Background and aims We recently identified ten novel SLE susceptibility loci in Asian populations and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci followed by meta-analysis, and perform a series of bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures.
Methods We investigated five loci in a Han Chinese cohort, and performed meta-analysis together with 11 656 cases and 23 968 controls from previously reported Asian and European populations. Epigenomic analysis was performed using ENCODE and GETEx data.
Results All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta=1.92×10-13), ATG16L2 (rs11235604, Pmeta=8.87×10-12), CCL22 (rs223881, Pmeta=5.87×10-16), ANKS1A (rs2762340, Pmeta=4.93×10-15) and RNASEH2C (rs1308020, Pmeta=2.96×10-19) and co-located with annotated gene regulatory elements. The novel SLE loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Using the correlated SNPs (r2 >0.8) from the 82 SLE loci, we found only 1.5% SNPs encode missense or synonymous mutations, and the majority (56%) were implicated in differential expression of cis-genes (9.81 × 10–198<P<5×10-3). Significant over-representation (p<0.05) of transcription factor binding sites for p53, MEF2A and E2F1. Enrichment analysis highlights the involvement of common pathways, gene ontology, protein domains, and.the importance of these loci in B and T cell biology.
Conclusions We provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 SLE loci revealed that SLE susceptibility loci share gene regulatory features, including significant enrichment of epigenetic marks and transcription factor binding sites, suggestive of shared regulatory mechanisms of SLE etiopathogenesis.
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