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Table 4 Genomic-wide association studies in other kidney diseases

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

PMID Author Year Patients Ethnicity Methodology Main findings
27333618 Sekula 2017 Discovery: 323 MGN, 
345 non-MGN
Men: 222 MGN/106 non-MGN
Women: 101 MGN/239 non-MGN
MGN replication: 137 MGN from GCKD, 
379 non-MGN
Caucasian HumanCNV370-Quad SNP chip HumanHap300 SNP chip
Discovery: 8.9 million and classical HLA alleles
Replication: HLA-DQA1 and PLA2R1
Two previously reported variants in PLA2R1 and HLA-DQA1 reached genome-wide significance with MGN
No additional signals in the pre-replication cohort when separated by men and women
Both SNPs were replicated
PLA2R1 was only associated with MGN, but no other CKD aetiology after correction for multiple testing
A significant association of the HLA-DQA1 risk variant was observed not only with MGN, but also with lupus nephritis (p = 2.8·10−6), CKD in T1DM (p = 6.9·10−5) and FSGS (p = 5.1·10−5)
No association with IgAN
26028593 Li 2015 Combined: 8313 IgAN, 
19680 non-IgAN
Han Chinese GWAMA Detected novel associations at ST6GAL1 (rs7634389, p = 7.27 × 10−10), ACCS (rs2074038, p = 3.93 × 10−9) and ODF1-KLF10 (rs2033562, p = 1.41 × 10−9)
Validated a previously reported association at ITGAX-ITGAM (rs7190997, p = 2.26 × 10−19)
Identified multiple independent signals in DEFA locus (rs2738058, p = 1.15 × 10−19; rs12716641, p = 9.53 × 10−9; rs9314614, p = 4.25 × 10−9)
25305756 Kiryluk 2014 Discovery: 2747 IgAN, 
3952 non-IgAN controls
Replication: 4911 IgAN, 
9002 non-IgAN
Imputation for > 1 million common SNPs
All variants with p-value < 5 × 10−5 in the discovery taken forward into the replication analysis
Combined meta-analysis of discovery and replication identified 6 novel variants reaching genome-wide significance
Four SNPs in 3 novel loci (VAV3, CARD9 and ITGAM-ITGAX) were identified, as well as novel a novel SNP in two previously reported regions, HLA-DQ/DR and DEFA
Confirmed association of SNPs in HLA-DQ/DR, TAP1/PSMB8, HLA-DP, CFHR3, DEFA, TNFSF and HORMAD2
22737082 Kiryluk 2012 8 individual cohorts, combined: 2228 IgAN, 
2561 non-IgAN controls
East Asian
Illumina HumanCNV370-duo Chip Replication of previous study by Gharavi et al. (2011)
Genotyped 12 SNPs in five loci: CFHR3/R1, TAP2/PSMB9, HLA-DPA1/DPB2, HORMAD2 and HLA-DQB1/DRB1
Ten out of 12 SNPs showed significant association with IgAN, but SNPs in the TAP2/PSMB9 did not
However, all 12 reached genome-wide significance in a meta-analysis of these cohorts and those previously assessed by Ghavari et al. (2011)
21323541 Stanescu 2011 French study: 75 MGN,  157 non-MGN
Dutch study: 146 MGN,  1832 non-MGN
British study: 335 MGN,  349 non-MGN
All racially matched
Caucasian HumanCNV370-Quad SNP chip
French: 315,049 SNPs
Dutch: 282,440 SNPs
British: 281,009 SNPs
French study: Three SNPs (rs2187668, rs9273327 and rs9272192) in HLA-DQA1 showed significant association with MGN (p = 1.8 × 10−9, p = 1.7 × 10−9, and p = 5.9 × 10−10, respectively)
Dutch study: MGN associated with rs2187668 in HLA-DQA1 and a total of 191 SNPs within the extended HLA locus showed significant associations with MGN. Six SNPs within PLA2R1 also showed association with MGN, all of which reached genome-wide significance (p < 5 × 10−8)
