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Nat Genet. 2015 Dec;47(12):1457-1464. doi: 10.1038/ng.3434. Epub 2015 Oct 26.

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

Author information

1
Division of Genetics and Molecular Medicine, King's College London, UK.
2
Genentech, Inc., South San Francisco, California, USA.
3
Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
5
Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
7
Toronto Western Research Institute (TWRI), University Health Network, Toronto, Ontario, Canada.
8
Université de Montréal, Montreal, Quebec, Canada.
9
Montreal Heart Institute, Montreal, Quebec, Canada.
10
Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain.
11
Division of Immunology, Infection and Inflammatory Disease, King's College London, UK.
#
Contributed equally

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.

PMID:
26502338
PMCID:
PMC4668589
DOI:
10.1038/ng.3434
[Indexed for MEDLINE]
Free PMC Article

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