Cardiovascular disease pathways associated with psoriasis, but not other immune-mediated diseases

In a recent study published in JAMA Cardiology, researchers investigated whether hereditary risk for cardiovascular illness predisposes individuals to immune-mediated disorders (IMIDs).

Background

Researchers link immune-mediated disorders and cardiovascular illness to systemic inflammatory processes. However, causation, confounding variables, and biological processes remain unknown.

Psoriasis is an excellent model for investigating this interaction since severe psoriasis is an independent risk factor for cardiovascular disease development. Cardiovascular risk factors, obesity, and dyslipidemia are common in the psoriasis community, particularly in those with severe cases.

Mechanistic evidence supports the hypothesis that psoriasis-associated systemic inflammation drives this causal link. Overactivation of the interleukin 17/23 pathway, its presence in blood and carotid atherosclerotic plaques, and targeted blockage enhance imaging-based indicators of subclinical coronary artery disease (CAD) in psoriasis patients, prompting some to call for early intervention to reduce cardiovascular risks.

About the study

In the present genetic association study, researchers examined the bidirectional links between genetic estimators of cardiovascular illness and IMIDs like psoriasis.

Mendelian randomizations (MR) assessed causality between the diseases. Researchers conducted a two-sample MR evaluation for each variable with summary-level information from the United Kingdom Biobank genome-wide association meta-analytic studies (GWAS).

The study exposures included genetic estimators of stroke, CAD, psoriasis, and nine additional IMIDs. These included asthma, atopic dermatitis, acne, Crohn's disease, celiac disease, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and ulcerative colitis.

The primary study outcomes included the associations between genetic estimators of coronary artery disease and stroke and risks of psoriatic disease and nine other IMIDs. Mendelian randomizations with inverse variance weighting (IVW) determined the associations. The data analysis period went from January 2023 until May 2024.

The researchers computed the odds ratio (OR) for the analysis. Study covariates were waist-to-hip ratio, BMI, blood pressure, smoking, glycated hemoglobin, LDL, total cholesterol, and triglycerides.

The researchers stratified cardiovascular genetic risk factors by medications, sex-related differences, human leukocyte antigen-C06:02 (HLA-C*06:02) status (primary allele for psoriasis susceptibility), and CAD cases (versus controls) to examine associations primarily among Europeans. They performed sensitivity analyses using simple median, weighted median, MR-Egger, MR-PRESSO, and MR-Lasso. MR-Steiger tests assessed the directionality of the genetic instrument. Cochran Q statistics indicated heterogeneity.

Results

The analysis comprised 181,249 patients with CAD and 1,165,690 control individuals, 110,182 patients of stroke and 1,503,898 control individuals, and 36,466 patients of psoriasis and 458,078 control individuals among nearly 3,400,000 people. Contrasting prior assumptions, genetic estimators of psoriasis showed no relationship with stroke or CAD. Reverse association analyses showed that genetic estimators of stroke (MR estimated and IV-weighted OR, 1.2) and CAD (OR, 1.1) showed risk-enhancing relationships with psoriasis.

After adjustments for stroke, the relationships between genetically estimated CAD and psoriasis risk became non-significant (also vice versa), showing that shared impacts underlying hereditary risks for stroke and CAD are related to an elevated risk of psoriasis.

The researchers found no risk-elevating connections between genetic estimators of cardiovascular illness and other common immune-related diseases, such as inflammatory bowel disease (IBD) and rheumatoid arthritis. The data showed that the correlations might be particular to psoriasis.

Sensitivity analyses and confounding adjustments produced similar findings. There were no differences in stroke or CAD Mendelian randomization effects on psoriasis between subgroups based on gender or HLA-C*06:02 status. Individuals on angiotensin-converting enzyme (ACE) inhibitors, β-blockers, angiotensin receptor blockers (ARBs), aspirin, or statins did not have increased effects on psoriasis from cardiovascular MR.

The findings suggest that drugs widely used to treat cardiovascular illness are unlikely to cause the observed cardiovascular MR effects.

Conclusions

The study showed that genetic estimators of cardiovascular illness were related to an increased risk of psoriasis without reciprocal effects or associations with other immune-mediated disorders. Since inflammation is crucial to cardiovascular disease pathophysiology, the shared mechanism that links these features may include an inflammatory component. According to the study, biological processes influencing cardiovascular disease risk may also influence the causative biology of psoriasis.

The findings could have significant implications for managing and preventing cardiovascular disease in psoriasis. Monitoring cardiovascular health and implementing early treatments to lower the risk of cardiovascular illness in people with psoriasis may potentially help with the treatment of the disease.

The discoveries might accelerate biomarker identification and lead to the development of innovative therapeutic techniques that target shared inflammatory pathways, thereby benefiting both psoriasis treatment and cardiovascular disease prevention.

Journal reference: