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Integrating Human and Rodent Data to Identify the Genetic Factors Involved in Chronic Kidney Disease

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Integrating Human and Rodent Data to Identify the Genetic Factors Involved in Chronic Kidney Disease BRIEF REVIEW www.jasn.org Integrating Human and Rodent Data to Identify the Genetic Factors Involved in Chronic Kidney Disease Michael R. Garrett,* Marcus G. Pezzolesi,† and Ron Korstanje‡ *Department of Medicine and Kidney Disease Center, Medical College of Wisconsin, Milwaukee, Wisconsin; †The Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, Massachusetts; and ‡The Jackson Laboratory, Bar Harbor, Maine ABSTRACT The increasing numbers of patients with chronic kidney disease combined with no drome, culminating in renal failure satisfying interventions for preventing or curing the disease emphasize the need to (Supplementary Tables 1 and 2). In these better understand the genes involved in the initiation and progression of complex cases, there has been strong linkage be- renal diseases, their interactions with other host genes, and the environment. Linkage tween observed phenotypes and specific and association studies in human, rat, and mouse have been successful in identifying chromosomal regions. This approach genetic loci for various disease-related phenotypes but have thus far not been very has yielded several successes, culminat- successful identifying underlying genes. The purpose of this review is to summarize the ing in the identification of mutations in progress in human, rat, and mouse genetic studies to show the concordance between several key genes (NPHS1, NPHS2, the loci among the different species. The collective utilization of human and nonhuman ACTN4, TRPC6, and PLCE1) that play mammalian datasets and resources can lead to a more rapid narrowing of disease loci structural and functional roles in main- and the subsequent identification of candidate genes. In addition, genes identified taining the glomerular filtration bar- through these methods can be further characterized and investigated for interactions rier.14–18 Unraveling the genetics of more using animal models, which is not possible in humans. common forms of kidney disease has been slower to progress, largely because of phe- J Am Soc Nephrol 21: 398–405, 2010. doi: 10.1681/ASN.2009080881 notypic limitations of these studies, their ability to only detect major genetic effects or their reliance on family-based collec- The extent of chronic kidney disease tify those genetic variants that either pre- tions and, perhaps, misconceptions about (CKD) is a growing national concern. Ap- dispose or cause the disease. Evidence of the underlying genetic model contributing proximately 25.6 million people in the familial aggregation and the heritability to their susceptibility; that is, the existence United States exhibit some degree of kid- of biomarkers, such as albuminuria, for of major disease loci and potential gene- ney injury and/or decline in kidney func- the development and progression of gene and gene-environment interactions. tion.1 Some estimate the number of CKD CKD, as well as various indices of renal More recently, genome-wide associa- patients progressing to end-stage renal dis- function, provide a foundation for inves- tion (GWA) studies, examining as many ease (ESRD) ballooning to more than 2 tigating the genetic predisposition of as 300,000 to 1 million single-nucleotide million in the next 20 years.2 Current treat- CKD.3–12 Efforts to map loci contribut- polymorphisms (SNPs) across the entire ment options are limited and serve only to ing to CKD susceptibility often rely on genome in thousands of unrelated pa- slow progression, not to cure or reverse family-based linkage approaches, which tient and control subjects, are powerful specific conditions. Therefore, under- look to establish statistical associations approaches to detecting disease loci. The standing the genetic basis of kidney disease using genetic markers with a given di- recent success of several GWA studies is of considerable importance because it chotomous (affected versus unaffected) has helped improve our relative under- could provide early diagnosis or more op- or quantitative (GFR or degree of albu- tions for potential targets useful in devel- minuria) phenotypic trait.13 The identi- oping new treatments. fication of genomic locations demon- Published online ahead of print. Publication date strating linkage provides the first line of available at www.jasn.org. evidence suggesting where disease-asso- Correspondence: Dr. Ron Korstanje, The Jackson HUMAN LINKAGE AND GENOME- Laboratory, 600 Main Street, Bar Harbor, ME 04609. ciated genes are likely to reside. The WIDE ASSOCIATION STUDIES Phone: 207-288-6000; Fax: 207-288-6078; E-mail: power of linkage analysis in CKD is best [email protected] The primary goal of studying the genetics demonstrated by the study of rare famil- Copyright ᮊ 2010 by the American Society of of complex disease in humans is to iden- ial, Mendelian forms of nephrotic syn- Nephrology 398 ISSN : 1046-6673/2103-398 J Am Soc Nephrol 21: 398–405, 2010 www.jasn.org BRIEF REVIEW standing of the genetic basis of complex the largest GWA study of diabetic ne- Project (www.1000genomes.org) prom- human disease. To date, more than 100 phropathy to date, Pezzolesi et al. re- ises to facilitate the identification of such loci for diseases such as coronary heart cently identified associations on chro- variants. Pending its completion, how- disease, type 1 and type 2 diabetes, bipo- mosomes 7p, 9q, 11p, and 13q.24 Lastly, ever, resequencing relevant individuals is lar disorder, Crohn disease, and rheuma- in a GWA study of participants from the still currently required to establish a toid arthritis have been identified using Framingham Heart Study, Hwang et al. comprehensive catalog of potential caus- this approach, providing valuable insight reported associations with albuminuria ative variants for subsequent functional to previously unsuspected biologic path- at loci on chromosomes 11q and 21q.29 analyses. Finally, current GWA plat- ways and improving our understanding As expected, the odds ratios detected forms poorly assess the contribution of of the allelic architecture that underlies in the majority of GWA studies of CKD rare variants to disease susceptibility, these conditions.19,20 These studies re- have been rather modest, ranging from and analytical methodologies used to veal the effect size of common variants to 1.25 to 1.45—effect sizes far below the evaluate the effects of gene-gene (epi- be more modest than previously sus- threshold detectable using linkage-based static) or gene-environment interactions pected, with odds ratios per risk allele approaches. Despite the early successes on disease remain limited. generally less than 1.4.19 Not surpris- of GWA studies in identifying loci asso- Another result of the HapMap project ingly, GWA studies have proven far su- ciated with CKD, a number of challenges is the identification of markers that differ perior to linkage-based studies, which still lie ahead that must be met to advance between ancestral populations. A novel are powered to identify major loci—loci our understanding of the genetic factors strategy for identifying genes underlying with effect sizes greater than 2.0—in that cause these diseases. At the forefront ancestry-driven diseases, like some identifying genetic variants in common of these challenges is the need for repli- forms of CKD, is mapping by admixture diseases. cation. Although support for several of linkage disequilibrium. Using mapping The promise of GWA approaches has the loci identified by Kottgen et al. and by admixture linkage disequilibrium, recently begun to reap rewards in CKD, Pezzolesi et al. has been demonstrated in both Kopp et al. and Koa et al. identified as five GWA studies have been published cohorts independent of the original asso- strong associations with focal segmental to date (Supplementary Table 3). The ciation signal, additional confirmation is glomerulosclerosis and nondiabetic strongest association identified thus far, necessary to bolster support for these ESRD in African-Americans on chromo- and one of only two reported associa- loci. Currently, a number of efforts are some 22q, and subsequently localized tions to reach a level indicative of “ge- underway to replicate these findings in these associations to the myosin heavy- nome-wide significance,” was reported additional collections, and more GWA chain type II isoform A (MYH9) in a meta-analysis of 41,000 subjects, in- studies in CKD are on the horizon, in- gene.30,31 Although this is a powerful and cluding more than 4300 patients with cluding a study in the Family Investiga- relatively inexpensive method to identify CKD.21 In this study, Kottgen et al. iden- tion of Nephropathy and Diabetes genes that can explain the increased bur- tified significant associations at the uro- (FIND) collection. Continued efforts to den of these diseases among some ethnic modulin (UMOD) locus on chromo- map CKD disease loci, specifically those groups, these genes are most likely only a some 16p for both CKD and the sharing a common genetic mechanism of small subset of the genes involved in the quantitative analysis of GFR. Three modest effect, will rely on meta-analyses disease and can only be applied to very GWA studies have been conducted in pa- of these data. However, such approaches specific cohorts. tients with diabetic nephropathy.22–24 are challenging because of the inherent Variants in the engulfment and cell mo- phenotypic heterogeneity of these collec- tility 1 (ELMO1) gene on chromosome tions and the resulting datasets. STUDIES IN RATS AND MICE 7p were initially associated with diabetic Additionally, despite offering far su- IDENTIFY CONCORDANT LOCI nephropathy in a GWA study performed perior resolution in comparison with in a Japanese cohort.22 Variants at this linkage-based approaches (disease loci The rat has been extensively used as a locus have since been reported in two can be localized to regions approxi- model system to study the pathophysiol- large African-American cohorts with mately 5 to 100 kbp in length in GWA ogy and genetics of kidney injury or dis- type 2 diabetes and ESRD and in a collec- studies versus several mega-base pair re- ease,32 including models that also exhibit tion of Caucasian type 1 diabetic patients gions in linkage studies), GWA studies hypertension.
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