Background/Purpose:

Systemic Lupus Erythematosus (SLE) is a phenotypically heterogeneous complex disease.  Our previous work has documented significant genetic heterogeneity, with some well-validated risk factors demonstrating strong sub-group effects.  Approximately 50% of patients have high circulating levels of interferon alpha (IFN-α), and many lines of investigation support IFN-α as a heritable and primary causal factor in human SLE.  This study aims to genetically map the serum IFN-α trait in SLE patients, allowing for novel genetic discovery in this heterogeneous disease.

Methods:

GWAS data were obtained from 450 European ancestry SLE cases who were genotyped as part of the Systemic Lupus Erythematosus Genetics (SLEGEN) study.  Genotypes were generated on the Illumina Infinium HumanHap 300 genotyping platform, and principal component analysis was used to correct for population stratification.  Sera were obtained from each of these subjects, and IFN-α activity was measured using a sensitive and specific reporter cell assay.  Associations between genome-wide SNP markers and serum IFN-α were detected using logistic regression conditioned on the principal components to control for structure.  IFN-α activity was studied as a categorical trait.  Patients with IFN-α levels 2SD above the mean of healthy controls were designated as high IFN-α, and the remainder as low IFN-α.

Results:

Top novel associated loci in the GWAS screen include multiple SNPs in the C7orf57, PRKG1, ANKRD44, and PNP loci.  Interestingly, three of the 5 top SNPs are missense SNPs.  Strong association signals were also detected in chromosomes 12 and 14. Genome-wide imputation using SNPs from the 1000 Genomes Project did not yield additional significant association signals beyond those identified by the directly genotyped SNPs.

Conclusion:

These novel loci have not been previously associated with SLE in case-control analyses.  This supports the concept that studying pathogenic subgroups within the complex disease SLE will be important in our efforts to fully map disease susceptibility.  These loci could provide novel therapeutic targets in the IFN-α pathway and assist in personalizing therapy in this disease.