CUBN is a gene locus for albuminuria

Abstract

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.

Figure 1.

Genome-wide log₁₀ P value plot from stage 1 analyses of UACR. Participants of European ancestry in the CKDGen Consortium (A) and the CARe Consortium [IBC chip analyses; (B)].

Figure 2.

Regional Association Plot for the CUBN gene region. CKDGen Consortium stage 1 analyses (A), CARe IBC SNP chip results in participants of European Ancestry (B) and African ancestry (C). log₁₀ P values are plotted versus genomic position (build 36). The lead SNP in each region is labeled. Other SNPs in each region are color-coded based on their LD to the lead SNP (LD based on the HapMap CEU and YRI for the participants of African ancestry; see color legend). Gene annotations are based on UCSC Genome Browser (RefSeq Genes, b36) and arrows indicate direction of transcription. Graphs were generated using the software SNAP (http://www.broadinstitute.org/mpg/snap/index.php). Regions vary between panels because there was no coverage beyond the CUBN gene on the IBC chip used to generate panels B and C.