title: Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus.
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.
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Kariuki
authors.affiliation: Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Y
authors.identifier: 0000000162320550
authors.initials: Y
authors.lastname: Ghodke-Puranik
authors.affiliation: Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Dorschner
authors.affiliation: Gwen Knapp Center for Lupus Research, University of Chicago, Chicago, IL, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Chrabot
authors.affiliation: Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: Department of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Tsao
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, AL, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Kimberly
authors.affiliation: 1] 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.
authors.forename: M E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: C O
authors.initials: CO
authors.lastname: Jacob
authors.affiliation: Rosalind Russell/Ephraim P Engleman Rheumatology Research Center, University of California, San Francisco, CA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Sivils
authors.affiliation: Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center, Cincinnati, OH, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Skol
authors.affiliation: Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: T B
authors.initials: TB
authors.lastname: Niewold
mesh_terms: D016022:Case-Control Studies; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D016898:Interferon-alpha; D011683:Purine-Nucleoside Phosphorylase; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569718:PRKG1 protein, human