A Non-Coding Variant in SLC15A4 Drives Lysosomal Deacidification and Lupus Susceptibility.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic basis. Despite the identification of several single nucleotide polymorphisms (SNPs) near the SLC15A4 gene that are significantly associated with SLE across multiple populations, specific causal SNP(s) and molecular mechanisms responsible for disease susceptibility are unknown. To address this gap, we employed bioinformatics, expression quantitative trait loci (eQTLs), and 3D chromatin interaction analysis to nominate a likely functional variant, rs35907548, in an active intronic enhancer of SLC15A4 . Through luciferase reporter assays followed by chromatin immunoprecipitation-qPCR, we identified significant allele-specific enhancer effects of rs35907548 in diverse cell lines. The rs35907548 risk allele T is associated with increased regulatory activity and target gene expression, as shown by eQTLs and chromosome conformation capture (3C)-qPCR. The latter revealed long-range chromatin interactions between the rs35907548 enhancer and the promoters of SLC15A4, GLTLD1 , and an uncharacterized lncRNA. The enhancer-promoter interactions and expression effects were validated by CRISPR/Cas9 knock-out of the locus in HL60 promyeloblast cells. Further, KO cells had dysregulated endolysosomal pH. This study highlights the significance of a non-coding variant, rs35907548, which may have a direct impact on the underlying regulatory mechanisms associated with SLE.