Exploration of the regulatory function of genetic variants at <i>FAM167A-BLK</i> locus in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with multi-organ involvement. The <i>FAM167A-BLK</i> locus at 8p23 has been identified as a genetic susceptibility locus for SLE by previous genome-wide association studies (GWAS). To explore the role of functional single-nucleotide polymorphisms (SNPs) within this locus on the regulation of <i>BLK</i> and <i>FAM167A</i> genes, we perform comprehensive functional annotation using GCTA and fnGWAS approaches to identify candidate functional SNPs，and verify them through dual-luciferase reporter assays, shRNA knockdown experiments, and CRISPR/dCas9 knockdown experiments. The results show that four functional SNPs exhibit allele-specific enhancing effect on <i>BLK</i> expression, while showing no discernible regulatory influence on <i>FAM167A</i> expression. Importantly, <i>BLK</i> is shown to regulate the expression of <i>FAM167A</i>. These findings highlight <i>FAM167A</i> as a potential pathogenic gene contributing to SLE. This study expands the mechanistic understanding of genetic regulation at the <i>FAM167A-BLK</i> locus and provides new insights into SLE development.