BACKGROUND: The reticulon 1 gene (RTN1) encodes reticulons, endoplasmic reticulum stress proteins recently implicated in kidney disease progression. METHODS: RTN1 single nucleotide polymorphisms (SNPs) were tested for association with type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) in African Americans (AAs) and European Americans (EAs), and AAs with non-diabetic ESKD. RTN1 SNPs that were associated with T2D-ESKD in AA cases compared to non-nephropathy controls were identified from a discovery genome-wide association study (n=1,797), then tested for replication in 1,847 additional AA T2D-ESKD cases and controls. RESULTS: Three intronic RTN1 variants were nominally associated with T2D-ESKD in both discovery and replication analyses: rs1952034, rs12431381 and rs12434215 (additive models); combined T2D-ESKD (discovery+replication) p values were 0.015-3.0×10(-4) (ORs 0.67-0.77; minor alleles protective). In addition, rs12434215 was weakly associated with T2D-ESKD in 557 EA T2D-ESKD cases contrasted with 753 EA non-nephropathy controls (p=0.019; OR 0.69, dominant model). Nominal association extended to non-diabetic causes of ESKD in 1,459 additional AA cases (rs12431381 and rs12434215 p values 0.014-0.015; OR 0.77). An all-cause ESKD association analysis contrasted the 3,594 AA ESKD cases with 1,489 AA non-nephropathy controls and detected association with rs12434215 (p=6.7×10(-4), OR 0.73) and rs12431381 (p=7.5×10(-4), OR 0.75) in dominant models. Of the 3 SNPs, only rs12434215 was weakly associated with T2D per se when contrasting T2D non-nephropathy cases with non-diabetic controls (additive model p=0.032 AAs; p=0.048 EAs). CONCLUSIONS: These results suggest evidence of genetic association between common variants in RTN1 and ESKD in AAs and EAs.
BACKGROUND: The reticulon 1 gene (RTN1) encodes reticulons, endoplasmic reticulum stress proteins recently implicated in kidney disease progression. METHODS:RTN1 single nucleotide polymorphisms (SNPs) were tested for association with type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) in African Americans (AAs) and European Americans (EAs), and AAs with non-diabetic ESKD. RTN1 SNPs that were associated with T2D-ESKD in AA cases compared to non-nephropathy controls were identified from a discovery genome-wide association study (n=1,797), then tested for replication in 1,847 additional AA T2D-ESKD cases and controls. RESULTS: Three intronic RTN1 variants were nominally associated with T2D-ESKD in both discovery and replication analyses: rs1952034, rs12431381 and rs12434215 (additive models); combined T2D-ESKD (discovery+replication) p values were 0.015-3.0×10(-4) (ORs 0.67-0.77; minor alleles protective). In addition, rs12434215 was weakly associated with T2D-ESKD in 557 EA T2D-ESKD cases contrasted with 753 EA non-nephropathy controls (p=0.019; OR 0.69, dominant model). Nominal association extended to non-diabetic causes of ESKD in 1,459 additional AA cases (rs12431381 and rs12434215 p values 0.014-0.015; OR 0.77). An all-cause ESKD association analysis contrasted the 3,594 AA ESKD cases with 1,489 AA non-nephropathy controls and detected association with rs12434215 (p=6.7×10(-4), OR 0.73) and rs12431381 (p=7.5×10(-4), OR 0.75) in dominant models. Of the 3 SNPs, only rs12434215 was weakly associated with T2D per se when contrasting T2D non-nephropathy cases with non-diabetic controls (additive model p=0.032 AAs; p=0.048 EAs). CONCLUSIONS: These results suggest evidence of genetic association between common variants in RTN1 and ESKD in AAs and EAs.
Authors: Giulio Genovese; David J Friedman; Michael D Ross; Laurence Lecordier; Pierrick Uzureau; Barry I Freedman; Donald W Bowden; Carl D Langefeld; Taras K Oleksyk; Andrea L Uscinski Knob; Andrea J Bernhardy; Pamela J Hicks; George W Nelson; Benoit Vanhollebeke; Cheryl A Winkler; Jeffrey B Kopp; Etienne Pays; Martin R Pollak Journal: Science Date: 2010-07-15 Impact factor: 47.728
Authors: Jason A Bonomo; Meijian Guan; Maggie C Y Ng; Nicholette D Palmer; Pamela J Hicks; Jacob M Keaton; Janice P Lea; Carl D Langefeld; Barry I Freedman; Donald W Bowden Journal: Hum Mol Genet Date: 2014-07-15 Impact factor: 6.150
Authors: Jasmin Divers; Nicholette D Palmer; Lingyi Lu; Thomas C Register; J Jeffrey Carr; Pamela J Hicks; R Caresse Hightower; S Carrie Smith; Jianzhao Xu; Amanda J Cox; Keith A Hruska; Donald W Bowden; Cora E Lewis; Gerardo Heiss; Michael A Province; Ingrid B Borecki; Kathleen F Kerr; Y-D Ida Chen; Walter Palmas; Jerome I Rotter; Christina L Wassel; Alain G Bertoni; David M Herrington; Lynne E Wagenknecht; Carl D Langefeld; Barry I Freedman Journal: Circ Cardiovasc Genet Date: 2012-12-11
Authors: Jessica N Cooke; Meredith A Bostrom; Pamela J Hicks; Maggie C Y Ng; Jacklyn N Hellwege; Mary E Comeau; Jasmin Divers; Carl D Langefeld; Barry I Freedman; Donald W Bowden Journal: Nephrol Dial Transplant Date: 2011-10-03 Impact factor: 5.992
Authors: Caitrin W McDonough; Nicholette D Palmer; Pamela J Hicks; Bong H Roh; S Sandy An; Jessica N Cooke; Jessica M Hester; Maria R Wing; Meredith A Bostrom; Megan E Rudock; Joshua P Lewis; Matthew E Talbert; Rebecca A Blevins; Lingyi Lu; Maggie C Y Ng; Michele M Sale; Jasmin Divers; Carl D Langefeld; Barry I Freedman; Donald W Bowden Journal: Kidney Int Date: 2010-12-08 Impact factor: 10.612
Authors: Donald W Bowden; Amanda J Cox; Barry I Freedman; Christina E Hugenschimdt; Lynne E Wagenknecht; David Herrington; Subhashish Agarwal; Thomas C Register; Joseph A Maldjian; Maggie C-Y Ng; Fang-Chi Hsu; Carl D Langefeld; Jeff D Williamson; J Jeffrey Carr Journal: Rev Diabet Stud Date: 2010-11-10