Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, Pmeta = 6.6×10-8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, Pmeta = 2.9×10-7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (Pmeta = 3.2×10-7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (Pmeta = 3.5×10-4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.
Details
Title
Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility
Author
Zhao, Jian : University of California Los Angeles Wu, Hui : University of California Los Angeles Khosravi, Melanie : University of California Los Angeles Cui, Huijuan : Chinese Academy of Sciences Qian, Xiaoxia : Chinese Academy of Sciences Kelly, Jennifer A. : Oklahoma Medical Research Foundation Kaufman, Kenneth M. : Oklahoma Medical Research Foundation Langefeld, Carl D. : Wake Forest University Williams, Adrienne H. : Wake Forest University Comeau, Mary E. : Wake Forest University Ziegler, Julie T. : Wake Forest University Marion, Miranda C. : Wake Forest University Adler, Adam : Oklahoma Medical Research Foundation Glenn, Stuart B. : Oklahoma Medical Research Foundation Alarcón-Riquelme, Marta E. : Oklahoma Medical Research Foundation BIOLUPUS Network GENLES Network Pons-Estel, Bernardo A. : Sanatorio Parque Harley, John B. : Cincinnati Children's Hospital Medical Center Niewold, Timothy B. : University of Chicago
National Institutes of Health, R01AR043814 National Institutes of Health, R01AR043274 National Institutes of Health, R01AI063274 National Institutes of Health, N01AR62277 National Institutes of Health, R37AI024717 National Institutes of Health, R01AR042460 National Institutes of Health, P01AI083194 National Institutes of Health, P20RR020143 National Institutes of Health, P01AR049084 National Institutes of Health, R01AR33062 National Institutes of Health, K08AI083790 National Institutes of Health, LRPAI071651 National Institutes of Health, R01CA141700 National Institutes of Health, RC1AR058621 National Institutes of Health, P30AR053483 National Institutes of Health, AR43727 National Institutes of Health, UL1RR025005 National Institutes of Health, K24AR002138 National Institutes of Health, P602AR30692 National Institutes of Health, P01AR49084 National Institutes of Health, UL1RR025741 National Institutes of Health, P20RR015577 National Institutes of Health, RC1AR058554 National Institutes of Health, U19AI082714 National Institutes of Health, N01AI50026 National Institutes of Health, R21AI070304 National Institutes of Health, P60AR053308 National Institutes of Health, M01RR00079 National Institutes of Health, UL1RR029882 National Institutes of Health, P60AR049459 National Institutes of Health, R01AR054459 Arthritis National Research Foundation, Eng Tan Scholar Korea Healthcare Technology, R&D Project, A080588 MKE/KEIT, Korean R&D Program, 10035615 US Department of Veterans Affairs, Merit Award US Department of Defense, PR094002 Lupus Research Institute Alliance for Lupus Research Arthritis National Research Foundation, Eng Tan Scholar Award Arthritis Foundation Lupus Foundation Swedish Research Council Swedish Association Against Rheumatism King Gustaf Vth, 80th Jubilee Foundation and the Fundación Instituto de Salud Carlos III, PS0900129 Consejería de Salud de Andalucía, PI-0012 Welcome Trust Arthritis Research UK UK Medical Research Council, G0701325 CTSA, I ULI RR025014-02 National Center for Research Resources Kirkland, Scholar Award Federico Wilhelm Agricola Foundation European Science Foundation
Publication Date
2011-05-26
Language
English
Copyright Statement
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Notes
Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.
