Mendelian randomization reveals DNA methylation-related pyroptosis genes associated with psoriasis risk.

BACKGROUND

Research has indicated a connection between pyroptosis and psoriasis, yet the specific genes involved remain largely unidentified. This study employed Mendelian randomization (MR) to evaluate the potential causal impact of both pyroptosis-related genes and DNA methylation signatures on psoriasis risk.

METHODS

Pyroptosis-related genes were sourced from the GeneCards database. We integrated quantitative trait locus (QTL) data, including expression (eQTLs), DNA methylation (mQTLs), and protein expression (pQTLs). The GCST90014456 database provided genome-wide association study (GWAS) data for psoriasis, using the FinnGen and UKB cohorts for validation. Summary data-based Mendelian randomization (SMR) analysis assessed interactions between these genes and psoriasis, while colocalization analysis identified shared causal genetic variants.

RESULTS

SMR analysis identified 82 methylation sites, 18 gene, and 2 protein were associated with psoriasis risk. Multi-omics integration highlighted ADAR, which increased methylation at cg27530370 was associated with decreased ADAR expression (OR = 0.505, 95% CI [0.421-0.607]). Additionally, DNMT3B, PROM2, and KIF11 were the intersection genes of mQTL and eQTL analysis, and were validated by the UKB cohort in eQTL analysis, and NFKB1 was validated by the UKB cohort in pQTL analysis.

CONCLUSION

This multi-omics analysis reveals that pyroptosis-related genes, particularly ADAR, DNMT3B, PROM2, KIF11, and NFKB1, may be involved in psoriasis development, providing important insights into its molecular mechanisms and potential therapeutic targets.