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.
Figure. Summary of the functional roles of likely causal genes in SLE and other autoimmune diseases.
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Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.
Bentham J, Morris DL, Cunninghame Graham DS, Pinder CL, Tombleson P, Behrens TW, Martín J, Fairfax BP, Knight JC, Chen L, Replogle J, Syvänen AC, Rönnblom L, Graham RR, Wither JE, Rioux JD, Alarcón-Riquelme ME, Vyse TJ.
Nat Genet. 2015 Oct 26. doi: 10.1038/ng.3434.