Open Access Research article

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

Trinidad Martin-Donaire12, Ignacio Losada-Fernandez1, Gema Perez-Chacon1, Iñigo Rua-Figueroa3, Celia Erausquin3, Antonio Naranjo-Hernandez3, Silvia Rosado1, Florentino Sanchez4, Ayoze Garcia-Saavedra4, Maria Jesus Citores2, Juan A Vargas2 and Paloma Perez-Aciego1*

Author Affiliations

1 Fundacion LAIR, Madrid, Spain

2 Servicio de Medicina Interna I, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, C/San Martin de Porres 4, 28035 Madrid, Spain

3 Servicio de Reumatologia, Hospital Universitario de Gran Canaria Doctor Negrin, Barranco de la Ballena s/n, 35010 Las Palmas de Gran Canaria, Spain

4 Servicio de Inmunologia, Hospital Universitario de Gran Canaria Doctor Negrin, Barranco de la Ballena s/n, 35010 Las Palmas de Gran Canaria, Spain

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Arthritis Research & Therapy 2007, 9:R89  doi:10.1186/ar2288

Published: 10 September 2007

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.