title: Gene-expression-guided selection of candidate loci and molecular phenotype analyses enhance genetic discovery in systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disorder characterized by differences in autoantibody profiles, serum cytokines, and clinical manifestations. We have previously conducted a case-case genome-wide association study (GWAS) of SLE patients to detect associations with autoantibody profile and serum interferon alpha (IFN-α). In this study, we used public gene expression data sets to rationally select additional single nucleotide polymorphisms (SNPs) for validation. The top 200 GWAS SNPs were searched in a database which compares genome-wide expression data to genome-wide SNP genotype data in HapMap cell lines. SNPs were chosen for validation if they were associated with differential expression of 15 or more genes at a significance of P < 9 × 10(-5). This resulted in 11 SNPs which were genotyped in 453 SLE patients and 418 matched controls. Three SNPs were associated with SLE-associated autoantibodies, and one of these SNPs was also associated with serum IFN-α (P < 4.5 × 10(-3) for all). One additional SNP was associated exclusively with serum IFN-α. Case-control analysis was insensitive to these molecular subphenotype associations. This study illustrates the use of gene expression data to rationally select candidate loci in autoimmune disease, and the utility of stratification by molecular phenotypes in the discovery of additional genetic associations in SLE.
authors.affiliation: Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Koldobskaya
authors.forename: Kichul
authors.initials: K
authors.lastname: Ko
authors.forename: Akaash A
authors.initials: AA
authors.lastname: Kumar
authors.forename: Sandra
authors.initials: S
authors.lastname: Agik
authors.forename: Jasmine
authors.initials: J
authors.lastname: Arrington
authors.forename: Silvia N
authors.initials: SN
authors.lastname: Kariuki
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Franek
authors.forename: Marissa
authors.initials: M
authors.lastname: Kumabe
authors.forename: Tammy O
authors.initials: TO
authors.lastname: Utset
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Jolly
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Skol
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
mesh_terms: D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016898:Interferon-alpha / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D001323:Autoantibodies; D016898:Interferon-alpha