Association testing of previously reported variants in a large case-control meta-analysis of diabetic nephropathy.
We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10(-9)). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Winfred W
WW
Williams
Rany M
RM
Salem
Amy Jayne
AJ
McKnight
Niina
N
Sandholm
Carol
C
Forsblom
Andrew
A
Taylor
Candace
C
Guiducci
Jarred B
JB
McAteer
Gareth J
GJ
McKay
Tamara
T
Isakova
Eoin P
EP
Brennan
Denise M
DM
Sadlier
Cameron
C
Palmer
Jenny
J
Söderlund
Emma
E
Fagerholm
Valma
V
Harjutsalo
Raija
R
Lithovius
Daniel
D
Gordin
Kustaa
K
Hietala
Janne
J
Kytö
Maija
M
Parkkonen
Milla
M
Rosengård-Bärlund
Lena
L
Thorn
Anna
A
Syreeni
Nina
N
Tolonen
Markku
M
Saraheimo
Johan
J
Wadén
Janne
J
Pitkäniemi
Cinzia
C
Sarti
Jaakko
J
Tuomilehto
Karl
K
Tryggvason
Anne-May
AM
Österholm
Bing
B
He
Steve
S
Bain
Finian
F
Martin
Catherine
C
Godson
Joel N
JN
Hirschhorn
Alexander P
AP
Maxwell
Per-Henrik
PH
Groop
Jose C
JC
Florez
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000453:epidemiology / Q000235:genetics*; D004921:Erythropoietin / Q000235:genetics; D005387:Finland / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D007676:Kidney Failure, Chronic / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C465214:ELMO1 protein, human; C554270:EPO protein, human; D004921:Erythropoietin