title: Brief report: candidate gene study in systemic sclerosis identifies a rare and functional variant of the TNFAIP3 locus as a risk factor for polyautoimmunity.
abstract: OBJECTIVE
  Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) share some pathophysiologic bases as evidenced by individual and familial polyautoimmunity and common susceptibility genetic factors. With regard to the latter, there has been a recent shift from the "common variant" to the "rare variant" paradigm, since rare variants of TNFAIP3 and TREX1 with large effect sizes have recently been discovered in SLE. The present study was undertaken to investigate whether rare variants of TNFAIP3 and TREX1 are also associated with SSc.
  
  
  METHODS
  TREX1 single-nucleotide polymorphisms (SNPs) rs3135946, rs7626978, rs3135943, and rs11797 and TNFAIP3 SNPs rs9494883, rs72063345, rs5029939, rs2230926, rs117480515, and rs7749323 were genotyped in a discovery set (985 SSc patients and 1,011 controls), and replication analysis of the most relevant results was performed in a second set (622 SSc patients and 493 controls).
  
  
  RESULTS
  No association between TREX1 variants and SSc was observed. For TNFAIP3, we first demonstrated that a low-frequency variant, rs117480515, tagged the recently identified TT>A SLE dinucleotide. In the discovery sample, we observed that all tested TNFAIP3 variants were in linkage disequilibrium and were associated with SSc and various SSc subsets, including the polyautoimmune phenotype. We subsequently genotyped rs117480515 in the replication sample and found it to be associated solely with the SSc polyautoimmune subset (odds ratio 3.51 [95% confidence interval 2.28-5.41], P = 8.58 × 10(-9) ) in the combined populations. Genotype-messenger RNA (mRNA) expression correlation analysis revealed that the TNFAIP3 rs117480515 risk allele was associated with decreased mRNA expression.
  
  
  CONCLUSIONS
  The present findings establish the TNFAIP3 locus as a susceptibility factor for the subset of SSc with a polyautoimmune phenotype. Our results support the implication of rare/low-frequency functional variants and the critical role of A20 in autoimmunity.
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, and Cochin Hospital, AP-HP, Paris, France.
authors.forename: Eugénie
authors.initials: E
authors.lastname: Koumakis
authors.forename: Matthieu
authors.initials: M
authors.lastname: Giraud
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.forename: Vanessa
authors.initials: V
authors.lastname: Cohignac
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cuomo
authors.forename: Paolo
authors.initials: P
authors.lastname: Airò
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci-Cerinic
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Diot
authors.forename: Paola
authors.initials: P
authors.lastname: Caramaschi
authors.forename: Luc
authors.initials: L
authors.lastname: Mouthon
authors.forename: Valeria
authors.initials: V
authors.lastname: Riccieri
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Cracowski
authors.forename: Kiet Phong
authors.initials: KP
authors.lastname: Tiev
authors.forename: Camille
authors.initials: C
authors.lastname: Francès
authors.forename: Zahir
authors.initials: Z
authors.lastname: Amoura
authors.forename: Jean
authors.initials: J
authors.lastname: Sibilia
authors.forename: Anne
authors.initials: A
authors.lastname: Cosnes
authors.forename: Patrick
authors.initials: P
authors.lastname: Carpentier
authors.forename: Gabriele
authors.initials: G
authors.lastname: Valentini
authors.forename: Mirko
authors.initials: M
authors.lastname: Manetti
authors.forename: Serena
authors.initials: S
authors.lastname: Guiducci
authors.forename: Olivier
authors.initials: O
authors.lastname: Meyer
authors.forename: André
authors.initials: A
authors.lastname: Kahan
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
mesh_terms: D000328:Adult; D000368:Aged; D015551:Autoimmunity / Q000235:genetics*; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005090:Exodeoxyribonucleases / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000235:genetics*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3