Abstract
BackgroundThe TNFSF13B (TNF superfamily member 13b) gene encodes BAFF, a cytokine with a crucial role in the differentiation and activation of B cells. An insertion-deletion variant (GCTGT→A) of this gene, leading to increased levels of BAFF, has been recently implicated in the genetic predisposition to several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Based on the elevated levels of this cytokine found in patients with giant cell arteritis (GCA) and systemic sclerosis (SSc), we aimed to assess whether this functional variant also represents a novel genetic risk factor for these two disorders.MethodsA total of 1,728 biopsy-proven GCA patients from 4 European cohorts, 4,584 SSc patients from 3 European cohorts and 5,160 ethnically-matched healthy controls were included in the study. The single nucleotide polymorphism (SNP) rs374039502, which colocalizes with the genetic variant previously implicated in autoimmunity, was genotyped using a custom TaqMan assay. First, association analysis was conducted in each independent cohort using χ2 test in Plink (v1.9). Subsequently, different case/control sets were meta-analyzed by the inverse variance method.ResultsNo statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts. Similarly, combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with GCA (P = 0.421; OR (95% CI) = 0.92 (0.75–1.13)) and SSc (P = 0.500; OR (95% CI) = 1.05 (0.91–1.22)). The stratified analysis considering the main clinical subphenotypes of these diseases yielded similar negative results.ConclusionOur data suggest that the TNFSF13B functional variant does not contribute to the genetic network underlying GCA and SSc.
Highlights
Autoimmune diseases are complex disorders caused for the combined effect of both environmental and polygenic risk factors
No statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts
Combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with giant cell arteritis (GCA) (P = 0.421; Odds ratios (OR) = 0.92 (0.75–1.13)) and systemic sclerosis (SSc) (P = 0.500; OR = 1.05 (0.91– 1.22))
Summary
Autoimmune diseases are complex disorders caused for the combined effect of both environmental and polygenic risk factors. Genetic studies have identified hundreds of loci implicated in the susceptibility of immune-mediated conditions, many of which are shared by different diseases, highlighting the existence of shared pathogenic mechanisms in autoimmunity [1] In this regard, a genetic variant of the TNFSF13B (TNF superfamily member 13b) gene has been recently involved in the susceptibility to several autoimmune disorders, including multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) [2]. The TNFSF13B autoimmune-associated variant is an insertion-deletion (GCTGT!A) that creates a shorter 30 UTR transcript lacking a miRNA binding site This leads to higher levels of soluble BAFF, which results in an increased number of B cells and a reduction of the circulating monocytes [2]. AM is recipient of a Miguel Servet fellowship (CP17/ 00008) from ISCIII (Spanish Ministry of Economy, Industry and Competitiveness) (AM)
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