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Table 3 Genomic-wide association studies in diabetic kidney disease

From: Genomic approaches in the search for molecular biomarkers in chronic kidney disease

PMID Author Year Patients Ethnicity Methodology Main findings
25493955 Gorski 2015 63,558 individuals
CKDGen:
Stage 1 MA: 16 cohorts
Stage 2 MA: 13 cohorts
Rapid decline: (annual eGFR decline ≥ 3 ml/min/1.73 m2)
Caucasian GWAMA Association of rs12917707 at the UMOD locus with an increase in eGFR over time at a genome-wide significant level (p = 2.6·10−14)
The novel CDH23, GALNTL5/GALNT11, MEOX2, IL1RAP/OSTN, C2orf48/HPCAL1 and NPPB/NPPA loci were associated with CKD or eGFR at a significance level of p < 10−6
In stage 2 MA, only rs12917707 at UMOD was significantly associated with the stage 1 trait after correcting for multiple testing (p = 4.7·10−5)
Two SNPs showed suggestive significance (one-sided p < 0.05) with their respective stage 1 trait: rs875860 in CDH23 with eGFR change in those with CKD at baseline, and rs1019173 at GALNTL5/GALNT11 with rapid decline in eGFR
The combined stage 1 and stage 2 analysis showed genome-wide significant association only for UMOD (rs12917707, p = 1.2·10 16)
The combined analysis also showed suggestive evidence of association for the two novel loci identified in stage 1 (rs875860 in CDH23: p = 1.5·10−6 with eGFR change in CKD patients; rs1019173 at GALNTL5/GALNT11: OR(A-allele) = 0.91, p = 2.2·10−7 with rapid decline in eGFR)
23586973 Deshmukh 2013 GoDARTS cohort
3028 T2DM
Sustained normoalbuminuria: ACR < 2.5 mg/mmol (males), < 3.5mh/mmol (females)
Caucasian Affymetrix Genome-Wide Human SNP Array 6.0
(16 SNPs)
Replication of the association of UMOD, GCKR and SHROOM3 with eGFR in patients with T2DM, confirming the findings of previous studies
No interaction of UMOD with age in patients with T2DM (p = 0.84)
None of the 16 SNPs were associated with time to stage 3B CKD at the predefined threshold of 0.003. UMOD and SLC7A9 were associated with time to stage 3B CKD at the threshold of 0.05 (consistent direction of effects with previous reports)
Clear difference in the effect sizes in patients with sustained normalbuminuria and those with albuminuria for UMOD and SLC7A9 genes. UMOD has twice the effect in patients with sustained normalbuminuria as compared with those with albuminuria (p-interaction = 0.002)
SHROOM3 (p-interaction = 0.003) and GCKR (p-interaction = 0.08) showed larger effect sizes in patients with albuminuria
23028342 Sandholm 2012 2916 T1DM (460 mAlb) 1399 T1DM-ESRD 5253 T1DM no kidney disease
GENIE cohort: UK-ROI, FinnDiane, GoKinD
Additional MA: 9 cohorts (n = 5873)
Caucasian UK-ROI: Omni1-Quad array
FinnDiane: Illumina’s BeadArray 610-Quad array
GoKinD: Affymetrix 500 K (≈ 2.4 million SNPs)
In the MA, only association of rs7583877 with ESRD analysis reached genome-wide significance
Five independent signals in total DKD and 6 other signals in ESRD anaylsis reached p < 10−5
In the combined meta-analysis with 41 SNPs and 9 additional cohorts, association of the intronic SNP rs7583877 in AFF3 with ESRD retained genome-wide significance (OR = 1.29; 95%CI 1.18–1.40; p =  1.2·10−8
Another locus (rs12437854), located between the RGMA and MCTP2 genes on chromosome 15q26 also reached genome-wide significance for association with ESRD (OR = 1.80; 95%CI 1.48–2.17; p = 2.0·10−9)
The top SNP associated with the primary DKD phenotype identified from the combined discovery and second stage analysis was rs7588550, an intronic SNP in the ERBB4 gene, which demonstrated consistent protective effects in the replication samples. However, this SNP did not reach genome-wide statistical significance (OR = 0.66; 95%CI 0.56–0.77; p = 2.1·10−7)
22721967 Williams 2012 903 UK-ROI
251 FinnDiane (n = 251; ESRD + laser)
