Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

被引:671
作者
Bentham, James [1 ]
Morris, David L. [1 ]
Graham, Deborah S. Cunninghame [1 ]
Pinder, Christopher L. [1 ]
Tombleson, Philip [1 ]
Behrens, Timothy W. [2 ]
Martin, Javier [3 ]
Fairfax, Benjamin P. [4 ]
Knight, Julian C. [4 ]
Chen, Lingyan [1 ]
Replogle, Joseph [5 ]
Syvanen, Ann-Christine [6 ]
Ronnblom, Lars [6 ]
Graham, Robert R. [2 ]
Wither, Joan E. [7 ]
Rioux, John D. [8 ,9 ]
Alarcon-Riquelme, Marta E. [10 ]
Vyse, Timothy J. [1 ,11 ]
机构
[1] Kings Coll London, Div Genet & Mol Med, London WC2R 2LS, England
[2] Genentech Inc, San Francisco, CA 94080 USA
[3] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain
[4] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England
[5] Harvard Univ, Sch Med, Boston, MA USA
[6] Uppsala Univ, Dept Med Sci, Sci Life Lab, Uppsala, Sweden
[7] Univ Hlth Network, TWRI, Toronto, ON, Canada
[8] Univ Montreal, Genet & Genom Med Inflammat, Montreal, PQ, Canada
[9] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada
[10] Pfizer Univ Granada Junta Andalucia, Ctr Genom & Invest Oncol GENYO, Granada, Spain
[11] Kings Coll London, Div Immunol Infect & Inflammatory Dis, London WC2R 2LS, England
基金
美国国家卫生研究院; 英国惠康基金; 瑞典研究理事会; 加拿大健康研究院;
关键词
GENOME-WIDE ASSOCIATION; POPULATION STRATIFICATION; SUSCEPTIBILITY VARIANTS; HLA ALLELES; T-CELLS; POLYMORPHISM; AUTOIMMUNE; EXPRESSION; RISK; IMPUTATION;
D O I
10.1038/ng.3434
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.
引用
收藏
页码:1457 / +
页数:11
相关论文
共 80 条
  • [1] Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus
    Adrianto, Indra
    Wen, Feng
    Templeton, Amanda
    Wiley, Graham
    King, Jarrod B.
    Lessard, Christopher J.
    Bates, Jared S.
    Hu, Yanqing
    Kelly, Jennifer A.
    Kaufman, Kenneth M.
    Guthridge, Joel M.
    Alarcon-Riquelme, Marta E.
    Anaya, Juan-Manuel
    Bae, Sang-Cheol
    Bang, So-Young
    Boackle, Susan A.
    Brown, Elizabeth E.
    Petri, Michelle A.
    Gallant, Caroline
    Ramsey-Goldman, Rosalind
    Reveille, John D.
    Vila, Luis M.
    Criswell, Lindsey A.
    Edberg, Jeffrey C.
    Freedman, Barry I.
    Gregersen, Peter K.
    Gilkeson, Gary S.
    Jacob, Chaim O.
    James, Judith A.
    Kamen, Diane L.
    Kimberly, Robert P.
    Martin, Javier
    Merrill, Joan T.
    Niewold, Timothy B.
    Park, So-Yeon
    Pons-Estel, Bernardo A.
    Scofield, R. Hal
    Stevens, Anne M.
    Tsao, Betty P.
    Vyse, Timothy J.
    Langefeld, Carl D.
    Harley, John B.
    Moser, Kathy L.
    Webb, Carol F.
    Humphrey, Mary Beth
    Montgomery, Courtney Gray
    Gaffney, Patrick M.
