Identification of , and as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning.

OBJECTIVES

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning.

METHODS

We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning.

RESULTS

We identified three novel loci that surpassed genome-wide significance, including (rs13238909, p=4.40E-08), (rs2428, p=1.17E-08) and (rs2731783, p=1.08E-09). We also confirmed the association of locus with SLE (rs763361, p=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in locus reside in an enhancer and are associated with expression of in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE.

CONCLUSION

This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.