GENIE cohort: UK-ROI: 903 T1DM + DKD 1001 T1DM
FinnDiane 251 T1DM + DKD 987 T1DM
GoKinD
Caucasian UK-ROI
(791,687 SNPs): sequenom iPLEX
TaqMan
FinnDiane
(549,530 SNPs): Illumina’s BeadArray,  610Quad array, 
TaqMan
GoKinD
(360,899 SNPs) Total tested: 2199
The rs1617640 variant in the EPO promoter showed same effect direction as seen in the original report
Fixed effects MA showed no genome-wide significance for association of rs741301 in ELMO1 with DKD. No association in individuals cohorts either
21150874 McDonough 2011 Discovery: 965 T2DM + ESRD,
1029 NDNN
Replication: 709 T2DM + ESRD,
690 NDNN
Trait GWAS: 1246 T2DM no kidney disease,
1216 non-diabetic
ESRD
African American Affymetrix 6.0 Chip
Discovery: 832,357 SNPs
Identification of 126 SNPs associated with a level of p < 10−4
Top discovery hit was rs5750250 in MYH9 gene
Of the top 724 hits taken into replication analysis, 67 SNPs showed nominal association (p < 0.05)
No genome-wide association SNPs for T2DM-ESRD
Trait discrimination GWAS identified 25 SNPs specifically associated with T2DM-ESRD, as no association was seen in T2DM patients without nephropathy
Association of SASH1, RPS12, AUH, MSRB3-HMGA2 and LIMK2-SFI1 with T2DM-ESRD
Association of LIMK2-SFI1 and MYH9 with ESRD
19929986 Craig 2009 GoKinD cohort
Discovery: 547 T1DM + persistent proteinuria or ESRD,
549 T1DM
Replication: 462 T1DM + ESRD,
470 T1DM
Caucasian Discovery: Infinium II HumanHap 550Beadchip
474,050 SNPs
Replication:
iPLEX assay
22 SNPs
Discovery: 2870 SNPs showing “substantial differences” in mean allele frequency (p < 0.05)
Twenty-two SNPs included in the Replication found nominal association (p = 0.05)
19183347 Leak 2009 Discovery: 577 T2DM-ESRD,
596 NDNN
Replication: 558 T2DM-ESRD,
328 T2DM,
326 non-diabetic ESRD
African American Illumina Genotyping Services
iPlex methodology on a MassARRAY genotyping system (311 SNPs)
Association of rs3778713, rs17171024 and rs1647791 in ELMO1 with T2DM-ESRD, although not later replicated
Replication of 20 SNPs out of the 98 included
The combined analysis found 27 SNPs (11 located in intron 13) nominally associated with T2DM-ESRD
None of these SNPs were associated with T2DM or ESRD as separate entities
Other SNPs did associated with T2DM or ESRD individually
19252134 Pezzolesi 2009 Discovery: GoKinD
Replication: DCCT/EDIC,
284 T1DM + Proteinuria,
536 T1DM + ESRD,
885 T1DM
Replication: 1304 T1DM + persistent proteinuria or ESRD
Caucasian Discovery: Affymetrix 5.0 500 K
TaqMan
467,144 SNPs
Replication: Illumina Human1M Beadchip
840,354 SNPs
No SNP achieved genome-wide significance in the discovery phase
Identification of 11 SNPs from four distinct chromosomal regions with p < 10−5, taken for replication
The rs10868025 variant on chromosome 9q showed the strongest association with DKD (OR = 1.45; p = 5.0 × 10−7). This SNP is located near the 5′ end of the 4.1 protein ezrin, radixin, moesin (FERM) domain-containing 3 (FRMD3) gene
Strong association (p = 3.1 × 10−6) also noted in the cysteinyl-tRNA synthase (CARS) gene
Multivariate Cox proportional hazard analyses showed significant association between both of these genes and time to onset of diabetic nephropathy (FRMD3: HR = 1.33, p = 0.02; CARS: HR = 1.32, p = 0.01)
19651817 Pezzolesi 2009 GoKinD cohort: 820 DKD,
885 T1DM
(284 proteinuria, 536 ESRD)
Caucasian Affymetrix 5.0 500 K SNP Array
359,193 SNPs
(106 genotyped and 12 imputed in ELMO1 locus)
Association of 8 SNPs in ELMO1 locus with DKD
The two strongest associations were found in SNPs located in intron 16
The variant rs7785934 was associated with ESRD
No variants were associated with proteinuria
18602983 Bento 2008 300 T2DM-ESRD
310 T2DM
Caucasian Sequenom MassArray genotyping system
390 SNPs
Identification of 11 significant SNPs/Genes associated with T2DM-ESRD.
