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

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.

Recent insights into the genetic basis of systemic lupus erythematosus

“…Variation in genes coding for transcription factors downstream of TLR, including IRF5,41 42 IRF743 and IRF8,44 45 has been associated with SLE susceptibility. Robust associations of four IRF5 functional variants in multiple ancestries define haplotypes associated with increased, decreased, or neutral levels of risk for SLE, with functional consequences on the expression of IRF5, IFN-α and IFN-inducible chemokines 16.…”

“…Several additional genes within or downstream of the type I IFN pathway have been associated with the risk of SLE, including STAT4 , IFIH1 (IFN induced with helicase C domain 1) , TYK2 (tyrosine kinase 2) and PRDM1 (PR domain zinc finger protein 1) 44 47. IFIH1 detects RNA before type I IFN pathway activation; an allele of IFIH1 was associated with anti-dsDNA antibodies among patients of multiple ancestries with SLE 14 .…”

“…Other genes with roles in B-cell function associated with SLE susceptibility in single ancestry groups include those that encode: ETS1 (Ets-1 protein, or p54), which negatively regulates B-cell and T helper type 17 cell differentiation;59 IKZF1 (IKAROS family zinc finger 1), which regulates lymphocyte differentiation, proliferation and B-cell receptor signalling;44 AFF1 (AF4/FMR2 family member 1), which functions in normal lymphocyte development;60 RASGRP3 (ras guanyl-releasing protein 3), which transmits B-cell signals via Ras-ERK after B-cell receptor ligation, with potential impact on immunoglobulin production and B-cell proliferation;48 interleukin (IL)-21, which sustains antibody production, mediates antibody class switching and promotes differentiation of T helper type 17 cells (association with SLE described in European and Hispanic ancestry);61 and IL-10, which inhibits T cells and antigen-presenting cells while enhancing B-cell survival and activity 47. Ongoing work from our laboratory has identified a functional SNP in the 5′ region of IL10 , which is associated with higher messenger RNA and protein expression in SLE 62…”

Association of interferon-induced helicase C domain (IFIH1) gene polymorphisms with systemic lupus erythematosus and a relevant updated meta-analysis

“…The first confirmed association involving IFIH1 SNPs and SLE was made by Gateva et al (2009), who identified the altered risk of SLE derived from the A946T polymorphism (rs1990760) in populations from Sweden and the USA. Later, these results were replicated by Cunninghame Graham et al (2011), confirming that risk allele A or protective allele G were associated to SLE onset. Our results reinforced a previous GWAS, which reported a trend for association between rs1990760 and SLE susceptibility (SLEGEN et al, 2008).…”

“…Eleven and 109 articles were retrieved, respectively. Finally, IFIH1 rs1990760 was assessed in nine different association studies from six peer-reviewed articles, including a genome-wide association study (GWAS) (SLEGEN et al, 2008;Gateva et al, 2009;Gono et al, 2010;Cunninghame Graham et al, 2011;Cen et al, 2013a;Enevold et al, 2014). All articles ranged from 2008 to 2015 (Figure 1).…”