Multi-Omics Mendelian Randomization and Clinical Validation Implicate NLRP6 as a Candidate Autophagy-Related Gene in Systemic Lupus Erythematosus.

Background/

Objectives

Autophagy plays a role in systemic lupus erythematosus (SLE) pathogenesis. Nevertheless, the specific genetic determinants underpinning this process remain poorly characterized. Summary data-based Mendelian randomization (SMR) analysis was therefore utilized to pinpoint autophagy-related genes associated with SLE risk.

Methods

We analyzed 700 autophagy-related genes, integrating methylation quantitative trait loci (mQTL), expression QTL (eQTL) from blood and relevant tissue, and protein QTL (pQTL) data with genome-wide association studies (GWAS) data on SLE from the IEU dataset (discovery). GWAS data from FinnGen and the GWAS Catalog were used as replication datasets. Colocalization analysis identified shared genetic variants. Blood samples from 10 healthy control and 20 SLE patients were collected and analyzed for the expression of candidate genes.

Results

Our SMR analysis identified suggestive associations between NLRP6 expression (OR = 0.528, 95%CI = 0.291-0.96) and p27Kip1 protein abundance (OR = 0.269, 95%CI = 0.08-0.904) with SLE susceptibility in the discovery cohort, supported by colocalization evidence. Additionally, we found that the methylation of the NLRP6 promoter (cg06432119) was significantly increased, while NLRP6 expression and p27Kip1 level were significantly decreased in SLE patients compared to controls. Furthermore, NLRP6 mRNA expression was significantly negatively correlated with the SLE severity (SLEDAI-2000).

Conclusions

These findings not only prioritized candidate genes via SMR analysis but also provided evidence of epigenetic dysregulation of NLRP6 and its correlation with disease activity in SLE, thereby offering novel insights into the underlying mechanisms.