Volume 16 Supplement 1
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
© Kariuki et al.; licensee BioMed Central Ltd. 2014
Published: 18 September 2014
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.
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 (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.