Association Analysis of the Reticulon 1 Gene in End-Stage Kidney Disease.
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.
Center for Genomics and Personalized Medicine Research, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, N.C., USA.
Jason A
JA
Bonomo
Nicholette D
ND
Palmer
John Cijiang
JC
He
Ying
Y
Fan
Pamela J
PJ
Hicks
Janice P
JP
Lea
Mark D
MD
Okusa
Donald W
DW
Bowden
Barry I
BI
Freedman
D001741:Black or African American / Q000235:genetics; D000368:Aged; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics*; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
D009419:Nerve Tissue Proteins; C081781:RTN1 protein, human