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SAT0013 Candidate gene study in systemic sclerosis identifies a rare and functional variant of TNFAIP3 locus as a risk factor for individual polyautoimmunity
  1. E. Koumakis1,2,
  2. M. Giraud2,
  3. P. Dieudé3,
  4. G. Cuomo4,
  5. P. Airo5,
  6. G. Chiocchia2,
  7. Y. Allanore1,2
  8. and GENESYS Consortium
  1. 1Paris Descartes University, Rheumatology A Department, Cochin Hospital
  2. 2INSERM U1016, Institut Cochin, Sorbonne Paris Cité
  3. 3Paris Diderot university, Rheumatology Department, Hôpital Bichat-Claude-Bernard, Paris, France
  4. 4Rheumatology Section, Department of Clinical and Experimental Medicine, Second University of Naples, Naples
  5. 5Rheumatology and Clinical Immunology, Spedali Civili, Brescia, Italy


Background Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) share some physiopathologic bases as supported by individual and familial polyautoimmunity and common susceptibility genetic factors. For the latter, there is a recent shift from the “common variant” to the “rare variant” paradigm, inasmuch as rare variants of TNFAIP3 and TREX1 with large effect size have recently been uncovered in SLE.

Objectives To investigate whether rare variants of TREX1 and TNFAIP3 are associated with SSc.

Methods TREX1 lupus-associated single-nucleotide polymorphisms (SNPs) rs3135946, rs7626978, rs3135943, rs11797 and TNFAIP3 rs9494883, rs72063345, rs5029939, rs2230926, rs117480515, rs7749323, together with the functional TT>-A dinucleotide variant located 41.5kb downstream of the TNFAIP3 promoter (1), were genotyped in a French “discovery” set consisting of 985 SSc and 1011 controls. The most relevant results were replicated in a second set consisting of Italian individuals (622 SSc and 493 controls). Expression of TNFAIP3 mRNA by peripheral blood mononuclear cells was assessed by quantitative real-time PCR using Taqman methodology in 38 SSc patients and 33 unaffected French donors genotyped for TNFAIP3 variants.

Results No association between any TREX1 variant and SSc or sub-phenotypes was observed. For TNFAIP3, we first observed that a low-frequency variant, rs117480515, tagged the TT>-A SLE dinucleotide polymorphism recently identified and that is highly suspected to be the causal variant (1). In the discovery sample, we observed that all tested TNFAIP3 variants were in linkage disequilibrium and were associated with SSc and various subsets including the polyautoimmune phenotype (i.e. SSc patients having at least one co-existing autoimmune disease, N=150, Padj=5.32×10-5, OR=3.94, [95%CI 2.25-6.90]). The rs117480515 SNP was subsequently genotyped in the replication sample. The allelic association with SSc was replicated solely for patients with the polyautoimmune phenotype, providing the following results in the combined French and Italian populations: Padj=8.58×10-9, OR=3.51, [95%CI 2.28-5.41]. Genotype-mRNA expression correlations revealed that the TNFAIP3 rs117480515 risk allele was associated with decreased TNFAIP3 mRNA expression (p=0.02).

Conclusions Our results establish the TNFAIP3 locus as susceptibility factor for the subset of SSc patients with a polyautoimmune phenotype and highlight the critical role of NFkB antagonist A20 in shared autoimmunity. It also supports the implication of rare/low-frequency functional variants in the genetic susceptibility to complex autoimmune diseases. The lack of association with the TREX1 locus in this study strengthens the knowledge that while some genetic loci may confer susceptibility to several autoimmune phenotypes, other genes may be restricted to specific diseases.

  1. Adrianto I et al. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat Genet 2011;43:253-8.

Disclosure of Interest None Declared

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