British study: rs2187668 in HLA-DQA1 showed significant association with MGN (p = 5.2 × 10−36) and a further 144 SNPs within the extended HLA locus showed significant association with MGN
Two SNPs, rs4664308 and rs187010, showed significant association with PLA2R1 (p = 2.1 × 10−10 and p = 8.2 × 10−10, respectively)
Combined analysis of all cohorts showed that strongest associations were found in the HLA-DQA1 and PLA2R1 genes
21399633 Gharavi 2011 Discovery: 1194 IgAN
902 non-IgAN controls
Replication: 1950 IgAN, 
1920 non-IgAN controls
Discovery: Han Chinese
Replication: Chinese and European
Illumina 610 Quad Platform Twenty-seven SNPs reached genome-wide significance in the discovery analysis, all of which were found within the MHC locus on chromosome 6
Sixty-seven SNPs in 10 other distinct loci showed nominal significance (p < 1.3 × 10−5) and the top 20 with the lowest p-values were taken forward for follow-up
Five SNPs reached genome-wide significance in the replication analysis:
The strongest variant showing strongest association with IgAN was rs9275596 (p = 1.6 × 10−26), which is found in a region containing the HLA-DRB1/DQA1/DQB1 locus
Variant rs9357155 was significantly associated with region containing TAP2, TAP1, PSMB8 and PSMB9 genes (p = 6.9 × 10−9)
Genome-wide significance was also reached for variant rs9275596 in the HLA-DPA1/DPB1/DPB2 gene region (p = 3.1 × 10−8)
Variant rs6677604 in the CFH region containing the CHFR1, CHFR2, CHFR3, CHFR4 and CHFR5 genes showed significance association with IgAN (p = 3.0 × 10−10)
The final variant reaching genome-wide significance was rs2412971 in the HORMAD2 gene
  1. ACCS: 1-aminocyclopropane-1-carboxylate synthase homolog (inactive); CARD9: caspase recruitment domain family member 9; CFH: complement factor H; CFHR1: complement factor H related 1; CFHR2: complement factor H related 2; CFHR3: complement factor H related 3; CFHR4: complement factor H related 4; CFHR5: complement factor H related 5; CKD: chronic kidney disease; DEFA: defensins; alpha; FSGS: Focal segmental glomerulosclerosis; GCKD: German Chronic Kidney Disease; GWAMA: genome-wide association meta-analysis; HLA-DP: major histocompatibility complex, class II, DP; HLA-DPA1: major histocompatibility complex, class II, DP alpha 1; HLA-DPB1: major histocompatibility complex, class II, DP beta 1; HLA-DPB2: major histocompatibility complex, class II, DP beta 2; HLA-DQA: major histocompatibility complex, class II, DQ alpha; HLA-DQA1: major histocompatibility complex, class II, DQ alpha 1; HLA-DQB1: major histocompatibility complex, class II, DQ beta 1; HLA-DQR: major histocompatibility complex, class II, DR; HLA-DRB1: major histocompatibility complex, class II, DR beta 1; HORMAD2: HORMA domain containing 2; IgAN: immunoglobulin A nephropathy; ITGAM: integrin subunit alpha M; ITGAX: integrin subunit alpha X; KLF10: Kruppel like factor 10; MA: meta-analysis; MGN: membranous glomerulonephritis; MHC: major histocompatibility complex; ODF1: outer dense fiber of sperm tails 1; PLA2R1: phospholipase A2 receptor 1; PSMB8: proteasome subunit beta 8; PSMB9: proteasome subunit beta 9; SNP: Single nucleotide polymorphism; ST6GAL1: ST6 beta-galactoside alpha-2,6-sialyltransferase 1; T1DM: type I diabetes mellitus; TAP1: transporter 1; ATP binding cassette subfamily B member; TAP2: transporter 2; ATP binding cassette subfamily B member; TNFSF: tumour necrosis factor superfamily; VAV3: vav guanine nucleotide exchange factor 3