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Genes Immun. 2015 Jan-Feb;16(1):15-23. doi: 10.1038/gene.2014.57. Epub 2014 Oct 23.

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

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  • 1Department of Human Genetics, University of Chicago, Chicago, IL, USA.
  • 2Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
  • 3Gwen Knapp Center for Lupus Research, University of Chicago, Chicago, IL, USA.
  • 4Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
  • 5Department of Medicine, University of California, Los Angeles, CA, USA.
  • 6Department of Medicine, University of Alabama, Birmingham, AL, USA.
  • 71] Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA [2] GENYO Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
  • 8Department of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 9Rosalind Russell/Ephraim P Engleman Rheumatology Research Center, University of California, San Francisco, CA, USA.
  • 10Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC, USA.
  • 11Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center, Cincinnati, OH, USA.


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. About 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 genome-wide association study and replication cohorts. In meta-analysis, the top associations in European ancestry were protein kinase, cyclic GMP-dependent, type I (PRKG1) rs7897633 (P(Meta) = 2.75 × 10(-8)) and purine nucleoside phosphorylase (PNP) rs1049564 (P(Meta) = 1.24 × 10(-7)). We also found evidence for cross-ancestral background associations with the ankyrin repeat domain 44 (ANKRD44) and pleckstrin homology domain containing, family F member 2 gene (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 sub-phenotypes becomes an attractive strategy for genetic discovery in complex disease.

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