Association of the microsatellite in the 3' untranslated region of the CD154 gene with rheumatoid arthritis in females from a Spanish cohort: a case-control study

Abstract

CD40–CD154 interaction is an important mediator of inflammation and has been implicated in T helper type 1-mediated autoimmune diseases including rheumatoid arthritis (RA). Linkage studies have shown association of markers in the proximity of the CD154 gene. In the present work we investigated whether specific allele variants of the microsatellite in the 3' UTR of the CD154 gene might modulate the risk of RA. The study, in a case-control setting, included 189 patients and 150 healthy controls from the Canary Islands, Spain. The 24CAs allele was less represented in female patients than in controls (0.444 in controls versus 0.307 in patients, P = 0.006, odds ratio (OR) 0.556, 95% confidence interval (CI) 0.372 to 0.831) but not in males (0.414 versus 0.408), and only when homozygous (P = 0.012; OR 0.35, 95% CI 0.16 to 0.77). We also verified that CD154 association with RA was independent of human leukocyte antigen (HLA) phenotype. A further functional study showed that after stimulation anti-CD3, CD154 mRNA was more stable in CD4+ T lymphocytes from patients with RA bearing the 24CAs allele (mRNA half-life 208 minutes) than in patients without the 24CAs allele (109 minutes, P = 0.009). However, a lower percentage of CD154+CD4+ T lymphocytes was seen in freshly isolated peripheral blood mononuclear cells from patients carrying 24CAs alleles (mean 4.28 versus 8.12; P = 0.033), and also in CD4+ T lymphocytes stimulated with anti-CD3 (median 29.40 versus 47.60; P = 0.025). These results were concordant with the smaller amounts of CD154 mRNA isolated from stimulated T lymphocytes with 24CAs alleles. The CD154 microsatellite therefore seems to affect the expression of the gene in a complex manner that implies not only mRNA stability. These data suggest that the CD154 microsatellite contributes to the regulation of mRNA and protein expression, although further studies will be necessary to elucidate its role in disease predisposition.

Separate cis-trans Pathways Post-transcriptionally Regulate Murine CD154 (CD40 Ligand) Expression

“…Studies of allelic variations suggest that 24 CA repeats limited CD154 expression to the greatest degree and conferred protection against the development of RA and SLE (23,24). Interestingly, CD154 expression by specific CARE polymorphisms correlated inversely with CD154 mRNA stability (24). These observations are consistent with our findings that the CARE regulates translation.…”

“…Our studies demonstrate that 3Ј-UTR CA-rich repeats regulate gene expression at the level of translation. Recent work indicates that the CA repeats in the CD154 3Ј-UTR are polymorphic and influence both gene expression and autoimmune disease risk (23,24). Our study not only defines the role of hnRNP L in regulating the function of exonic CA repeats but also provides a molecular mechanism of how CA repeat polymorphisms influence CD154 expression to increase the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).…”

“…The 3Ј-UTR CARE is polymor- phic in humans, ranging from 20 to 30 CA repeats (23). Studies of allelic variations suggest that 24 CA repeats limited CD154 expression to the greatest degree and conferred protection against the development of RA and SLE (23,24). Interestingly, CD154 expression by specific CARE polymorphisms correlated inversely with CD154 mRNA stability (24).…”

Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions?

“…The (CA) 24 allele (corresponding to (CA) 26 in our study) appears to confer more stability on its mRNA, and longer alleles confer higher expression levels434548.…”

“…For example, polymorphisms of longer (CA) n alleles are seen in autoimmune processes such as seen in patients with systemic lupus erythematosus43, those with a high risk of thromboembolic disease44, or rheumatoid arthritis3945. However, no association was found in the context of alloimmunity (e.g.…”