Genetics of Childhood-Onset Systemic Lupus Erythematosus.
Academic Article
Overview
abstract
OBJECTIVE: Genome-wide association studies (GWAS) have identified >100 loci for systemic lupus erythematosus (SLE). These loci may also affect age at diagnosis. We aimed to identify genetic variants for age at SLE diagnosis and to complete a GWAS of childhood-onset SLE (cSLE) in children diagnosed <18 years of age. METHODS: Patients met American College of Rheumatology and/or Systemic Lupus Erythematosus International Collaborative Clinics classification criteria, had documented age at diagnosis, and were genotyped on multiethnic arrays. Ungenotyped single nucleotide polymorphisms (SNPs) and HLA alleles were imputed to multiethnic 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 principal components (significance threshold P < 1.6 × 10-4). We also completed a GWAS of 346 patients with cSLE and 4,080 children and adolescents without SLE of European and East Asian ancestry (genome-wide significance P < 5 × 10-8). RESULTS: We included 1,489 patients with SLE, 51% of patients had cSLE, 88% of patients were female, 39% of patients were of European ancestry, 19% of patients were of East Asian ancestry, and 17% of patients were of Admixed ancestry. The median age at diagnosis was 17.7 years (interquartile range 14.0-30.9). One SLE-risk SNP, intronic to coiled-coil domain containing 113 (CCDC113) (chromosome 16), was associated with younger age at SLE diagnosis (β = -0.12, SE = 0.03, P = 6.3 × 10-6) and with cSLE versus adult-onset SLE (aSLE). GWAS of cSLE compared to controls without SLE identified significant chromosome 6 SNP rs9268469, intronic to TSBP1-AS1 (odds ratio 2.04 [95% confidence interval 1.59-2.63], P = 1.79 × 10-8) and HLA-DQA1. CONCLUSION: We identified a significant locus for younger age at SLE diagnosis, intronic to CCDC113, among a large multiancestral 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.
