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Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis
Kiryluk, Krzysztof1; Li, Yifu1; Sanna-Cherchi, Simone1,2; Rohanizadegan, Mersedeh1; Suzuki, Hitoshi3; Eitner, Frank4; Snyder, Holly J.1; Choi, Murim5; Hou, Ping6; Scolari, Francesco7,8; Izzi, Claudia7,8; Gigante, Maddalena9; Gesualdo, Loreto9; Savoldi, Silvana10; Amoroso, Antonio11,12,13; Cusi, Daniele14; Zamboli, Pasquale15; Julian, Bruce A.16,17; Novak, Jan16,17; Wyatt, Robert J.18,19; Mucha, Krzysztof20; Perola, Markus21,22,23; Kristiansson, Kati21; Viktorin, Alexander24; Magnusson, Patrik K.24; Thorleifsson, Gudmar25,26; Thorsteinsdottir, Unnur25,26; Stefansson, Kari25,26; Boland, Anne27; Metzger, Marie28; Thibaudin, Lise29; Wanner, Christoph30; Jager, Kitty J.31; Goto, Shin32; Maixnerova, Dita33,34; Karnib, Hussein H.35,36; Nagy, Judit37,38; Panzer, Ulf39; Xie, Jingyuan40; Chen, Nan40; Tesar, Vladimir33,34; Narita, Ichiei32; Berthoux, Francois29; Floege, Juergen4; Stengel, Benedicte28; Zhang, Hong6; Lifton, Richard P.5; Gharavi, Ali G.1
WOS标题词Science & Technology
类目[WOS]Genetics & Heredity
研究领域[WOS]Genetics & Heredity

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5x10(-32) 3x10(-10)), with heterogeneity detected only at the PSMB9/TAP1 locus (I-2 = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5x10(-4)). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3x10(-128)). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

项目编号K23DK090207 ; RC1DK087445 ; R01DK082753 ; 0930151N ; PHRC AOM 00022 ; EN00D08 ; 01P0513
资助机构Center for Glomerular Diseases at Columbia University ; NIH/NIDDK ; AHA Scientist Development Grant ; ASN Carl W Gottschalk Research Scholar Grant ; Ministry of Health ; Ministry of Environment ; Ministry of Research ; Biomedecine Agency (AO Recherche et Greffes)
被引频次:131[WOS]   [WOS记录]     [WOS相关记录]
作者单位1.Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia
2.deCODE Genet, Reykjavik, Iceland
3.Univ Iceland, Fac Med, Reykjavik, Iceland
4.CEA, Ctr Natl Genotypage, Inst Genom, Evry, France
5.Univ Hosp, Dept Med, Div Nephrol, Wurzburg, Germany
6.Niigata Univ, Div Clin Nephrol & Rheumatol, Niigata, Japan
7.St Lukes Roosevelt Hosp, Dept Med, New York, NY USA
8.Charles Univ Prague, Gen Univ Hosp, Prague, Czech Republic
9.Al Rassoul Al Aazam Hosp, Clin Res Ctr, Beirut, Lebanon
10.Al Rassoul Al Aazam Hosp, Div Nephrol, Beirut, Lebanon
11.Univ Pecs, Nephrol Ctr, Fac Med, Pecs, Hungary
12.Rhein Westfal TH Aachen, Dept Nephrol, Aachen, Germany
13.Univ Pecs, Dept Internal Med 2, Fac Med, Pecs, Hungary
14.Univ Brescia, Montichiari, Italy
15.Montichiari Hosp, Div Nephrol 2, Montichiari, Italy
16.Cirie Hosp, Nephrol & Dialysis Unit, Turin, Italy
17.Univ Turin, Dept Genet, Turin, Italy
18.Univ Turin, Dept Biol, Turin, Italy
19.Univ Turin, Dept Biochem, Turin, Italy
20.Univ Naples 2, Dept Nephrol, Naples, Italy
21.Le Bonheur Childrens Hosp, Childrens Fdn, Res Ctr, Memphis, TN USA
22.Univ Klinikum Hamburg Eppendorf, Med Klin 3, Hamburg, Germany
23.Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY 10027 USA
24.Juntendo Univ, Div Nephrol, Dept Internal Med, Fac Med, Tokyo, Japan
25.Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, New Haven, CT 06510 USA
26.Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland
27.Peking Univ, Div Renal, Hosp 1, Inst Nephrol, Beijing 100871, Peoples R China
28.Univ Bari, Nephrol Sect, Dept Emergency & Organ Transplantat, Bari, Italy
29.Univ Milan, Sch Med, Div Renal, DMCO,San Paolo Hosp, Milan, Italy
30.Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA
31.Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA
32.Univ Tennessee, Ctr Hlth Sci, Div Pediat Nephrol, Memphis, TN 38163 USA
33.Warsaw Med Univ, Dept Immunol Transplantol & Internal Med, Warsaw, Poland
34.Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland
35.Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden
36.Ctr Res Epidemiol & Populat Hlth, INSERM, Villejuif, France
37.Univ N Hosp, Nephrol Dialysis & Renal Transplantat Dept, St Etienne, France
38.Univ Amsterdam, Acad Med Ctr, ERA EDTA Registry, Dept Med Informat, NL-1105 AZ Amsterdam, Netherlands
39.Charles Univ Prague, Dept Nephrol, Fac Med 1, Prague, Czech Republic
40.Shanghai Jiao Tong Univ, Dept Nephrol, Ruijin Hosp, Sch Med, Shanghai 200030, Peoples R China
GB/T 7714
Kiryluk, Krzysztof,Li, Yifu,Sanna-Cherchi, Simone,et al. Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis[J]. PLOS GENETICS,2012,8(6).
APA Kiryluk, Krzysztof.,Li, Yifu.,Sanna-Cherchi, Simone.,Rohanizadegan, Mersedeh.,Suzuki, Hitoshi.,...&Gharavi, Ali G..(2012).Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis.PLOS GENETICS,8(6).
MLA Kiryluk, Krzysztof,et al."Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis".PLOS GENETICS 8.6(2012).
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