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-) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. 4050% of patients have high IFN-, 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- in over 1550 SLE cases, including GWAS and replication cohorts. 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 genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN- 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.

... 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- 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

... association in both European-American and African-American ancestral backgrounds, those with homogenous effects by Breslow-Day testing were analyzed in meta-analysis assuming a fixed-effect model. The two SNPs included in this cross-ancestral background meta-analysis were ANKRD44 rs4850410 [OR=0.64; 95%CI (0.48 0.84); P Meta =1.3 10 6 ] and pleckstrin homology domain containing, family F member 2 gene ( PLEKHF2 ) rs297573 [OR=0.70; 95%CI (0.50 0.98); P Meta =1.2 10 4 ]. Association of GWAS candidates with autoantibody subsets in the replication cohort Because the presence of particular autoantibodies has been strongly associated with high IFN- in SLE 15 , we also tested the SNPs which were replicated from the GWAS study for association with SLE autoantibodies. Supplemental Tables 4 and 5 show the autoantibody associations observed in different ancestral groups in replication cohort. These include some of the SNPs which were associated with IFN-, such as PRKG1 and PLEKHF2, as well as one SNP in

... relationships between genotype and the two phenotypes. In the case of PRKG1, the IFN and serological associations were independent ( Supplemental Figure 1 ). For the PLEKHF2 rs297573 SNP, we found that the association with IFN- was secondary to the serological association ( Supplemental Figure 2 ). Canonical pathway analysis of GWAS candidate SNPs A pathway analysis of the networks enriched among the top SNPs in the discovery cohort was generated through the use of IPA (Ingenuity Systems, www.ingenuity.com

...- and African-American ancestral backgrounds. Both ANKRD44 (rs4850410; P Meta =1.3 10 6 ) and PLEKHF2 (rs297573; P Meta =1.2 10 4 ) were associated with IFN- in African-American and European ancestral backgrounds. PLEKHF2 is an endosome-associated protein responsible for modulating the structure and function of endosomes, as well as the endocytotic process 43 . PLEKHF2 can increase the activity of caspase 12, and a role for in ER-related apoptotic pathway has been suggested 44 . ENCODE ChIP-seq data demonstrate that rs297573 SNP downstream of PLEKHF2 which was associated with IFN- in our study resides in NFB transcription factor binding site. ANKRD44 has not been extensively studied, but it binds to the catalytic subunit of protein phosphatase 6 45 , which plays a role in cell cycle progression. Our initial discovery cohort showed association of two SNPs in the C7orf57 locus in chromosome 7 with serum IFN- activity; however, this locus failed to replicate. One of the possible reasons for

... relationships between PNP, PRKG1, ANKRD44 and PLEKHF2 to other molecules in immune cells. Edges with weight (relative confidence) greater than 0.4 are shown. Each network diagram represents a different immune cell type as follows: A: B lymphocyte, B: Dendritic cell, C: Monocyte, D: Neutrophil, E: NK cell, F: T lymphocyte. Figure 3 Principal component analyses to detect population structure. A. and B. show principal components from all SNPs studied in the SLEGEN GWAS data set. All studied subjects are

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Gene: PLEKHF2 - pleckstrin homology domain containing, family F (with FYVE domain) member 2 - (NCBI)

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