Systemic lupus erythematosus (SLE) confers up to a 50-fold increased risk of cardiovascular disease (CVD), and African Americans with SLE experience accelerated damage accrual and doubled cardiovascular risk when compared to their European American counterparts.

Genome-wide association studies have identified a substantial signal at 22q13, now assigned to variation at apolipoprotein L1 (APOL1), which has associated with progressive nondiabetic nephropathy, cardiovascular disease, and many immune-associated renal diseases, including lupus nephritis.

We contend that alterations in crucial APOL1 intracellular pathways may underpin associated disease states based on structure-functional differences between variant and ancestral forms. While ancestral APOL1 may be a key driver of autophagy, nonconserved primary structure changes result in a toxic gain of function with attenuation of autophagy and an unsupervised pore-forming feature. Thus, the divergent intracellular biological pathways of ancestral and variant APOL1 may explain a worsened prognosis as demonstrated in SLE.