Genetic associations in diabetic nephropathy: a meta-analysis.
OBJECTIVE
This meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy.


METHODS
PubMed, EMBASE and Web of Science were searched for articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants were included. The association between these variants and diabetic nephropathy (defined as macroalbuminuria/proteinuria or end-stage renal disease [ESRD]) was calculated at the allele level and the main measure of effect was a pooled odds ratio. Pre-specified subgroup analyses were performed, stratifying for type 1/type 2 diabetes mellitus, proteinuria/ESRD and ethnic group.


RESULTS
The literature search yielded 3,455 citations, of which 671 were genetic association studies investigating diabetic nephropathy. We identified 34 replicated genetic variants. Of these, 21 remained significantly associated with diabetic nephropathy in a random-effects meta-analysis. These variants were in or near the following genes: ACE, AKR1B1 (two variants), APOC1, APOE, EPO, NOS3 (two variants), HSPG2, VEGFA, FRMD3 (two variants), CARS (two variants), UNC13B, CPVL and CHN2, and GREM1, plus four variants not near genes. The odds ratios of associated genetic variants ranged from 0.48 to 1.70. Additional variants were detected in subgroup analyses: ELMO1 (Asians), CCR5 (Asians) and CNDP1 (type 2 diabetes).


CONCLUSIONS
This meta-analysis found 24 genetic variants associated with diabetic nephropathy. The relative contribution and relevance of the identified genes in the pathogenesis of diabetic nephropathy should be the focus of future studies.
Department of Pathology, Bldg.1, L1-Q, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, the Netherlands. a.l.mooyaart@lumc.nl
A L
AL
Mooyaart
E J J
EJ
Valk
L A
LA
van Es
J A
JA
Bruijn
E
E
de Heer
B I
BI
Freedman
O M
OM
Dekkers
H J
HJ
Baelde
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D053302:Apolipoprotein C-I / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D002268:Carboxypeptidases / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics*; D004150:Dipeptidases / Q000235:genetics; D004921:Erythropoietin / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D019713:Receptors, CCR5 / Q000235:genetics
C505803:APOC1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D053302:Apolipoprotein C-I; D001057:Apolipoproteins E; C465214:ELMO1 protein, human; C554270:EPO protein, human; C486399:GREM1 protein, human; D019812:Heparan Sulfate Proteoglycans; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D019713:Receptors, CCR5; C485548:UNC13B protein, human; D004921:Erythropoietin; C071927:perlecan; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D002268:Carboxypeptidases; C522928:CNDP1 protein, human; D004150:Dipeptidases; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; C508747:CPVL protein, human