Deciphering the Genetic Link: APOL1 Missense Mutations and Their Association with ESKD Risk Beyond MYH9

The APOL1 gene, encoding apolipoprotein L-1, is linked to various biological functions including trypanosomal lysis, autophagy, lipid metabolism, and vascular processes. Recent findings from the 1000 Genomes Project have highlighted two specific missense mutations within APOL1, S342G and I384M, which are predominantly found in western African populations and are more strongly associated with end stage kidney disease (ESKD) than previously known MYH9 variants. The distribution of these APOL1 mutations correlates with the risk of ESKD in African ancestry populations, which was previously attributed to MYH9.

Previous studies have implicated MYH9, a gene encoding a major cytoskeletal protein, in the development of certain ESKD forms, such as HIV-associated nephropathy and focal segmental glomerulosclerosis. Despite extensive research and identification of coding region mutations in MYH9 associated with Giant Platelet Syndromes, no definitive causative mutation for ESKD was found within MYH9.

The identification of APOL1 variants has emerged as a significant advancement in understanding the genetic factors contributing to ESKD, particularly in populations of African descent. The discovery of these mutations has shifted the focus from MYH9 to APOL1 as a key genetic determinant of ESKD risk.