    [J]. NATURE GENETICS, 2011, 43 (03) : 253 - U102
  • [2] Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort
    Alarcon-Segovia, D
    Alarcón-Riquelme, ME
    Cardiel, MH
    Caeiro, F
    Massardo, L
    Villa, AR
    Pons-Estel, BA
    [J]. ARTHRITIS AND RHEUMATISM, 2005, 52 (04): : 1138 - 1147
  • [3] Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus
    Alexander, Tobias
    Sattler, Arne
    Templin, Lars
    Kohler, Siegfried
    Gross, Christian
    Meisel, Andreas
    Sawitzki, Birgit
    Burmester, Gerd-Ruediger
    Arnold, Renate
    Radbruch, Andreas
    Thiel, Andreas
    Hiepe, Falk
    [J]. ANNALS OF THE RHEUMATIC DISEASES, 2013, 72 (09) : 1549 - 1558
  • [4] An integrated map of genetic variation from 1,092 human genomes
    Altshuler, David M.
    Durbin, Richard M.
    Abecasis, Goncalo R.
    Bentley, David R.
    Chakravarti, Aravinda
    Clark, Andrew G.
    Donnelly, Peter
    Eichler, Evan E.
    Flicek, Paul
    Gabriel, Stacey B.
    Gibbs, Richard A.
    Green, Eric D.
    Hurles, Matthew E.
    Knoppers, Bartha M.
    Korbel, Jan O.
    Lander, Eric S.
    Lee, Charles
    Lehrach, Hans
    Mardis, Elaine R.
    Marth, Gabor T.
    McVean, Gil A.
    Nickerson, Deborah A.
    Schmidt, Jeanette P.
    Sherry, Stephen T.
    Wang, Jun
    Wilson, Richard K.
    Gibbs, Richard A.
    Dinh, Huyen
    Kovar, Christie
    Lee, Sandra
    Lewis, Lora
    Muzny, Donna
    Reid, Jeff
    Wang, Min
    Wang, Jun
    Fang, Xiaodong
    Guo, Xiaosen
    Jian, Min
    Jiang, Hui
    Jin, Xin
    Li, Guoqing
    Li, Jingxiang
    Li, Yingrui
    Li, Zhuo
    Liu, Xiao
    Lu, Yao
    Ma, Xuedi
    Su, Zhe
    Tai, Shuaishuai
    Tang, Meifang
    [J]. NATURE, 2012, 491 (7422) : 56 - 65
  • [5] The expanding genetic overlap between multiple sclerosis and type I diabetes
    Booth, David R.
    Heard, Robert N.
    Stewart, Graeme J.
    Goris, An
    Dobosi, Rita
    Dubois, Benedicte
    Lorentzen, Aslaug R.
    Celius, Elisabeth G.
    Harbo, Hanne F.
    Spurkland, Anne
    Olsson, Tomas
    Kockum, Ingrid
    Link, Jenny
    Hillert, Jan
    Ban, Maria
    Baker, Amie
    Sawcer, Stephen
    Compston, Alastair
    Mihalova, Tania
    Strange, Richard
    Hawkins, Clive
    Ingram, Gillian
    Robertson, Neil P.
    De Jager, Philip L.
    Hafler, David A.
    Barcellos, Lisa F.
    Ivinson, Adrian J.
    Pericak-Vance, Margaret
    Oksenberg, Jorge R.
    Hauser, Stephen L.
    McCauley, Jacob L.
    Sexton, David
    Haines, Jonathan
    [J]. GENES AND IMMUNITY, 2009, 10 (01) : 11 - 14
  • [6] The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus
    Bronson, P. G.
    Goldstein, B. A.
    Ramsay, P. P.
    Beckman, K. B.
    Noble, J. A.
    Lane, J. A.
    Seldin, M. F.
    Kelly, J. A.
    Harley, J. B.
    Moser, K. L.
    Gaffney, P. M.
    Behrens, T. W.
    Criswell, L. A.
    Barcellos, L. F.
    [J]. GENES AND IMMUNITY, 2011, 12 (08) : 667 - 671
  • [7] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
    Burton, Paul R.
    Clayton, David G.
    Cardon, Lon R.
    Craddock, Nick
    Deloukas, Panos
    Duncanson, Audrey
    Kwiatkowski, Dominic P.
    McCarthy, Mark I.
    Ouwehand, Willem H.
    Samani, Nilesh J.
    Todd, John A.
    Donnelly, Peter
    Barrett, Jeffrey C.
    Davison, Dan
    Easton, Doug
    Evans, David
    Leung, Hin-Tak
    Marchini, Jonathan L.
