title: Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations.
abstract: TNFAIP3 encodes the ubiquitin-modifying enzyme, A20, a key regulator of inflammatory signaling pathways. We previously reported association between TNFAIP3 variants and systemic lupus erythematosus (SLE). To further localize the risk variant(s), we performed a meta-analysis using genetic data available from two Caucasian case-control datasets (1453 total cases, 3381 total control subjects) and 713 SLE trio families. The best result was found at rs5029939 (P=1.67 x 10(-14), odds ratio=2.09, 95% confidence interval 1.68-2.60). We then imputed single nucleotide polymorphisms (SNPs) from the CEU Phase II HapMap using genotypes from 431 SLE cases and 2155 control subjects. Imputation identified 11 SNPs in addition to three observed SNPs, which together, defined a 109 kb SLE risk segment surrounding TNFAIP3. When evaluating whether the rs5029939 risk allele was associated with SLE clinical manifestations, we observed that heterozygous carriers of the TNFAIP3 risk allele at rs5029939 have a twofold increased risk of developing renal or hematologic manifestations compared to homozygous non-risk subjects. In summary, our study strengthens the genetic evidence that variants in the region of TNFAIP3 influence risk for SLE, particularly in patients with renal and hematologic manifestations, and narrows the risk effect to a 109 kb DNA segment that spans the TNFAIP3 gene.
authors.affiliation: Oklahoma Medical Research Foundation, Arthritis and Immunology Research Program, Oklahoma City, OK 73104, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Bates
authors.forename: C J
authors.initials: CJ
authors.lastname: Lessard
authors.forename: J M
authors.initials: JM
authors.lastname: Leon
authors.forename: T
authors.initials: T
authors.lastname: Nguyen
authors.forename: L J
authors.initials: LJ
authors.lastname: Battiest
authors.forename: J
authors.initials: J
authors.lastname: Rodgers
authors.forename: K M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: J A
authors.initials: JA
authors.lastname: James
authors.forename: G S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: J A
authors.initials: JA
authors.lastname: Kelly
authors.forename: M B
authors.initials: MB
authors.lastname: Humphrey
authors.forename: J B
authors.initials: JB
authors.lastname: Harley
authors.forename: C
authors.initials: C
authors.lastname: Gray-McGuire
authors.forename: K L
authors.initials: KL
authors.lastname: Moser
authors.forename: P M
authors.initials: PM
authors.lastname: Gaffney
mesh_terms: D004268:DNA-Binding Proteins; D055106:Genome-Wide Association Study; D006239:Haplotypes; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008181:Lupus Nephritis / Q000235:genetics* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3