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.
Funding Information
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
