Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.
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.
Division of Genetics and Molecular Medicine, King's College London, UK.
James
J
Bentham
Division of Genetics and Molecular Medicine, King's College London, UK.
David L
DL
Morris
Division of Genetics and Molecular Medicine, King's College London, UK.
Deborah S Cunninghame
DSC
Graham
Division of Genetics and Molecular Medicine, King's College London, UK.
Christopher L
CL
Pinder
Division of Genetics and Molecular Medicine, King's College London, UK.
Philip
P
Tombleson
Genentech, Inc., South San Francisco, California, USA.
Timothy W
TW
Behrens
Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
Javier
J
Martín
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Benjamin P
BP
Fairfax
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Julian C
JC
Knight
Division of Genetics and Molecular Medicine, King's College London, UK.
Lingyan
L
Chen
Harvard Medical School, Boston, Massachusetts, USA.
Joseph
J
Replogle
Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Ann-Christine
AC
Syvänen
Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Lars
L
Rönnblom
Genentech, Inc., South San Francisco, California, USA.
Robert R
RR
Graham
Toronto Western Research Institute (TWRI), University Health Network, Toronto, Ontario, Canada.
Joan E
JE
Wither
Université de Montréal, Montreal, Quebec, Canada.|Montreal Heart Institute, Montreal, Quebec, Canada.
John D
JD
Rioux
Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain.
Marta E
ME
Alarcón-Riquelme
Division of Genetics and Molecular Medicine, King's College London, UK.|Division of Immunology, Infection and Inflammatory Disease, King's College London, UK.
Timothy J
TJ
Vyse
D056704:Adaptive Immunity / Q000235:genetics*; D016022:Case-Control Studies; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D056426:Genetic Loci; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
D005819:Genetic Markers