Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. 40–50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs. low IFN-α in over 1550 SLE cases, including GWAS and replication cohorts. In meta-analysis, the top associations in European ancestry were PRKG1 rs7897633 (PMeta=2.75 × 10−8) and PNP rs1049564 (PMeta=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 genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic subphenotypes becomes an attractive strategy for genetic discovery in complex disease.

Widely divergent transcriptional patterns between SLE patients of different ancestral backgrounds in sorted immune cell populations

“…To control for genetic ancestry and admixture, we genotyped 332 ancestry-informative markers (AIMs) designating continental ancestry in all of our cases and controls, as described in [38]. The AIMs data were analyzed using principal component analysis, and the first principal component designated African vs. non-African ancestry, as would be expected.…”

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

“…ITGAM SNPs correlate with elevated IFN-I activity in SLE patients. (A) Functional IFN-I activity, as determined using reporter cell assay (3,78), in serum samples from 171 SLE subjects genotyped for 3 ITGAM SNPs (rs1143678, rs1143679, and rs1143683) and its association with minor allele carriers compared with carriers of major alleles, stratified by high versus low IFN-I levels. Each dot represents a unique sample.…”

Advances in lupus genetics

“…Studies have been conducted to identify novel genetic risk factors for SLE using serum IFN as the genetic trait and determining which genetic polymorphisms are associated with high IFN levels in lupus patients 39–41 . These studies have demonstrated number of novel polymorphisms, including PNP and PRKG1 41 , which have not been reported in case-control design studies, suggesting that the study of sub-phenotypes within SLE will be important to fully map the genetic architecture of the disease. The model would be that the genetic variations induce functional genetic changes, which then modulate important immune system phenotypes such as type I IFN or autoantibodies, and then these immune system phenotypes impact disease manifestations (See Figure 1).…”