The Variant rs2706682 at PITPNC1, Which Enhances Vehicular Secretion, Associated With Systemic Lupus Erythematosus Susceptibility in Chinese Populations.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease in which genetic and environmental factors play important role in SLE pathogenesis. Recently, cytoplasmic phosphatidylinositol transfer protein 1 (PITPNC1) was reported to be capable of enhancing vesicular secretion, which was correlated with autoimmune disorders contributing to SLE. Here, we aimed to explore the genetic association between PITPNC1 polymorphisms and SLE susceptibility. The genetic association analysis included two cohorts: a discovery cohort (490 SLE cases vs. 493 healthy controls) and replication cohort (1003 SLE cases and 815 healthy controls). rSNPBASE, RegulomeDB databases, and Three-dimensional (3D) chromatin looping data were used for functional annotation, and luciferase reporter assay was performed for validation. The expression data from ArrayExpress were used for PITPNC1 gene expression analysis. Three variants (rs4239092, p = 3.04×10-2; rs6504516, p = 3×10-2; rs2706682, p = 3.88×10-4) were significantly associated with the increased susceptibility to SLE in a previous GWAS cohort. The prominent rs2706682 was successfully replicated (p = 1.44×10-3), and the significance of genetic association was reinforced reaching 6.21×10-6 (OR 2.36, 95% CI 1.63-3.42). Functional analysis showed that rs2706682 is a regulatory SNP located within the strong transcription and enhancer chromatin state region. Further, dual-luciferase reporter gene assay demonstrated that the risk G allele correlated with increased expression. Finally, the gene expression analysis showed that the level of PITPNC1 expression was significantly higher in patients with SLE. Our study identified that the variant rs2706682 in PITPNC1, encoding an important player in enhancing extracellular vesicles, was associated with SLE susceptibility.