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Association Analysis of the Cubilin (CUBN) and Megalin (LRP2) Genes with ESRD in African Americans.

ABSTRACT: Genetic variation in the cubilin (CUBN) gene is associated with albuminuria and CKD. Common and rare coding variants in CUBN and the gene encoding its transport partner megalin (LRP2) were assessed for association with ESRD in blacks.Sixty-six CUBN and LRP2 single-nucleotide polymorphisms (SNPs) were selected and analyzed in this multistage study. Exome sequencing data from 529 blacks with type 2 diabetes (T2D) -associated ESRD and 535 controls lacking T2D or nephropathy (the Type 2 Diabetes Genes [T2D-GENES] Consortium) were first evaluated, focusing on coding variants in CUBN and LRP2; 15 potentially associated SNPs identified from the T2D-GENES Consortium as well as 51 other selected SNPs were then assessed in an independent T2D-ESRD sample set of blacks (the Affymetrix Axiom Biobank Genotyping Array [AXIOM]; 2041 patients with T2D-ESRD, 627 patients with T2D without nephropathy, and 1140 nondiabetic, non-nephropathy controls). A meta-analysis combining the T2D-GENES Consortium and the AXIOM data was performed for 18 overlapping SNPs. Additionally, all 66 SNPs were genotyped in the Wake Forest School of Medicine samples of blacks with nondiabetic ESRD (885 patients with nondiabetic ESRD and 721 controls). Association testing with ESRD was performed in models including age, sex, African ancestry proportion, and apolipoprotein L1 gene renal-risk variants.CUBN SNP rs1801239 (I2984V), previously associated with albuminuria, was significantly associated with T2D-ESRD in blacks (the T2D-GENES Consortium and the AXIOM meta-analysis, P=0.03; odds ratio, 1.31; 95% confidence interval, 1.03 to 1.67; minor allele frequency =0.028). A novel LRP2 missense variant, rs17848169 (N2632D), was also significantly protective from T2D-ESRD (the T2D-GENES Consortium and the AXIOM, P<0.002; odds ratio, 0.47; 95% confidence interval, 0.29 to 0.75; meta-analysis minor allele frequency =0.007). Neither SNP was associated with T2D when contrasting patients with T2D with controls lacking diabetes. CUBN and LRP2 SNPs were not associated with nondiabetic etiologies of ESRD.Evidence for genetic association exists between a cubilin and a rare megalin variant with diabetes-associated ESRD in populations with recent African ancestry.

SUBMITTER: Ma J

PROVIDER: S-EPMC4891762 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Association Analysis of the Cubilin (CUBN) and Megalin (LRP2) Genes with ESRD in African Americans.

Ma Jun J Guan Meijian M Bowden Donald W DW Ng Maggie C Y MCY Hicks Pamela J PJ Lea Janice P JP Ma Lijun L Gao Chuan C Palmer Nicholette D ND Freedman Barry I BI

Clinical journal of the American Society of Nephrology : CJASN 20160519 6

<h4>Background and objectives</h4>Genetic variation in the cubilin (CUBN) gene is associated with albuminuria and CKD. Common and rare coding variants in CUBN and the gene encoding its transport partner megalin (LRP2) were assessed for association with ESRD in blacks.<h4>Design, setting, participants, & measurements</h4>Sixty-six CUBN and LRP2 single-nucleotide polymorphisms (SNPs) were selected and analyzed in this multistage study. Exome sequencing data from 529 blacks with type 2 diabetes (T2 ...[more]

PMID: 27197912

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Project description:Non-diabetic forms of nephropathy commonly lead to end-stage renal disease (non-DM ESRD). Previous studies have demonstrated that African Americans are more susceptible to non-DM ESRD compared to other ethnic groups, and this risk has a strong genetic component. A genome-wide scan for ESRD in African American families enriched for non-DM ESRD showed evidence for linkage in chromosome 13q33.3, and a candidate gene in this region, klotho, was selected for a detailed analysis in a follow-up case-control association study.Thirty-four single-nucleotide polymorphisms (SNPs) in the klotho gene were genotyped in 317 unrelated African American non-DM ESRD cases and 354 non-nephropathy controls, including 12 SNPs identified by re-sequencing a region around exon 4.Two SNPs demonstrated modest admixture-adjusted evidence of association with non-DM ESRD, rs650439 (P = 0.013, recessive model) and rs643780 (P = 0.017, recessive model), while rs17643698 approached significance (P = 0.0953, two degrees of freedom test). Eight of the most significant SNPs were tested for replication in a second case-control collection (557 African American non-DM ESRD cases and 187 controls), and there was no evidence of association in replicate cases and controls; nor when the samples were combined for a total of 874 non-DM cases and 541 controls. Cox proportional hazards models were computed to test for association between polymorphisms in klotho and age at onset of ESRD. A three-SNP haplotype, rs526906, rs525014 and rs571118 (T/T/A), was associated with age of onset of ESRD [P = 0.007, recessive model; hazard ratio (HR) = 0.70]. Subjects homozygous for this haplotype had a mean 4 years later onset of ESRD, suggesting a slower disease progression. HapMap subjects homozygous for this haplotype had increased expression of klotho, further supporting a protective role of this variant in ESRD.We conclude that three SNPs in intron 1 of the klotho gene are associated with delayed age at onset of non-DM ESRD in African Americans.

Project description:The reduced folate carrier (RFC1) is an integral membrane protein and facilitative anion exchanger that mediates delivery of 5-methyltetrahydrofolate into mammalian cells. Adequate maternal-fetal transport of folate is necessary for normal embryogenesis. Targeted inactivation of the murine RFC1 gene results in post-implantation embryolethality, but daily folic acid supplementation of pregnant dams prolongs survival of homozygous embryos until mid-gestation. At E10.5 RFC1-/- embryos are developmentally delayed relative to wildtype littermates, have multiple malformations, including neural tube defects, and die due to failure of chorioallantoic fusion. The mesoderm is sparse and disorganized, and there is a marked absence of erythrocytes in yolk sac blood islands. The identification of alterations in gene expression and signaling pathways involved in the observed dysmorphology following inactivation of RFC1-mediated folate transport are the focus of this investigation.Affymetrix microarray analysis of the relative gene expression profiles in whole E9.5 RFC1-/- vs. RFC1+/+ embryos identified 200 known genes that were differentially expressed. Major ontology groups included transcription factors (13.04%), and genes involved in transport functions (ion, lipid, carbohydrate) (11.37%). Genes that code for receptors, ligands and interacting proteins in the cubilin-megalin multiligand endocytic receptor complex accounted for 9.36% of the total, followed closely by several genes involved in hematopoiesis (8.03%). The most highly significant gene network identified by Ingenuitytrade mark Pathway analysis included 12 genes in the cubilin-megalin multiligand endocytic receptor complex. Altered expression of these genes was validated by quantitative RT-PCR, and immunohistochemical analysis demonstrated that megalin protein expression disappeared from the visceral yolk sac of RFC1-/- embryos, while cubilin protein was widely misexpressed.Inactivation of RFC1 impacts the expression of several ligands and interacting proteins in the cubilin-amnionless-megalin complex that are involved in the maternal-fetal transport of folate and other nutrients, lipids and morphogens such as sonic hedgehog (Shh) and retinoids that play critical roles in normal embryogenesis.

Dataset Information

Association Analysis of the Cubilin (CUBN) and Megalin (LRP2) Genes with ESRD in African Americans.

Publications

Association Analysis of the Cubilin (CUBN) and Megalin (LRP2) Genes with ESRD in African Americans.

Similar Datasets

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