Genetics of Childhood-onset Systemic Lupus Erythematosus (cSLE)

Abstract

Objectives: Genome wide association studies (GWAS) have identified >100 loci for systemic lupus erythematosus (SLE). These loci may also impact age of diagnosis. We aimed to identify genetic variants for age of SLE diagnosis, and to complete a GWAS of childhood-onset SLE (cSLE) diagnosed <18 years of age.

Methods: Patients met ACR and/or SLICC SLE classification criteria, had documented age at diagnosis and were genotyped on multiethnic arrays. Ungenotyped SNPs and HLA alleles were imputed to multi-ethnic referents. Ancestry was genetically inferred. We tested known SLE loci (142 non-HLA, 166 HLA) with log-transformed age of SLE diagnosis, adjusted for sex and five PCs (significance threshold P<1.6x10^-4). We also completed a GWAS of 346 cSLE patients and 4080 non-SLE children/adolescents of European and East Asian ancestry (genome-wide significance P<5x10^-8).

Results: We included 1489 SLE patients, 51% cSLE, 88% female, 39% of European ancestry, 19% East Asian, 17% Admixed. The median age at diagnosis was 17.7 years (IQR:14.0, 30.9). One SLE risk SNP, intronic to CCDC113 (chr.16), was associated with younger age of SLE diagnosis (beta=-0.12, SE=0.03, P=6.3x10^-6), and with cSLE versus adult-onset SLE (aSLE). GWAS of cSLE compared to non-SLE controls identified significant chr.6 SNP rs9268469, intronic to TSBP1-AS1 (OR=2.04, [95%CI: 1.59, 2.63], P=1.79x10^-8), and HLA-DQA1.

Conclusions: We identified a significant locus for younger age of SLE diagnosis, intronic to CCDC113, among a large multi-ancestral cohort of children and adults with SLE. In the first GWAS of cSLE we identified a TSBP1-AS1 locus, and an HLA-DQA1 previously identified for aSLE.