Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

Abstract

Objectives Following up the SLE GWAS identification of NMNAT2 at rs2022013, we fine-mapped its 150kb flanking regions containing NMNAT2 and SMG7 in a 15,292 case-control multi-ancestry population and tested functions of identified variants. Methods We performed genotyping using custom array, imputation by IMPUTE 2.1.2, and allele specific functions using qRT-PCR and luciferase reporter transfections. SLE PBMCs were cultured with siRNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. Results We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (P=2.4×10−8, OR=1.23 [95%CI=1.14–1.32]). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 SLE patients and 119 controls (P=1.1×10−3 and 6.8×10−8, respectively) and conferred reduced transcription activity in transfected HEK-293 and Raji cells (P=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including RNP and Sm. We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titers of SLE patients (r=−0.31, P=0.01), and SMG7 knockdown increased levels of ANA IgG and CCL19 in SLE PBMCs (P=2.0×10−5 and 2.0×10−4, respectively). Conclusions We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk-allele associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.

Meta-analysis of 208,370 East Asians identifies 113 genomic loci and yields new non-immune cell relevant biological insights for systemic lupus erythematosus

“…Our gene-level analysis showed that rs66977652 confers a significant eQTL effect on SMG7 (P=3.1×10 -15 in whole blood; Fig. 4c and Supplementary Figure 3) , suggesting the secondary signal might influence the risk of SLE by modulating SMG7 expression, which is supported by functional studies 39 . These findings suggest two potential effector genes, NCF2 and SMG7 , in a single locus 25,26 .…”

Genetics of systemic lupus erythematosus and Sjögren's syndrome: an update

“…95] shows all the risk loci for SLE and pSS that have been clearly replicated and confirmed up to date.…”

TGF-β1/p53 signaling in renal fibrogenesis

“…The mechanism appears to involve promotion of ATM-dependent phosphorylation and subsequent inhibition of the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2). This role for SMG7 may well have an impact on expression/function of p53 and recovery from AKI, particularly in patients with lupus nephitis who exhibit reduced expression of SMG7 [111]. The participation of MDM2 in fibrosis, however, is complex.…”