A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature1. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1-GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production2, predisposes to SLE (odds ratio (OR)=3.47 in Asians (Pmeta=3.1×10−104), OR=2.61 in European Americans, OR=2.02 in African Americans) and other autoimmune diseases, including primary Sjögren’s syndrome (OR=2.45 in Chinese, OR=2.35 in European Americans) and rheumatoid arthritis (OR=1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.

A single nucleotide polymorphism in theNCF1gene leading to reduced oxidative burst is associated with systemic lupus erythematosus

“…NCF1 genotyping requires specialised methods to exclude the non-functional NCF1- pseudo genes, and capture all functional gene copies. During the finalisation of this paper, a similar study was published confirming a strong effect of the NCF1-339 T allele on SLE and also on Sjögren’s syndrome and RA,24 thus two independently performed reports show that NCF1-339 is one of the strongest SNPs, outside the HLA region, associated with autoimmune diseases.…”

Metabolic abnormalities and oxidative stress in lupus

“…Conversely, a deficiency in NOX2 activity due to a missense mutation in the p47phox (NCF1) subunit of NOX is associated with enhanced risk to develop lupus and other autoimmune diseases [69]. Further, when greater copy numbers of NCF1 are present, corresponding with enhanced NOX2-derived ROS, protection against lupus was reported [69].…”

“…Further, when greater copy numbers of NCF1 are present, corresponding with enhanced NOX2-derived ROS, protection against lupus was reported [69]. This is akin to individuals with chronic granulomatous disease (CGD), which lack NOX activity and have an increased risk for autoimmune disease development and exhibit type I-IFN signatures [70].…”

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex

“…The importance of ROS in the regulation of inflammation also gains support from our earlier studies in which we through positional cloning of a disease linked genetic polymorphism, have identified Ncf1 (encoding for the p47 phox subunit of the NADPHoxidase complex) as a disease-associated gene [19] and the molecular basis being linked to a compromised ROS production [20]. Similarly, polymorphism of Ncf1 plays a role in human autoimmune diseases [21,22], and in animal models, it has been shown to be of importance for disease severity of arthritis, psoriasis, colitis, and lupus, reviewed in [14,23]. It is apparent from both pharmacological and genetic deletion studies, that FPRs have multiple roles in diseases conditions associated with a dysregulated inflammation.…”