title: The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease.
abstract: Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 × 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10(-7) and 3.70 × 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants.
authors.affiliation: Department of Molecular Medicine and Translational Science, Center for Genomics and Personalized Medicine Research.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bonomo
authors.affiliation: Center for Genomics and Personalized Medicine Research.
authors.forename: Meijian
authors.initials: M
authors.lastname: Guan
authors.affiliation: Center for Genomics and Personalized Medicine Research.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.affiliation: Center for Genomics and Personalized Medicine Research, Department of Biochemistry.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Center for Genomics and Personalized Medicine Research.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.affiliation: Center for Genomics and Personalized Medicine Research.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Keaton
authors.affiliation: Department of Internal Medicine - Nephrology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Janice P
authors.initials: JP
authors.lastname: Lea
authors.affiliation: Center for Genomics and Personalized Medicine Research, Department of Biostatistical Sciences.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Center for Genomics and Personalized Medicine Research, Department of Internal Medicine - Nephrology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA and.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Center for Genomics and Personalized Medicine Research, Department of Biochemistry, dbowden@wakehealth.edu.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D001741:Black or African American; D000368:Aged; D017398:Alternative Splicing; D000808:Angiotensinogen / Q000235:genetics; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D044465:White People
chemical_list: C534931:AGT protein, human; D004268:DNA-Binding Proteins; C101743:RREB1 protein, human; D014157:Transcription Factors; D000808:Angiotensinogen