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

S. N. Kariuki, Y. Ghodke-Puranik, J. M. Dorschner, B. S. Chrabot, J. A. Kelly, B. P. Tsao, R. P. Kimberly, M. E. Alarcón-Riquelme, C. O. Jacob, L. A. Criswell, K. L. Sivils, C. D. Langefeld, J. B. Harley, A. D. Skol, T. B. Niewold

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34 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)15-23
Number of pages9
JournalGenes and Immunity
Volume16
Issue number1
DOIs
StatePublished - Jan 24 2015

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)

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    Kariuki, S. N., Ghodke-Puranik, Y., Dorschner, J. M., Chrabot, B. S., Kelly, J. A., Tsao, B. P., Kimberly, R. P., Alarcón-Riquelme, M. E., Jacob, C. O., Criswell, L. A., Sivils, K. L., Langefeld, C. D., Harley, J. B., Skol, A. D., & Niewold, T. B. (2015). Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus. Genes and Immunity, 16(1), 15-23. https://doi.org/10.1038/gene.2014.57