Abstract
Systemic lupus erythematosus (SLE) is a complex trait characterised by the production of a range of auto-antibodies and a diverse set of clinical phenotypes. Currently, ∼8% of the genetic contribution to SLE in Europeans is known, following publication of several moderate-sized genome-wide (GW) association studies, which identified loci with a strong effect (OR>1.3). In order to identify additional genes contributing to SLE susceptibility, we conducted a replication study in a UK dataset (870 cases, 5,551 controls) of 23 variants that showed moderate-risk for lupus in previous studies. Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (Pcomb<5×10−8): NCF2 (P comb = 2.87×10−11), IKZF1 (P comb = 2.33×10−9), IRF8 (P comb = 1.24×10−8), IFIH1 (P comb = 1.63×10−8), and TYK2 (P comb = 3.88×10−8). Each of the five new loci identified here can be mapped into interferon signalling pathways, which are known to play a key role in the pathogenesis of SLE. These results increase the number of established susceptibility genes for lupus to ∼30 and validate the importance of using large datasets to confirm associations of loci which moderately increase the risk for disease.
Highlights
Systemic lupus erythematosus (SLE) is a relapsing-remitting complex trait which most commonly affects women of childbearing age, with a ratio of 9:1 in female to males
Increased understanding of the underlying genetic basis for lupus is of key importance in improving the prognosis for lupus patients
The aim of the current work was to perform a replication study using our UK SLE cohort on loci that showed some evidence for Genome-wide association studies have revolutionised our ability to identify common susceptibility alleles for systemic lupus erythematosus (SLE)
Summary
Systemic lupus erythematosus (SLE) is a relapsing-remitting complex trait which most commonly affects women of childbearing age, with a ratio of 9:1 in female to males. The disease prevalence varies with ethnicity, being more prevalent in nonEuropean populations (approximately 1:500 in populations with African ancestry and 1:2500 in Northern Europeans) [1]. The wide-ranging clinical phenotypes include skin rash, neuropsychiatric and musculosketal symptoms and lupus nephritis, which may be partially mediated by the extensive deposition of immune complexes. Thanks to improved treatments, the 10-year survival rate after diagnosis has increased to 90%, with lower survival rates being related to disease severity or complications from treatment [3]. Increased understanding of the underlying genetic basis for lupus is of key importance in improving the prognosis for lupus patients
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