CD40: Novel Association with Crohn's Disease and Replication in Multiple Sclerosis Susceptibility

Abstract

BackgroundA functional polymorphism located at −1 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves' disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves' disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn's disease (CD) lesions.MethodologyGenotyping of rs1883832C>T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry.Principal FindingsThe observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p = 0.025; OR (95% CI) = 1.12 (1.01–1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p = 0.002; OR (95% CI) = 1.19 (1.06–1.33)]. This increased predisposition was not detected in UC patients [p = 0.5; OR (95% CI) = 1.04 (0.93–1.17)].ConclusionThe impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions.

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

“…This finding therefore suggests that the linked causal variants in these regions are likely to be expression quantitative trait loci (eQTL), at which polymorphism affects the expression of one or more transcripts. Indeed, the data obtained on candidate genes for several autoimmune diseases strongly support the hypothesis that most of the genetically encoded risk of disease is conferred by eQTL [38,71,103,[156][157][158][159][160][161][162][163].…”

CD40 functional gene polymorphisms and mRNA expression in rheumatoid arthritis patients from western Mexico

“…The CD40 SNPs rs1883832 and rs4810485 have been identified as susceptibility markers for this and other autoimmune diseases, such as GD (Tomer et al, 2002;Kim et al, 2003;Li et al, 2012), MS (Blanco-Kelly et al, 2010;Sokolova et al, 2013), and SLE (Vazgiourakis et al, 2011;Chen et al, 2015;Lee et al, 2015). In addition, several studies suggest that these polymorphisms affect CD40 expression at the mRNA and protein level (Jacobson et al, 2005;Vazgiourakis et al, 2011;Field et al, 2015;Wagner et al, 2015).…”

“…Other non-HLA risk loci for RA, including the CD40 gene, have been identified based on genome-wide association studies and meta-analysis (Wellcome Trust Case Control Consortium, 2007;Raychaudhuri et al, 2008;Perricone et al, 2011;Suzuki et al, 2011). Interestingly, CD40 has been implicated in other autoimmune diseases, such as multiple sclerosis [MS; Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene), 2009], Grave's disease (GD; Li et al, 2012), systemic lupus erythematosus (SLE; Vazgiourakis et al, 2011), and Crohn's disease (Blanco-Kelly et al, 2010).…”

Autoimmune Thyroid Diseases Concomitant with Crohn’s Disease and Ulcerative Colitis

“…Moreover, some studies reported that CTLA4 may also influence the risk of developing CD [15,16]. Moreover, in a Spanish meta-analysis, the frequency of the minor allele rs1883832T of the CD40 gene was observed to be significantly higher in CD patients than that in control individuals, but it was not significantly higher in UC patients [17].…”