Beyond APOL1: Genetic Inroads into Understanding Population Disparities in Diabetic Kidney Disease.

A compelling genetic basis for the excess burden of nondiabetic kidney disease in blacks has been provided.APOL1 kidney risk variants account for approximately 70% of the African ancestry disparity in the progression of a rather wide spectrum of etiologies of nondiabetic CKD. The discovery was enabled by combining population genetics and evolutionary medicine approaches, which have been the subject of several recent reviews (1–3). The odds ratios (ORs) for increased risk of progressive kidney injury conferred by these variants (ranging from OR, 7 to OR, .80 depending on underlying etiology) compared with those previously described in other population–based disease risk association studies (typically ranging from OR, 1.1 to OR, 2.0) places the APOL1 kidney disease risk variants among the highest ever reported for a common variant associated with a common disease. Consistent high–level APOL1 risk variant association has been conspicuously absent for diabetic kidney disease (1), save for some studies inwhich it was difficult to exclude nondiabetic etiologies among subjects with concomitant diabetes and kidney disease enrolled without pathologic validation of diabetic kidney disease (4,5). Therefore, the underpinnings of increased risk for diabetic kidney disease in blacks remain an enigmatic health disparitywith resolution that presents a challenging research imperative. Genome–wide association studies (GWASs) as well as candidate gene approaches to study diabetic nephropathy more generally have identified several genomic regions of possible interest (6). A relevant area of inquiry has included identification of possible genetic risk loci for albuminuria (7,8). Such loci should be mechanistically revealing to the understanding of CKD progression, because albuminuria reflects damage to glomerular macromolecular ultrafiltration and/or dysfunctional proximal tubule processing of albumin with consequent abnormalities in downstream vasoactive and fibrotic pathways (9) The reported heritability of albuminuria in the general population and in patients with diabetes ranges from 0.2 to 0.46 (8). Albuminuria is the most frequently assessed marker of kidney damage measured in clinical practice, and it has been associated in a meta-analyses of approximately 1.5 million individuals from multiple cohorts with all-cause mortality, cardiovascular mortality, and ESRD (10,11). Boger et al. (7) reported the statistical association of a common cubilin (CUBN) missense variation (rs1801239; I2984V) with both an elevated urine albumin excretion ratio (P,0.001) and albuminuria (P50.001) in population sample sets including diabetic and nondiabetic subjects. Although the CUBN variant association was statistically significant after appropriate false discovery rate corrections in this meta-analysis comprising 63,153 individuals of European ancestry and 6981 African ancestry individuals, the identified variants only accounted for a fraction of heritability. Tzur et al. (12) reported a unique extended haplotype structure at theCUBN locus and suggested that population ancestry–based haplotype structure could be leveraged to identify causative variants predicting albuminuria–related diabetic kidney disease risks in African ancestry individuals. In this issue of the Clinical Journal of the American Society of Nephrology, Ma et al. (13) took advantage of next generation exome sequencing at both the CUBN and the megalin (LRP2) –encoding gene loci. CUBN encodes a large 460-kD glycosylated extracellular protein that interacts with other membrane proteins involved in endocytosis. In the proximal tubule, CUBN interacts withmegalin, forming amultireceptor complex. Megalin is a 600-kD transmembrane protein initially identified as the autoantigen inHeymann nephritis, the classic historical experimental model for membranous nephropathy. Amnionless is responsible for trafficking of CUBN to the membrane. The multiligand endocytic receptor CUBN interacting with megalin has been identified as essential in the process of kidney proximal tubular uptake of filtered proteins (reviewed in ref. 14). Mendelian recessive loss of function mutations in either CUBN or AMN cause Megaloblastic Anemia 1 (Online Mendelian Inheritance in Man no. 261100) combining proteinuria and B12 deficiency, whereas rare recessive loss of function mutations in LRP2 cause severe multisystem syndromes, which include proteinuria. Reabsorption at these sites is responsible for recovery of essential components but also, clears other biologically active substances from the ultrafiltrate so that more distal kidney tubular segments are not exposed to these substances. The relationship between genes with complete loss of function that results in such high–penetrance rare Mendelian inheritance disorders and the association of common variants at these same loci with corresponding common disease phenotypes is never predictable but worthy of exploration. *Department of Genetics and Developmental Biology, Rappaport Faculty of Medicine and Research Institute, Technion, Haifa, Israel Institute of Technology, Israel; Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; and Division of Nephrology, Mayanei HaYeshua Medical Center, Bnei Brak, Israel