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Arthritis Research & Therapy

Open Access

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

  • Silvia N Kariuki1,
  • Yogita Ghodke-Puranik2,
  • Jessica M Dorschner2,
  • Beverly S Chrabot3,
  • Jennifer A Kelly4,
  • Betty P Tsao5,
  • Robert P Kimberly6,
  • Marta E Alarcón-Riquelme4, 7,
  • Chaim O Jacob8,
  • Lindsey A Criswell9,
  • Kathy L Sivils4,
  • Carl D Langefeld10,
  • John B Harley11,
  • Andrew D Skol1 and
  • Timothy B Niewold2Email author
Arthritis Research & Therapy201416(Suppl 1):A10

Published: 18 September 2014


Systemic Lupus ErythematosusInterferon AlphaEuropean AncestryMultiple Organ SystemInterferon Response


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.


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.


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 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.


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.



SNK and YG-P contributed equally to the manuscript.

Authors’ Affiliations

University of Chicago, Chicago, USA
Mayo Clinic, Rochester, USA
Gwen Knapp Center for Lupus Research, University of Chicago, Chicago, USA
Oklahoma Medical Research Foundation, Oklahoma City, USA
University of California, Los Angeles, USA
University of Alabama, Birmingham, USA
GENYO Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Grenada, Spain
University of Southern California, Los Angeles, USA
Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, USA
Wake Forest University, Winston-Salem, USA
Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center, Cincinnati, USA, USA


© Kariuki et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.