Simeone Christopher A, McNulty Michelle T, Gupta Yask, Genovese Giulio, Sampson Matthew G, Sanna-Cherchi Simone, Friedman David J, Pollak Martin R
Harvard Medical School, Boston, MA 02215, USA.
Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
G3 (Bethesda). 2025 Feb 5;15(2). doi: 10.1093/g3journal/jkae290.
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.
非裔美国人患非糖尿病肾病的可能性是其他人群的3至4倍。载脂蛋白L1（APOL1）中的风险变异G1和G2仅在近期有非洲（AFR）血统的人群中发现，它们对这种易感性增加有显著影响。我们团队和其他研究表明，APOL1中的一个错义变异rs73885316（p.N264K，“M1”）与G2风险等位基因共同遗传时，对APOL1肾病具有显著的保护作用。由于M1和G2变异之间的距离仅为367个碱基对，我们最初怀疑发生了2次独立的突变事件，以产生无风险的M1-G0和M1-G2单倍型。在这里，我们研究了来自千人基因组计划、肾病综合征研究网络（NEPTUNE）的AFR血统个体以及艾伦古代基因组多样性计划中的一个古代个体的APOL1单倍型，以确定M1-G2单倍型是如何产生的。我们证明M1最有可能首先出现在无风险的G0单倍型上，随后的重组事件绕过了APOL1侧翼的强重组热点，发生在G2单倍型上的p.N388Y389del和G0单倍型上的M1之间，从而产生了M1-G2单倍型。在临床相关位点之间的小区域内观察到重组事件，强调了研究疾病基因的整个单倍型库以及单倍型背景对疾病易感性影响的重要性。
