title: Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus.
abstract: OBJECTIVE
  Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway.
  
  
  METHODS
  We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively.
  
  
  RESULTS
  We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.
  
  
  CONCLUSIONS
  Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.
authors: Oklahoma Medical Research Foundation, Oklahoma City, USA.
authors: Indra
authors: I
authors: Adrianto
authors: Shaofeng
authors: S
authors: Wang
authors: Graham B
authors: GB
authors: Wiley
authors: Christopher J
authors: CJ
authors: Lessard
authors: Jennifer A
authors: JA
authors: Kelly
authors: Adam J
authors: AJ
authors: Adler
authors: Stuart B
authors: SB
authors: Glenn
authors: Adrienne H
authors: AH
authors: Williams
authors: Julie T
authors: JT
authors: Ziegler
authors: Mary E
authors: ME
authors: Comeau
authors: Miranda C
authors: MC
authors: Marion
authors: Benjamin E
authors: BE
authors: Wakeland
authors: Chaoying
authors: C
authors: Liang
authors: Kenneth M
authors: KM
authors: Kaufman
authors: Joel M
authors: JM
authors: Guthridge
authors: Marta E
authors: ME
authors: Alarcón-Riquelme
authors: Graciela S
authors: GS
authors: Alarcón
authors: Juan-Manuel
authors: JM
authors: Anaya
authors: Sang-Cheol
authors: SC
authors: Bae
authors: Jae-Hoon
authors: JH
authors: Kim
authors: Young Bin
authors: YB
authors: Joo
authors: Susan A
authors: SA
authors: Boackle
authors: Elizabeth E
authors: EE
authors: Brown
authors: Michelle A
authors: MA
authors: Petri
authors: Rosalind
authors: R
authors: Ramsey-Goldman
authors: John D
authors: JD
authors: Reveille
authors: Luis M
authors: LM
authors: Vilá
authors: Lindsey A
authors: LA
authors: Criswell
authors: Jeffrey C
authors: JC
authors: Edberg
authors: Barry I
authors: BI
authors: Freedman
authors: Gary S
authors: GS
authors: Gilkeson
authors: Chaim O
authors: CO
authors: Jacob
authors: Judith A
authors: JA
authors: James
authors: Diane L
authors: DL
authors: Kamen
authors: Robert P
authors: RP
authors: Kimberly
authors: Javier
authors: J
authors: Martín
authors: Joan T
authors: JT
authors: Merrill
authors: Timothy B
authors: TB
authors: Niewold
authors: Bernardo A
authors: BA
authors: Pons-Estel
authors: R Hal
authors: RH
authors: Scofield
authors: Anne M
authors: AM
authors: Stevens
authors: Betty P
authors: BP
authors: Tsao
authors: Timothy J
authors: TJ
authors: Vyse
authors: Carl D
authors: CD
authors: Langefeld
authors: John B
authors: JB
authors: Harley
authors: Edward K
authors: EK
authors: Wakeland
authors: Kathy L
authors: KL
authors: Moser
authors: Courtney G
authors: CG
authors: Montgomery
authors: Patrick M
authors: PM
authors: Gaffney
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001741:Black or African American / Q000235:genetics / Q000706:statistics & numerical data; D001213:Asian / Q000235:genetics / Q000706:statistics & numerical data; D001402:B-Lymphocytes / Q000166:cytology; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006630:Hispanic or Latino / Q000235:genetics / Q000706:statistics & numerical data; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology* / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C120635:TAX1BP1 protein, human; C117046:TNIP1 protein, human; C434062:TNIP2 protein, human