Confirmation ofTNIP1but notRHOBandPSORS1C1as systemic sclerosis risk factors in a large independent replication study

Abstract

Introduction A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry. Methods 4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci. Results Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 pMH=1.94×10−4, OR 1.19; rs4958881 pMH=3.26×10−5, OR 1.19; rs3792783 pMH=2.16×10−4, OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets. Conclusions These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor.

Immunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways

“…TNIP1 regulates TNFAIP3 activity, thus it is also involved in the negative feedback regulation of the NF-kB signaling pathway. The association of this locus was reported for the first time in the GWAS by Allanore et al, and has been replicated in an independent study [17,49]. Interestingly, Allanore et al found a reduced expression of the gene in fibroblasts and affected skin samples from SSc patients [17].…”

The role of genetics and epigenetics in the pathogenesis of systemic sclerosis

“…41 A large followup study corroborated the association of TNIP1, but did not find any association with PSORS1C1 or RHOB. 42 Data from a followup of the French GWAS suggested that PPARG, which encodes peroxisome proliferatoractivated receptorγ, was asso ciated with SSc, although genomewide significance was not reached. 43 Another followup study found that IL12RB2, which encodes the β2 subunit of the IL12 receptor that is functionally linked to STAT4, CD247 and IFNγ, was associated with SSc.…”

Review: A20‐Binding Inhibitor of NF‐κB Activation 1 Is a Physiologic Inhibitor of NF‐κB: A Molecular Switch for Inflammation and Autoimmunity

“…Over the past decade, genome‐wide association studies (GWAS) identified numerous NF‐κB susceptibility loci associated with autoimmune disease. Among these loci, TNIP1 polymorphisms have been strongly associated with psoriasis, psoriatic arthritis, SLE, and systemic sclerosis (SSc) (Figure ). Nair et al identified rs17728338 as a risk variant for psoriasis in patients of European ancestry .…”