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, P(meta) = 6.6x10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9x10(-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 similar to 146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1 Delta), 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 CFHR3-1D (P(meta) = 3.2x10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5x10(-4), OR = 1.14). These results suggested that the CFHR3-1D 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.Support for this work was obtained from the US National Institutes of Health grants: R01AR043814 (BP Tsao), R01AR043274 (KL Moser), R01AI063274 (PM Gaffney), N01AR62277 (JB Harley), R37AI024717 (JB Harley), R01AR042460 (JB Harley), P01AI083194 (JB Harley), P20RR020143 (JB Harley), P01AR049084 (RP Kimberly), R01AR33062 (RP Kimberly, EE Brown), K08AI083790 (TB Niewold), LRPAI071651 (TB Niewold), R01CA141700 (ME Alarcón-Riquelme), RC1AR058621 (ME Alarcón-Riquelme) and UL1RR024999 (TB Niewold), R01AR051545-01A2 (AM Stevens), P30AR053483 (JA James and JM Guthridge), AR43727 (MA Petri), UL1RR025005 (MA Petri), K24AR002138 (R Ramsey-Goldman), P602AR30692 (R Ramsey-Goldman), P01AR49084 (R Ramsey-Goldman), UL1RR025741 (R Ramsey-Goldman), P20RR015577 (JA James), RC1AR058554 (JA James), U19AI082714 (JA James), N01AI50026 (JA James and JM Guthridge), R21AI070304 (SA Boackle), P60AR053308 (LA Criswell), M01RR00079 (LA Criswell), UL1RR029882 (GS Gilkeson and DL Kamen), P60AR049459 (GS Gilkeson and DL Kamen), and R01AR054459 (C-Y Yu). The first author (J Zhao) is an Eng Tan Scholar supported by the Arthritis National Research Foundation. This study was also supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A080588; S-C Bae), Korean R&D Program of MKE/KEIT (10035615; YW Song), the Merit Award from the US Department of Veterans Affairs (JB Harley and GS Gilkeson), the US Department of Defense PR094002 (JB Harley), Lupus Research Institute (BP Tsao, AM Stevens, and TB Niewold), The Alliance for Lupus Research (KL Moser, TB Niewold, LA Criswell, and CO Jacob), the Arthritis National Research Foundation Eng Tan Scholar Award (TB Niewold), the Arthritis Foundation (AM Stevens and PM Gaffney), and the Lupus Foundation (AM Stevens). Additional funding awarded from the Swedish Research Council, Swedish Association Against Rheumatism, and the King Gustaf Vth 80th Jubilee. Foundation and the Fundación Instituto de Salud Carlos III PS0900129 and the Consejería de Salud de Andalucía PI-0012 (ME Alarcón-Riquelme), the Welcome Trust (TJ Vyse), Arthritis Research UK (TJ Vyse), UK Medical Research Council grant (G0701325; THJ Goodship), CTSA Grant Number I ULI RR025014-02 (AM Stevens) from the National Center for Research Resources (NCRR), Kirkland Scholar Award (LA Criswell and JA James), and Federico Wilhelm Agricola Foundation Research Grant (BA Pons-Estel). The work reported on in this publication has been in part financially supported by the ESF, in the framework of the Research Networking Programmers European Science Foundation – The Identification of Novel Genes and Biomarkers for Systemic Lupus Erythematosus (BIOLUPUS)-RNP-083. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
