title: Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production.
abstract: Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with p(heterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.
authors.affiliation: Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, United States of America. sharon.chung@ucsf.edu
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Chung
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Taylor
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Joanne
authors.initials: J
authors.lastname: Nititham
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Ward A
authors.initials: WA
authors.lastname: Ortmann
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: F Yesim
authors.initials: FY
authors.lastname: Demirci
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.forename: Susan
authors.initials: S
authors.lastname: Manzi
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
mesh_terms: D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics; D016022:Case-Control Studies; D004247:DNA / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D050797:STAT4 Transcription Factor / Q000235:genetics
chemical_list: D001323:Autoantibodies; D039481:CD11b Antigen; C431713:IRF5 protein, human; C509295:ITGAM protein, human; D050835:Interferon Regulatory Factors; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D004247:DNA