Rare and common single nucleotide variants in childhood-onset systemic lupus erythematosus

Abstract

Background: SLE is a systemic autoimmune disease with a large number of common risk gene variants, but several rare gene variants can cause monogenic SLE. The relationship between common and rare variants in SLE is unclear. We therefore investigated the occurrence of rare deleterious variants in patients with childhood-onset SLE (cSLE) and adult-onset SLE (aSLE) and compared the frequency of these variants with their individual SLE polygenic risk score (PRS).

Materials and methods: Targeted sequencing of 1832 gene regions, including coding regions of 31 genes associated with monogenic SLE, was performed in 958 patients with SLE and 1026 healthy individuals. A total of 116 patients with SLE had disease onset before the age of 18 (cSLE). An SLE common variant PRS was created from 37 SLE genome-wide association study single nucleotide variants (SNVs).

Results: Rare coding deleterious SNVs (RD SNVs) were observed in 23 of the monogenic SLE-associated genes. Six per cent of patients with cSLE, compared with 3.2% of controls and 4.6% of patients with aSLE, carried rare deleterious alleles. In cSLE, RD SNVs were observed in the C1S, DDX58, IFIH1, IKZF1, RNASEH2A and C8A genes. A PRS analysis showed that patients with cSLE with any of these gene variants had a similar average PRS as control individuals.

Conclusion: RD SNVs were observed in a small proportion of cSLE and carriers of these RD SNVs had a PRS similar to healthy individuals, suggesting the importance of rare coding heterozygous variants in driving disease risk in a subset of children with SLE.

Keywords: Polymorphism, Genetic; Risk Factors; Systemic Lupus Erythematosus.

Figure 1. Boxplot of SLE polygenic risk score (PRS) values divided into five groups based on age at diagnosis and carrier status for rare deleterious single nucleotide variants (SNVs) in patients with SLE and healthy controls. The groups were compared pairwise using Student’s t-test. ****P<0.0001. aSLE, adult-onset SLE; cSLE, childhood-onset SLE; cSLE RD SNVs−, childhood-onset SLE without rare deleterious SNVs; cSLE RD SNVs+, childhood-onset SLE with rare deleterious SNVs; ns, not significant.