@article{39d13ce320a94d8cb50754e29be9d92e,
title = "Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA",
abstract = "Objectives Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. Methods Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. Results The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10-4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10-7, OR 0.71; case-only pmeta=1.9×10-4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. Conclusions These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.",
author = "{BIOLUPUS and GENLES Networks} and Jian Zhao and Giles, {Brendan M.} and Taylor, {Rhonda L.} and Yette, {Gabriel A.} and Lough, {Kara M.} and Ng, {Han Leng} and Abraham, {Lawrence J.} and Hui Wu and Kelly, {Jennifer A.} and Glenn, {Stuart B.} and Adler, {Adam J.} and Williams, {Adrienne H.} and Comeau, {Mary E.} and Ziegler, {Julie T.} and Miranda Marion and Alarc{\'o}n-Riquelme, {Marta E.} and Alarc{\'o}n, {Graciela S.} and Anaya, {Juan Manuel} and Bae, {Sang Cheol} and Dam Kim and Lee, {Hye Soon} and Criswell, {Lindsey A.} and Freedman, {Barry I.} and Gilkeson, {Gary S.} and Guthridge, {Joel M.} and Jacob, {Chaim O.} and James, {Judith A.} and Kamen, {Diane L.} and Merrill, {Joan T.} and Sivils, {Kathy Moser} and Niewold, {Timothy B.} and Petri, {Michelle A.} and Rosalind Ramsey-Goldman and Reveille, {John D.} and Scofield, {R. Hal} and Stevens, {Anne M.} and Vil{\'a}, {Luis M.} and Vyse, {Timothy J.} and Kaufman, {Kenneth M.} and Harley, {John B.} and Langefeld, {Carl D.} and Gaffney, {Patrick M.} and Brown, {Elizabeth E.} and Edberg, {Jeffrey C.} and Kimberly, {Robert P.} and Daniela Ulgiati and Tsao, {Betty P.} and Boackle, {Susan A.} and Johan Frosteg{\aa}rd and Lennart Truedsson",
note = "Funding Information: The quality of the RNA samples prepared from healthy human subjects was evaluated in the University of Colorado Cancer Center Microarray Core, which is supported by the NIH/NCI Cancer Core Support Grant (P30 CA046934). Flow cytometry was carried out in the Barbara Davis Center Flow Cytometry Core Facility, which was supported by National Institutes of Health (NIH) grant P30 DK57516. This work was also supported by the US National Institutes of Health [R01AI070983 (S.A.B, B.P.T., D.U.), K24AI078004 (S.A.B.), T32AR07534 (B.M.G.), K24AR002138 (R.R.G.), LRPAI071651 (T.B.N.), K08AI083790 (T.B.N.), N01AR062277 ( J.B.H.), P01AI083194 ( J.B.H.), P01AR049084 (R.P.K., J.B.H., J.C.E., E.E.B., G.S.A., J.D.R., R.R.G., and M.A.P.), P20RR020143 ( J.B.H.), P30AR048311 (E.E.B.), P30AR053483 ( J.A.J and J.M.G.), P30AR055385 (E.E.B.), P30GM103510 ( J.A.J.), P60AR030692 (R.R.G.), P60AR062755 (D.L.K.), P60AR053308 (L.A.C.), R01AI063274 (P.M.G.), R01AR033062 (R.P.K.), R01AR042460 ( J.B.H.), R01AR043274 (K.M.S.), R01AR43727 (M.A.P.), R01AR043814 (B.P.T.), R01AR051545 (A.M.S.), R01AR057172 (C.O.J.), R01CA141700 (M.E.A.R.), R21AI070304 (S.A.B.), R37AI024717 ( J.B.H.), RC1AR058621 (M.E.A.R.), U01AI101934 ( J.A.J. and J.M. G.), U19AI082714 ( J.A.J. and J.M.G.), U54RR023417 ( J.D.R.), UL1RR024999 (T.B. N.), UL1RR025014 (A.M.S.), UL1RR025741 (R.R.G.), UL1RR025777 (R.P.K. and J.C. E.), UL1RR029882 (D.L.K.), and UL1TR000004 (L.A.C.)], the Alliance for Lupus Research (S.A.B., B.P.T., D.U., K.M.S., T.B.N., L.A.C. and C.O.J.), the Lupus Research Institute (B.P.T., T.B.N.), the US Department of Veterans Affairs (Merit Awards; J.B. H., G.S.G.), the US Department of Defense (PR094002, J.B.H.), the Arthritis National Research Foundation (Eng Tan Scholar Award; J.Z. and T.B.N.), the Arthritis Foundation (A.M.S., and P.M.G.), the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A121983; S.C.B.), the European Science Foundation RNP (BIOLUPUS Research Network), the Wellcome Trust (T.J.V.), Arthritis Research UK (T.J.V.), a Kirkland Scholar Award (L.A.C.), and the Wake Forest School of Medicine Center for Public Health Genomics (C.D.L.). The funders had no role in study design, data collection, analysis and interpretation, writing of the report or decision to submit the paper for publication.",
year = "2016",
month = jan,
day = "1",
doi = "10.1136/annrheumdis-2014-205584",
language = "English (US)",
volume = "75",
pages = "242--252",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",
number = "1",
}