Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus

TLDR

Systemic lupus erythematosus is a complex autoimmune disease with diverse phenotypes, and only about 8 % of its genetic contribution is known, though several loci with strong effects have been identified, including five new loci that map to interferon‑signalling pathways. The study aimed to identify additional SLE‑susceptibility genes by replicating 23 moderate‑risk variants in a UK cohort of 870 cases and 5,551 controls. The authors performed association analysis on the UK cohort and meta‑analyzed the results with published data to identify genome‑wide significant SLE susceptibility genes. The meta‑analysis identified five genome‑wide significant SLE susceptibility genes—NCF2, IKZF1, IRF8, IFIH1, and TYK2—raising the total to about 30 genes and underscoring the value of large datasets for confirming moderate‑risk loci.

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 (Pcomb = 2.87×10−11), IKZF1 (Pcomb = 2.33×10−9), IRF8 (Pcomb = 1.24×10−8), IFIH1 (Pcomb = 1.63×10−8), and TYK2 (Pcomb = 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.