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TRAC Variants Associate with IgA Nephropathy

Ru Li^*, Chao Xue, Caixia Li, Tanqi Lou, Yu Tao^||, Youji Li, Weijun Huang^*, Jun Zhang, Joseph C. K. Leung^¶, Man F. Lam^¶, Tim J. Vyse^**, Kar N. Lai^¶, Changyou Wu and Yiming Wang^*

^* Department of Medical Genetics and Center for Genome Research, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Medical Statistics, School of Public Health, Sun Yat-Sen University, Guangzhou, China; Department of Nephrology Third Affiliated Hospital, ^|| Department of Pathology First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; ^¶ Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong; ^** Faculty of Medicine, Section of Molecular Genetics and Rheumatology, Imperial College London, Hammersmith Hospital, London, United Kingdom

Correspondence: Dr. Yiming Wang, Department of Medical Genetics and Center for Genome Research, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, 510089, China. Phone: 86 20 87333136; Fax: 86 20 87335785; E-mail: ywzhong{at}hotmail.com; or Dr. Changyou Wu, Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, 510089, China. Phone: 86 20 87331552; Fax: 86 20 87331552; E-mail: changyou_wu{at}yahoo.com

Received for publication August 11, 2008. Accepted for publication December 29, 2008.

The T cell receptor alpha constant gene (TRAC) encodes the constant region of the chain for the T cell receptor, and the association of its gene variants with IgA nephropathy remains controversial. The authors resequenced the gene in 100 patients with IgA nephropathy and 100 controls, tested its linkage disequilibrium pattern, constructed haplotypes, and performed association and functional studies. First, the association between TRAC variants and IgA nephropathy was tested in 704 patients and 704 controls. Next, these 704 patients were divided into two independent datasets—310 with family member(s) and 394 single patients—to test the association separately. Results showed that the gene is located in a recombination hot spot, with nine linkage disequilibrium blocks within a 6.9-kb region. There is a hypervariable region with six single-nucleotide polymorphisms (SNPs) in an 85-bp stretch in intron 1. We identified multiple SNPs and two haplotypes that associate with IgA nephropathy (P = 0.0000013–0.0096 by logistic regression for SNPs; P = 0.0003 and P = 0.0398 for haplotype associations). The family-based study replicated both haplotype findings, and the 394 single-patient case-control study replicated the association with haplotype 1 (P = 0.0033). The overtransmitted/observed haplotypes demonstrated reduced transcription activity compared with the undertransmitted/observed haplotypes. In conclusion, this study suggests an association between TRAC variants and susceptibility to IgA nephropathy.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673