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Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus.
- Source :
-
Genes and immunity [Genes Immun] 2015 Jan-Feb; Vol. 16 (1), pp. 15-23. Date of Electronic Publication: 2014 Oct 23. - Publication Year :
- 2015
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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.
- Subjects :
- Case-Control Studies
Female
Gene Regulatory Networks
Humans
White People genetics
Cyclic GMP-Dependent Protein Kinase Type I genetics
Interferon-alpha immunology
Lupus Erythematosus, Systemic genetics
Lupus Erythematosus, Systemic immunology
Polymorphism, Single Nucleotide
Purine-Nucleoside Phosphorylase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5470
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Genes and immunity
- Publication Type :
- Academic Journal
- Accession number :
- 25338677
- Full Text :
- https://doi.org/10.1038/gene.2014.57