title: 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.
authors.affiliation: Department of Internal Medicine, Section on Nephrology and.|Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Meijian
authors.initials: M
authors.lastname: Guan
authors.affiliation: Department of Biochemistry and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Department of Biochemistry and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Maggie C Y
authors.initials: MCY
authors.lastname: Ng
authors.affiliation: Department of Biochemistry and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.affiliation: Division of Renal Medicine, Department of Medicine, Emory School of Medicine, Atlanta, Georgia.
authors.forename: Janice P
authors.initials: JP
authors.lastname: Lea
authors.affiliation: Department of Internal Medicine, Section on Nephrology and.
authors.forename: Lijun
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Chuan
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Department of Internal Medicine, Section on Nephrology and.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D016022:Case-Control Studies; D003928:Diabetic Nephropathies / Q000150:complications / Q000235:genetics*; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor
keywords: African Americans; Diabetes Mellitus, Type 2; Genotype; Humans; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; albuminuria; chronic kidney disease; diabetic nephropathy; end stage kidney disease