Subphenotype mapping in systemic lupus erythematosus identifies multiple novel loci associated with circulating interferon alpha

Background

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems, loss of tolerance to self-antigens, and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, and we hypothesize that this greatly reduces the power of overall case-control studies in SLE. Increased circulating level of the cytokine interferon alpha (IFNα) is a stable, heritable trait in SLE which has been implicated in primary disease pathogenesis. Forty to 50% of patients have high IFNα, and high levels correspond with clinical differences.

Methods

To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high versus low IFNα in over 1,800 SLE cases. Four hundred European ancestry cases formed the discovery GWAS set, and 1,443 cases from a large independent multi-ancestral replication cohort were used to validate associations.

Results

In meta-analysis, the top associations in European ancestry were PRKG1 rs7897633 (P_Meta = 2.75 × 10^-8) and PNP rs1049564 (P_Meta = 1.24 × 10^-7). We also found evidence for cross-ancestral background associations with the ANKRD44 and PLEKHF2 loci. These loci have not been previously identified in case-control SLE genetics studies. Bioinformatic analyses implicate these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFNα production in SLE.

Conclusions

As case-control studies of complex heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic subphenotypes becomes a highly attractive and efficient strategy for genetic discovery in complex human disease.