The <i>APOL1</i> p.N264K variant is co-inherited with the G2 kidney disease risk variant through a proximity recombination event

Black Americans are 3-4 times more likely to develop nondiabetic kidney disease than other populations. Exclusively found in people of recent African (AFR) ancestry, risk variants in Apolipoprotein L1 (APOL1) termed G1 and G2 contribute significantly to this increased susceptibility. Our group and others showed that a missense variant in APOL1, rs73885316 (p.N264K, "M1"), is remarkably protective against APOL1 kidney disease when co-inherited with the G2 risk allele. Since the distance between the M1 and G2 variants is only 367 base pairs, we initially suspected that 2 independent mutation events occurred to create non-risk M1-G0 and M1-G2 haplotypes. Here, we examined APOL1 haplotypes in individuals of AFR ancestry from the 1000 Genomes Project, the Nephrotic Syndrome Study Network (NEPTUNE), and an ancient individual from the Allen Ancient Genome Diversity Project to determine how the M1-G2 haplotype arose. We demonstrate that M1 most likely first appeared on a non-risk G0 haplotype, and that a subsequent recombination event bypassed strong recombination hotspots flanking APOL1 and occurred between p.N388Y389del on a G2 haplotype and M1 on a G0 haplotype to create the M1-G2 haplotype. Observing a recombination event within a small region between clinically relevant loci emphasizes the importance of studying the entire haplotype repertoire of a disease gene and the impact of haplotype backgrounds in disease susceptibility.