TY  - JOUR
A1  - Kiryluk, Krzysztof
A1  - Yifu, Li
A1  - Sanna-Cherchi, Simone
A1  - Rohanizadegan, Mersedeh
A1  - Suzuki, Hitoshi
A1  - Eitner, Frank
A1  - Snyder, Holly J.
A1  - Choi, Murim
A1  - Hou, Ping
A1  - Scolari, Francesco
A1  - Izzi, Claudia
A1  - Gigante, Maddalena
A1  - Gesualdo, Loreto
A1  - Savoldi, Silvana
A1  - Amoroso, Antonio
A1  - Cusi, Daniele
A1  - Zamboli, Pasquale
A1  - Julian, Bruce A.
A1  - Novak, Jan
A1  - Wyatt, Robert J.
A1  - Mucha, Krzysztof
A1  - Perola, Markus
A1  - Kristiansson, Kati
A1  - Viktorin, Alexander
A1  - Magnusson, Patrik K.
A1  - Thorleifsson, Gudmar
A1  - Thorsteinsdottir, Unnur
A1  - Stefansson, Kari
A1  - Boland, Anne
A1  - Metzger, Marie
A1  - Thibaudin, Lise
A1  - Wanner, Christoph
A1  - Jager, Kitty J.
A1  - Goto, Shin
A1  - Maixnerova, Dita
A1  - Karnib, Hussein H.
A1  - Nagy, Judit
A1  - Panzer, Ulf
A1  - Xie, Jingyuan
A1  - Chen, Nan
A1  - Tesar, Vladimir
A1  - Narita, Ichiei
A1  - Berthoux, Francois
A1  - Floege, Jürgen
A1  - Stengel, Benedicte
A1  - Zhang, Hong
A1  - Lifton, Richard P.
A1  - Gharavi, Ali G.
T1  - Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis
JF  - PLoS Genetics
N2  - 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.
KW  - linkage
KW  - genome-wide association
KW  - multiple sclerosis
KW  - renal disease
KW  - New mexico
KW  - recombination hotspot
KW  - italian population
KW  - natural history
KW  - HLA
KW  - glomerulonephritis
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130195
VL  - 8
IS  - 6
ER  -