Identification of genetic variants in B cell expressed genes associated with systemic lupus erythematosus in African American females.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by dysregulated B cell responses and pathogenic autoantibody production. Given the central role that B cells play in SLE pathogenesis, we aimed to characterize genetic variation within the B cell compartment of African ancestry (AFR) women with SLE who are disproportionately and more severely affected by SLE. Here, we analyzed RNA-seq data from a previously published study of high disease activity AFR SLE individuals and healthy controls (HC) to identify coding variants in B cells with potential functional consequence that may underpin disease. In this cohort, we identified 575 missense variants associated with 158 unique genes. While many variant-containing genes did not exhibit large transcriptional changes between cohorts, a subset occurred within genes involved in B cell signaling, activation, and differentiation. However, genes enriched in AFR SLE were consistently upregulated across multiple B cell subtypes, suggesting that variant-associated transcriptional changes occur broadly across the B cell compartment and not within a single subset. Among these, the TNFAIP3 variant rs2230926 was enriched in AFR SLE individuals and occurs at a substantially higher allele frequency in AFR populations. This study provides insights into genetic variation found within the B cell compartment that may contribute to immune dysregulation and disease pathogenesis in SLE in AFR populations.