Genetics of Childhood-Onset Systemic Lupus Erythematosus

Area of Science:

• Genetics
• Immunology
• Pediatrics

Background:

• Genome-wide association studies (GWAS) have identified over 100 loci associated with systemic lupus erythematosus (SLE).
• These known SLE risk loci may also influence the age at which individuals are diagnosed with the disease.
• Understanding genetic factors affecting SLE onset age is crucial for early diagnosis and management.

Purpose of the Study:

• To identify genetic variants associated with the age of SLE diagnosis.
• To conduct a GWAS specifically for childhood-onset SLE (cSLE), defined as diagnosis before 18 years of age.
• To investigate the role of known SLE loci in determining age of SLE diagnosis.

Main Methods:

• Analysis of 1489 SLE patients with documented age at diagnosis, genotyped on multiethnic arrays with imputation for ungenotyped SNPs and HLA alleles.
• Testing of 142 non-HLA and 166 HLA SLE risk loci for association with log-transformed age of SLE diagnosis, adjusting for sex and principal components.
• A GWAS was performed comparing 346 cSLE patients to 4080 non-SLE controls of European and East Asian ancestry.

Main Results:

• A significant SLE risk SNP within CCDC113 was associated with a younger age of SLE diagnosis (P=6.3x10⁻⁶) and cSLE versus adult-onset SLE (aSLE).
• The first GWAS of cSLE identified a significant SNP (rs9268469) in TSBP1-AS1 on chromosome 6 (P=1.79x10⁻⁸).
• The HLA-DQA1 locus, previously associated with aSLE, was also identified in the cSLE GWAS.

Conclusions:

• A novel genetic locus, CCDC113, is significantly associated with earlier age of SLE diagnosis in a multi-ancestral cohort.
• The first GWAS for cSLE has identified a new risk locus, TSBP1-AS1.
• The findings highlight genetic contributions to SLE onset timing and specific risk factors for childhood disease.