Table 3.
Genomic-wide association studies in diabetic 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 |
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