More than 500,000 Americans suffer from end-stage renal disease (ESRD). African Americans develop kidney failure at rates 4-5 fold higher than European Americans. Recently, we discovered two coding sequence variants in ApolipoproteinL1 (APOL1) that account for a large proportion of this major health disparity. APOL1 kidney disease variants have a major impact on multiple different types of kidney disease including hypertension-associated ESRD, focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy (HIVAN). Risk inheritance is recessive: individuals with two variant APOL1 alleles have a 7-30 fold increased risk for kidney disease. We predict that more than 3.5 million African Americans have the high risk APOL1 genotype. The presence of two risk alleles does not lead to kidney disease in all individuals, indicating that other genetic and environmental factors are important modifiers. Understanding why some individuals with the high-risk genotype develop kidney disease while others do not will improve risk stratification and may illuminate the pathways most amenable to therapy. We therefore propose to:
Aim 1 : Identify additional genetic modifiers at the APOL1 gene locus. Our data suggest that APOL1 kidney disease risk variants are gain-of- function alleles. Since not all individuals with two risk alleles develop disease, other local polymorphisms may regulate expression of APOL1, modulating the effect of the disease-causing APOL1 coding mutations. We will define structural variants that may alter APOL1 gene expression, and test their effects on the penetrance of the two disease-causing alleles. We will test whether polymorphisms in transcription factor and microRNA binding sites affect the penetrance of these APOL1 risk alleles.
Aim 2 : Find epistatic modifiers of APOL1 penetrance. The APOL1 renal risk variants increased in frequency in Africa, at least in part, because they provided protection against trypanosomes. We hypothesize that additional genetic loci were simultaneously selected that protect against renal injury from the major coding risk alleles, and that the protective effect of these loci may have diminished after admixture with Europeans. Here, we will perform a genome-wide screen for polymorphisms that may protect against or exacerbate APOL1 variant-induced renal injury. We will identify proteins that bind differentially to wild type and coding variant ApoL1, as these binding partners may modulate injury caused by the risk variants.
Aim 3 : Identify biochemical modifiers of APOL1-mediated renal disease. ApoL1 kidney disease risk variants may be most deleterious in the setting of additional risk factors. Here, we explore how two important factors may interact with APOL1 genotype to cause renal disease. Vitamin D is believed to be protective against renal injury, while certain lipid profiles may promote injury. We ask whether these molecules alter APOL1 biology in vitro, and whether biochemical levels of these mediators predict which individuals with the APOL1 risk genotype are likely to develop kidney disease.
We have recently found that specific genetic variants in the APOL1 gene account for the very high rate of kidney disease in African Americans, and also confer resistance to Sleeping Sickness in Africa. We now want to understand the factors that combine with the high risk APOL1 genotype to cause overt kidney disease. Understanding how these differences in the APOL1 gene cause kidney disease in African Americans will have direct implications for improving all aspects of care for the growing number of people with this serious public health problem and for reducing the very large disparity in the rates of kidney disease.
|Zhang, Jia-Yue; Wang, Minxian; Tian, Lei et al. (2018) UBD modifies APOL1-induced kidney disease risk. Proc Natl Acad Sci U S A 115:3446-3451|
|Skorecki, Karl L; Lee, Jessica H; Langefeld, Carl D et al. (2018) A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy. Nephrol Dial Transplant 33:323-330|
|Olabisi, Opeyemi A; Heneghan, John F (2017) APOL1 Nephrotoxicity: What Does Ion Transport Have to Do With It? Semin Nephrol 37:546-551|
|Wang, Hanghang; Pun, Patrick H; Kwee, Lydia et al. (2017) Apolipoprotein L1 Genetic Variants Are Associated with Chronic Kidney Disease but Not with Cardiovascular Disease in a Population Referred for Cardiac Catheterization. Cardiorenal Med 7:96-103|
|Friedman, David J; Pollak, Martin R (2016) Apolipoprotein L1 and Kidney Disease in African Americans. Trends Endocrinol Metab 27:204-215|
|Mukamal, Kenneth J; Tremaglio, Joseph; Friedman, David J et al. (2016) APOL1 Genotype, Kidney and Cardiovascular Disease, and Death in Older Adults. Arterioscler Thromb Vasc Biol 36:398-403|
|Olabisi, Opeyemi A; Zhang, Jia-Yue; VerPlank, Lynn et al. (2016) APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases. Proc Natl Acad Sci U S A 113:830-7|
|Sharma, Alok K; Friedman, David J; Pollak, Martin R et al. (2016) Structural characterization of the C-terminal coiled-coil domains of wild-type and kidney disease-associated mutants of apolipoprotein L1. FEBS J 283:1846-62|
|Heneghan, J F; Vandorpe, D H; Shmukler, B E et al. (2015) BH3 domain-independent apolipoprotein L1 toxicity rescued by BCL2 prosurvival proteins. Am J Physiol Cell Physiol 309:C332-47|
|Ruchi, Rupam; Genovese, Giulio; Lee, Jessica et al. (2015) Copy Number Variation at the APOL1 Locus. PLoS One 10:e0125410|
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