Cardiometabolic Candidate Endotypes in Psoriatic Disease: Integration of Clinical, Metabolic, and Immunogenetic Data Across Psoriasis and Psoriatic Arthritis

Background/objectives: Psoriatic disease (PsD) encompasses psoriasis (PsO) and psori-atic arthritis (PsA) and is associated with heterogeneous cardiometabolic risk. Inte-grating immunogenetic markers such as HLA-Cw6 into data-driven analyses may re-fine phenotyping and uncover clinically meaningful endotypes. We aimed to identify cardiometabolic phenotypes across PsD, integrating HLA-Cw6 and exploring dis-ease-specific heterogeneity and predictors of high-risk profiles. Methods: In a cross-sectional study of 572 PsD patients (401 PsO, 171 PsA), eight demographic and clinical variables including HLA-Cw6 were entered into k-means clustering (k = 4). Cardiometabolic risk factors were profiled post hoc. Cluster validity was assessed by Gaussian Mixture Models and principal component analysis (PCA). Stratified analyses (k = 3) were conducted separately for PsO and PsA. Predictors of the high-risk pheno-type were examined using bootstrap-resampled logistic regression. Results: Four global clusters were identified, ranging from inflammation-dominant/low-risk to a small high-risk group (C4, 5.8 %). C4 combined older age (median 66 years) with universal CVD and the highest prevalence of hypertension (75.8 %) and dyslipidemia (69.7 %). PCA confirmed two dominant orthogonal axes: cardiometabolic and inflammato-ry/immunogenetic. Validation showed high concordance (adjusted Rand index 0.83). In stratified analyses, HLA-Cw6 showed opposite associations—enriched in high-risk PsO (OR 2.0, 95 % CI 1.3–3.1) but depleted in high-risk PsA (OR 0.24, 95 % CI 0.11–0.52). Conclusions: Incorporating HLA-Cw6 into clustering identified reproducible cardiometabolic phenotypes with distinct genetic signatures. The inverse HLA Cw6–risk patterns in PsO and PsA suggest disease-specific endotypes with differing cardi-ometabolic trajectories, supporting genetic–clinical integration for targeted prevention.