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

Research output: Contribution to journalArticle

James Bentham, David L. Morris, Deborah S. Cunninghame Graham, Christopher L. Pinder, Philip Tombleson, Timothy W. Behrens, Javier Martín, Benjamin P. Fairfax, Julian C. Knight, Lingyan Chen, Joseph Replogle, Ann Christine Syvänen, Lars Rönnblom, Robert R. Graham, Joan E. Wither, John D. Rioux, Marta E. Alarcón-Riquelme, Timothy J. Vyse

Original languageEnglish
Pages (from-to)1457-1464
Number of pages8
JournalNature Genetics
Volume47
Issue number12
Early online date26 Oct 2015
DOIs
Accepted/In press2 Oct 2015
E-pub ahead of print26 Oct 2015
Published1 Dec 2015

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    41110_3_merged_1440442063.pdf, 772 KB, application/pdf

    Uploaded date:12 Jan 2016

    Version:Accepted author manuscript

King's Authors

Abstract

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.

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