15793258 Shimazaki 2005 Discovery: 94 T2DM + DKD,
94 T2DM
Replication: 466 T2DM + DKD,
266 T2DM
Japanese Invader assay 81,315 SNPs Identification of 1615 loci associated with DKD at a p < 0.01 level
ELMO1 strongly associated with DKD in the replication stage
Other 516 polymorphisms in ELMO1 significantly associated with DKD in a combined analysis of discovery and replication patient and control groups
  1. ACR: Albumin-to-creatinine ratio; AFF3: AF4/FMR2 family member 3; AUH: AU RNA binding methylglutaconyl-CoA hydratase; C2orf48: chromosome 2 open reading frame 48; CARS: cysteinyl-tRNA synthetase; CDH23: cadherin related 23; CI: confidence interval; CKD: chronic kidney disease; CKDGen: Chronic Kidney Disease Genetics Consortium; DCCT/EDIC: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; DKD: diabetic kidney disease; eGFR: estimated glomerular filtration rate; ELMO1: engulfment and cell motility 1; EPO: erythropoietin; ERBB4: erb-b2 receptor tyrosine kinase 4; ESRD: end-stage renal disease; FinnDiane: Finnish Diabetic Nephropathy Study, GENIE: Genetics of Nephropathy—an international effort Consortium; GALNT11: polypeptide N-acetylgalactosaminyltransferase 11; GALNTL5: polypeptide N-acetylgalactosaminyltransferase like 5; GCKR: glucokinase regulator; FRMD3: FERM domain containing 3; GoDARTS: Genetics of Diabetes Audit and Research in Tayside, Scotland; GoKinD: Genetics of Kidneys in Diabetes US Study; GWAMA: genome-wide association meta-analysis; HMGA2: high mobility group AT-hook 2; HPCAL1: hippocalcin like 1; HR: hazard ratio; IL1RAP: interleukin 1 receptor accessory protein; LIMK2: LIM domain kinase 2; MA: meta-analysis; mAlb: microalbuminuria; MCTP2: multiple C2 domains; transmembrane 2; MEOX2: mesenchyme homeobox 2; MSRB3: methionine sulfoxide reductase B3; MYH9: myosin heavy chain 9; NDNN: non-diabetic, non-nephropathy; NPPA: natriuretic peptide A; NPPB: natriuretic peptide B; OR: odds ratio; OSTN: osteocrin; RGMA: RGM domain family, member A; RPS12: ribosomal protein S12; SASH1: SAM and SH3 domain containing 1; SHROOM3: shroom family member 3; SFI1: SFI1 centrin binding protein; SLC7A9: solute carrier family 7 member 9; SNP(s): single nucleotide polymorphism(s); T1DM: type I diabetes mellitus; T2DM: type II diabetes mellitus; UK-ROI: All Ireland Warren 3 Genetics of Kidneys in Diabetes UK Collection; UMOD: uromodulin