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CUBN is a gene locus for albuminuria.
J. Am. Soc. Nephrol. 22, 555-570 (2011)
Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes. Elevated levels of urinary albumin (albuminuria) are a cardinal manifestation of chronic kidney disease (CKD) and affect as many as 8% of adults from the United States and 6% of adults from Germany. Higher levels of albuminuria, even within the low normal range, are associated with not only increased risks of ESRD but also cardiovascular disease and mortality. Moreover, the presence of albuminuria offers key prognostic information at each stage of decline in GFR. However, the pathophysiologic basis of albuminuria remains incompletely understood, and as a result, interventions for the prevention and treatment of albuminuria are limited. Diabetes mellitus and hypertension are key risk factors for albuminuria, but neither of these factors fully account for the high prevalence of albuminuria nor its association with adverse health outcomes. Heritability of albuminuria ranges from 0.16 to 0.49 in families enriched with hypertension or diabetes. Rare genetic variants are known to cause monogenic diseases featuring severe, nephrotic range proteinuria. However, linkage or candidate gene studies have not reproducibly identified common genetic variants in association with lower levels of albuminuria. Given recent successes in the use of genome-wide association studies (GWAS) of quantitative traits that can lead to the identification of relevant variants for a disease phenotype, we conducted a genome-wide association (GWA) analysis of albuminuria in 31,580 participants of European ancestry from the CKDGen Consortium, with follow-up in 27,746 additional participants. Albuminuria was analyzed as the quantitative trait urinary albumin-to-creatinine ratio (UACR) and as the dichotomous trait microalbuminuria (MA). Concurrently, we performed an analysis of albuminuria in the CARe Consortium using the ITMAT/Broad/CARE Vascular Disease 50k (IBC) single-nucleotide polymorphism (SNP) chip array in 19,499 Europeans and 6981 African Americans. Here, we report the results of our combined findings.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide association; Chronic kidney-disease; Type-1 diabetes-mellitus; Low-grade albuminuria; Renal-function; Albumin/creatinine ratio; Atherosclerosis risk; Linkage analysis; Proximal tubule; Design