Genetic and tissue-level analyses prioritize HDL-associated apolipoprotein M in psoriasis.

OBJECTIVE

Dysregulated lipid metabolism is associated with psoriasis, but the HDL-related molecular traits linked to psoriatic disease remain incompletely defined. We integrated epidemiological, Mendelian randomization (MR), and multi-omics analyses to investigate HDL-C and HDL-associated molecular traits in psoriasis.

METHODS

Survey-weighted analyses of NHANES 2013-2014 were used to examine the association between HDL-C and self-reported physician-diagnosed psoriasis. Two-sample MR evaluated genetically predicted HDL-C and psoriasis risk. Eight prespecified HDL-associated genes (APOA1, APOA2, APOC2, APOC3, APOM, CLU, HPR, and PON1) were then assessed using blood cis-eQTL, skin cis-eQTL, and plasma pQTL data with MR and Bayesian colocalization. Prioritized candidates were evaluated using bulk transcriptomics, single-cell RNA sequencing, and immunohistochemistry in an independent skin-biopsy cohort.

RESULTS

In NHANES, HDL-C was modestly lower in participants with psoriasis, but the association was not significant after survey weighting and multivariable adjustment. Genetically predicted higher HDL-C was associated with lower psoriasis risk (OR = 0.940, P < 0.001). Among the eight genes, APOM showed the most consistent genetic support across molecular datasets. APOM expression was reduced in psoriatic lesional skin in two independent transcriptomic cohorts, and apoM immunoreactivity was reduced in biopsy specimens. Single-cell analysis showed sparse APOM detection, with no cell-type-specific differences remaining significant after multiple-testing correction.

CONCLUSION

Integrated genetic and tissue-level evidence prioritizes APOM as an HDL-associated molecular candidate in psoriasis. Further biochemical and functional studies are needed to determine whether lesional APOM/apoM changes relate to circulating apoM, HDL composition, or sphingolipid signaling.