GENETIC VARIANTS IN SLE SUSCEPTIBILITY LOCI, XKR6 AND GLT1D1, ARE ASSOCIATED WITH CHILDHOOD-ONSET SLE IN A KOREAN COHORT

Abstract

Background Systemic lupus erythematosus (SLE) is a polygenic autoimmune disease that occurs in all ages. It has been well documented that younger age of SLE onset is associated with more severe clinical manifestations and worse outcomes. However, impact of genetic variants on age of SLE onset was not fully understood.

Objectives We investigated a cumulative effect of reported SLE-risk variants on childhood-onset SLE and searched for new risk loci of childhood-onset SLE using a genome-wide SNP analysis.

Methods We analysed 96 Korean childhood-onset (<16 years old) and 685 adult-onset SLE (≥16 years old) who were previously genotyped by both Immunochip and genome-wide SNP arrays. Individual genetic risk scores (GRS) from well-validated SLE susceptibility loci (45 Asian confirmed non-HLA loci and an HLA-DRB1 amino acid haplotype model) were calculated and tested for their association with childhood-onset SLE. Association of each genetic variant with childhood-onset SLE was analysed using a multivariable logistic regression adjusting for population substructure.

Results Mean age of SLE onset was 12.5±2.5 years in childhood-onset SLE and 29.0±9.4 in adult-onset SLE. GRS from SLE susceptibility loci was significantly higher in childhood-onset SLE than adult-onset SLE (p=0.001). Two SNPs, rs7460469 in XKR6 and rs7300146 in GLT1D1, showed the most significant associations with childhood-onset SLE (p=1.26x10–8, OR=0.18, and p=1.49x10–8, OR=0.35, respectively). Especially, rs7300146 in GLT1D1 was the cis expression quantitative trait locus (eQTL) for SLC15A4, which has been known an SLE susceptibility gene in a Chinese population. The model consisting of SLE GRS and the two newly identified loci to predict childhood-onset SLE attained an area under curve (AUC) of 0.71 in a receiver operating characteristics (ROC) curve.