APOL1 variants and kidney disease in people of recent African ancestry
Stanley Center, Broad Institute, Cambridge, MA 02142, USA. Nature Reviews Nephrology
(Impact Factor: 8.54).
02/2013; 9(4). DOI: 10.1038/nrneph.2013.34
Coding variants within the APOL1 gene have been associated with kidney disease, explaining an association that was previously attributed to variants within the neighbouring MYH9 gene. To better define the role of APOL1 in causing kidney disease in individuals of African ancestry, we performed an extensive survey of the common variation in the region surrounding the APOL1 gene, as seen through the lens of the 1000 Genomes Project. Arguing by exclusion, it is reasonable to conclude that the putative APOL1 causal variants are not proxies for any other variants with more direct roles in kidney disease. Our statistical argument is in part made possible by the exceptionally young age of the APOL1 coding variants coupled with the unusually high rate of genetic recombination surrounding this gene. Although no biological evidence currently exists for the causality of APOL1 variants with kidney disease, our statistical reasoning provides a strong case for causality, and a region to target in future functional studies.
Available from: Waldemar Popik
- "Cumulative evidence over many years have demonstrated that African Americans (AAs) develop 4–5 fold higher rates of diverse forms of progressive kidney disease, including focal segmental glomerulosclerosis (FSGS), HIVAN, and hypertension-attributed end stage kidney disease (ESKD), compared with European Americans (EAs) (Tzur et al., 2010; Kopp et al., 2011; Quaggin and George, 2011; Genovese et al., 2013; Kasembeli et al., 2015). In several forms of nephropathy, this disparity reaches a greater than 10-fold difference. "
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ABSTRACT: Increasing lines of evidence have demonstrated that the development of higher rates of non-diabetic glomerulosclerosis (GS) in African Americans can be attributed to two coding sequence variants (G1 and G2) in the Apolipoprotein L1 (APOL) gene. Recent studies indicate that the gene products of these APOL1 risk variants have augmented toxicity to kidney cells. However, the biological characteristics of APOL1 and its risk variants are not well elucidated. The APOL1 protein can be divided into several functional domains, including signal peptide (SP), pore forming domain (PFD), membrane address domain (MAD), and SRA-interacting domain. To investigate the relative contribution of each domain to cell injury, we constructed a serial expression vectors to delete or express each domain. These vectors were transfected into the human embryonic kidney cell line 293T, and then compared the cytotoxicity. In addition, we conducted studies in which APOL1 wild type (G0) was co-transfected in combination with G1 or G2 to see whether G0 could counteract the toxicity of the risk variants. The results showed that deleting the SP did not abolish the toxicity of APOL1, though deletion of 26 amino acid residues of the mature peptide at the N-terminal partially decreased the toxicity. Deleting PFD or MAD or SRA-interacting domain abolished toxicity, while, overexpressing each domain alone could not cause toxicity to the host cells. Deletion of the G2 sites while retaining G1 sites in the risk state resulted in persistent toxicity. Either deletion or exchanging the BH3 domain in the PFD led to complete loss of the toxicity in this experimental platform. Adding G0 to either G1 or G2 did not attenuate the toxicity of the either moiety. These results indicate that the integrity of the mature APOL1 protein is indispensable for its toxicity. Our study not only reveals the contribution of each domain of the APOL1 protein to cell injury, but also highlights some potential suggested targets for drug design to prevent or treat APOL1-associated nephropathy.
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ABSTRACT: Dramatic improvements have been seen in short-term kidney allograft survival over recent decades with introduction of more potent immunosuppressant medications and regimens. Unfortunately, improvements in long-term graft survival have lagged behind. The genomics revolution is providing new insights regarding the potential impact of kidney donor genotypes on long-term graft survival. Variation in the donor apolipoprotein L1 (APOL1), caveolin 1 (CAV1), and multi-drug resistance 1 encoding P-glycoprotein genes (ABCB1) are all associated with graft survival after kidney transplantation. Although the precise mechanisms whereby these donor gene variants confer risk for graft loss have yet to be determined, these findings provide novel opportunities for modifying interactive environmental factors and optimizing kidney allocation with the ultimate goal of improving long-term graft survival rates.
Available from: Debbie L Cohen
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