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IL5RA and TNFRSF6B Gene Variants Are Associated With Sporadic IgA Nephropathy

Xiao-Qing Liu^*, Andrew D. Paterson^*,, Ning He^,, Peter St. George-Hyslop, Virpi Rauta^||, Carola Gronhagen-Riska^||, Markku Laakso^¶, Lise Thibaudin^**, Francois Berthoux^**, Daniel Cattran and York Pei^,

^* Program in Genetics and Genome Biology, Hospital for Sick Children, Department of Public Health Sciences, University of Toronto, Divisions of Nephrology and Genomic Medicine, University Health, Network and University of Toronto, Toronto, Ontario, Canada, ^|| Division of Nephrology, Helsinki University Hospital, Helsinki, Finland, ^¶ Department of Medicine, University of Kuopio, Kuopio, Finland, and ^** Division of Nephrology, CHU de Saint-Etienne, University of St-Etienne, St-Etienne, France

Correspondence: York Pei, Division of Nephrology, University Health Network, 8N838, 585 University Avenue, Toronto, Ontario, Canada M5G 2N2. Phone: 416-340-4257; Fax: 416-340-4999; E-mail: york.pei{at}uhn.on.ca

Received for publication September 17, 2007. Accepted for publication November 28, 2007.

Familial clustering and genome-wide linkage scans strongly support a genetic susceptibility to familial IgA nephropathy (IgAN), but genetic factors that predispose to sporadic IgAN are unknown. A high-throughput single nucleotide polymorphism (SNP) association study was conducted using a customized Illumina BeadChip in 732 white patients with biopsy-proven IgAN and 503 control subjects from Canada, France, and Finland. Approximately 93% of 1536 SNPs on the array were tag SNPs from Phase I+II of the HapMap with a minor allele frequency 5%, designed to capture the common variants of genes within the critical interval of IGAN1 on chromosome 6q22 and 69 biologic candidate genes for IgAN. SNPs of suggestive or significant association were identified by using logistic regression to adjust for age, gender, study site, and population stratification. Despite using a dense marker set that covered an average interval of 6.5 kb between SNPs, there was no strong and consistent association signal within the IGAN1 critical interval. Among the biologic candidate genes examined, two significant association signals were found at IL5RA and TNFRSF6B, the latter being particularly interesting because this gene encodes a decoy receptor for a TNF family ligand that causes IgAN in mice when overexpressed. Pending replication, these data suggest that variants of IL5RA and TNFRSF6B may predispose to sporadic IgAN.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673