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Association of Genetic Variants in Complement Factor H and Factor H-Related Genes with Systemic Lupus Erythematosus Susceptibility

Lookup NU author(s): Professor Tim Goodship

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Abstract

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.


Publication metadata

Author(s): Zhao J, Wu H, Khosravi M, Cui HJ, Qian XX, Kelly JA, Kaufman KM, Langefeld CD, Williams AH, Comeau ME, Ziegler JT, Marion MC, Adler A, Glenn SB, Alarcon-Riquelme ME, Pons-Estel BA, Harley JB, Bae SC, Bang SY, Cho SK, Jacob CO, Vyse TJ, Niewold TB, Gaffney PM, Moser KL, Kimberly RP, Edberg JC, Brown EE, Alarcon GS, Petri MA, Ramsey-Goldman R, Vila LM, Reveille JD, James JA, Gilkeson GS, Kamen DL, Freedman BI, Anaya JM, Merrill JT, Criswell LA, Scofield RH, Stevens AM, Guthridge JM, Chang DM, Song YW, Park JA, Lee EY, Boackle SA, Grossman JM, Hahn BH, Goodship THJ, Cantor RM, Yu CY, Shen N, Tsao BP, BIOLUPUS Network, GENLES Network

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2011

Volume: 7

Issue: 5

Print publication date: 26/05/2011

Date deposited: 04/11/2011

ISSN (print): 1553-7390

ISSN (electronic):

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pgen.1002079

DOI: 10.1371/journal.pgen.1002079


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Funding

Funder referenceFunder name
Arthritis Foundation
Arthritis Research UK
ESF
Federico Wilhelm Agricola Foundation
Kirkland Scholar Award
Welcome Trust
Alliance for Lupus Research
Arthritis National Research Foundation
King Gustaf Vth 80th Jubilee
Lupus Foundation
Lupus Research Institute
National Center for Research Resources (NCRR)
Networking Programmers European Science Foundation
Swedish Association Against Rheumatism
Swedish Research Council
US Department of Veterans Affairs
10035615MKE/KEIT
A080588Ministry for Health and Welfare, Republic of Korea
AR43727US National Institutes of Health
K08AI083790US National Institutes of Health
K24AR002138US National Institutes of Health
G0701325UK Medical Research Council
M01RR00079US National Institutes of Health
N01AI50026US National Institutes of Health
I ULI RR025014-02CTSA
LRPAI071651US National Institutes of Health
P01AI083194US National Institutes of Health
P20RR015577US National Institutes of Health
P20RR020143US National Institutes of Health
P30AR053483US National Institutes of Health
P60AR053308US National Institutes of Health
N01AR62277US National Institutes of Health
R01AI063274US National Institutes of Health
R01AR043814US National Institutes of Health
R01AR33062US National Institutes of Health
R01CA141700US National Institutes of Health
RC1AR058554US National Institutes of Health
P01AR049084US National Institutes of Health
P01AR49084US National Institutes of Health
P602AR30692US National Institutes of Health
P60AR049459US National Institutes of Health
PI-0012Consejeria de Salud de Andalucia
PR094002US Department of Defense
PS0900129Fundacion Instituto de Salud Carlos III
U19AI082714US National Institutes of Health
UL1RR024999US National Institutes of Health
UL1RR029882US National Institutes of Health
R01AR042460US National Institutes of Health
R01AR043274US National Institutes of Health
R01AR051545-01A2US National Institutes of Health
R01AR054459US National Institutes of Health
R21AI070304US National Institutes of Health
R37AI024717US National Institutes of Health
RC1AR058621US National Institutes of Health
UL1RR025005US National Institutes of Health
UL1RR025741US National Institutes of Health

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