal ingredients like kaempferol and naringenin, might treat the comorbidities. Notably, these candidates were computational predictions requiring subsequent experimental validation. TF prediction for BCL2A1, CSTA and LY96 highlighted related TFs.

Our study validates the PsA-CHD correlation and identifies shared novel molecular characteristics. It offers genetic evidence supporting a causal effect of PsA on CHD (not definitive clinical causation). The predicted drugs and herbs can become candidate targets for subsequent research. Due to the limitations of the European population and the limited sample size of public transcriptome data, our findings require further external validation.