    Morris, Andrew P.
    Spencer, Chris C. A.
    Tobin, Martin D.
    Attwood, Antony P.
    Boorman, James P.
    Cant, Barbara
    Everson, Ursula
    Hussey, Judith M.
    Jolley, Jennifer D.
    Knight, Alexandra S.
    Koch, Kerstin
    Meech, Elizabeth
    Nutland, Sarah
    Prowse, Christopher V.
    Stevens, Helen E.
    Taylor, Niall C.
    Walters, Graham R.
    Walker, Neil M.
    Watkins, Nicholas A.
    Winzer, Thilo
    Jones, Richard W.
    McArdle, Wendy L.
    Ring, Susan M.
    Strachan, David P.
    Pembrey, Marcus
    Breen, Gerome
    St Clair, David
    Caesar, Sian
    Gordon-Smith, Katherine
    Jones, Lisa
    Fraser, Christine
    Green, Elain K.
    [J]. NATURE, 2007, 447 (7145) : 661 - 678
  • [8] ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis
    Caster, Dawn J.
    Korte, Erik A.
    Nanda, Sambit K.
    McLeish, Kenneth R.
    Oliver, Rebecca K.
    G'Sell, Rachel T.
    Sheehan, Ryan M.
    Freeman, Darrell W.
    Coventry, Susan C.
    Kelly, Jennifer A.
    Guthridge, Joel M.
    James, Judith A.
    Sivils, Kathy L.
    Alarcon-Riquelme, Marta E.
    Scofield, R. Hal
    Adrianto, Indra
    Gaffney, Patrick M.
    Stevens, Anne M.
    Freedman, Barry I.
    Langefeld, Carl D.
    Tsao, Betty P.
    Pons-Estel, Bernardo A.
    Jacob, Chaim O.
    Kamen, Diane L.
    Gilkeson, Gary S.
    Brown, Elizabeth E.
    Alarcon, Graciela S.
    Edberg, Jeffrey C.
    Kimberly, Robert P.
    Martin, Javier
    Merrill, Joan T.
    Harley, John B.
    Kaufman, Kenneth M.
    Reveille, John D.
    Anaya, Juan-Manuel
    Criswell, Lindsey A.
    Vila, Luis M.
    Petri, Michelle
    Ramsey-Goldman, Rosalind
    Bae, Sang-Cheol
    Boackle, Susan A.
    Vyse, Timothy J.
    Niewold, Timothy B.
    Cohen, Philip
    Powell, David W.
    [J]. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2013, 24 (11): : 1743 - 1754
  • [9] Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK
    Castillejo-Lopez, Casimiro
    Delgado-Vega, Angelica M.
    Wojcik, Jerome
    Kozyrev, Sergey V.
    Thavathiru, Elangovan
    Wu, Ying-Yu
    Sanchez, Elena
    Pollmann, David
    Lopez-Egido, Juan R.
    Fineschi, Serena
    Dominguez, Nicolas
    Lu, Rufei
    James, Judith A.
    Merrill, Joan T.
    Kelly, Jennifer A.
    Kaufman, Kenneth M.
    Moser, Kathy L.
    Gilkeson, Gary
    Frostegard, Johan
    Pons-Estel, Bernardo A.
    D'Alfonso, Sandra
    Witte, Torsten
    Luis Callejas, Jose
    Harley, John B.
    Gaffney, Patrick M.
    Martin, Javier
    Guthridge, Joel M.
    Alarcon-Riquelme, Marta E.
    [J]. ANNALS OF THE RHEUMATIC DISEASES, 2012, 71 (01) : 136 - 142
  • [10] Genetic variation near IRF8 is associated with serologic and cytokine profiles in systemic lupus erythematosus and multiple sclerosis
    Chrabot, B. S.
    Kariuki, S. N.
    Zervou, M. I.
    Feng, X.
    Arrington, J.
    Jolly, M.
    Boumpass, D. T.
    Reder, A. T.
    Goulielmos, G. N.
    Niewold, T. B.
    [J]. GENES AND IMMUNITY, 2013, 14 (08) : 471 - 478