Association of the +49-A/G polymorphism of CTLA-4 in Mexican patients with ankylosing spondylitis
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1
Universidad Autonoma de Nayarit, Unidad Académica de Ciencias Químico Biológicas y Farmacéuticas, Mexico
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2
Instituto Mexicano del Seguro Social HGZ No. 1, Medicina Interna, Mexico
The spondyloarthropathies (SpA), now better denominated as spondyloarthritides (SpAs), are a diverse group of interrelated inflammatory arthritides that share multiple clinical features and common genetic predisposing factors. This group includes not only the prototypical disease, ankylosing spondylitis (AS), but also reactive arthritis, psoriatic arthritis, Chron’s disease, undifferentiated SpA, and juvenile-onset spondyloarthritis (1).
The clinical features of AS include inflammatory back pain, asymmetrical peripheral oligoarthritis, enthesitis, and specific organ involvement, such as anterior uveitis, psoriasis and chronic inflammatory bowel disease (2). Its major clinical features include sacroilitis, loss of spinal mobility and spinal inflammation. Chronic inflammation leads to fibrosis and ossification, where bridging spurs of bone known as syndesmophytes form, especially at the edges of the inter-vertebral discs, producing the ankylosing (3).
AS is of unknown etiology, but is considered an autoimmune disease that involves environmental and genetic factors. It is known to be highly heritable, as >90% of the risk of developing the disease has been shown to be genetically determined (4). As is the case of most common heritable diseases, progress in identifying candidate genes associated with the disease, and their possible role in pathogenesis, is one of the challenges that must be confronted in the near future.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4, CD154) is a co-stimulatory molecule that is expressed by activated T cells and interacts with the B7 molecules on the surface of antigen-presenting cells to induce down-regulation of T cell activation. CTLA-4, which is encoded on chromosome 2p33, is a structural homologue of CD28 (5). Engagement of CTLA-4 appears to regulate ongoing T cell responses and induce peripheral T cell tolerance, while the absence of this function appears to be involved in autoimmunity (6). In addition, CTLA-4 is highly expressed by regulatory T cells, and could play an important role in their functioning (7). Theoretically, polymorphisms of CTLA4 that reduce CTLA-4 expression may cause autoimmune T cell clonal proliferation, thus contributing to the pathogenesis of autoimmune diseases (5). The CTLA4 gene has many single nucleotide polymorphisms (SNP), but the most important one is located at the leader sequence (+49 A/G; rs231775) (8-10). The +49-A/G is located at position +49 of the first exon of the CTLA4 gene, where it provokes a threonine-to-alanine change in amino acid 17 of the leader peptide (7). It has been reported that +49A/G polymorphism in CTLA4 gene (rs231775) alter the intracellular distribution of CTLA-4, IL-2 production and T cell proliferation (7, 11); suggesting their possible role in autoimmune diseases. These SNP have been analyzed in patients with AS in different populations, but so far results are contradictory (5, 8, 12), though higher levels of circulating CTLA-4 in SpAs have been found (13), indicating a possible role in the pathogenesis of AS.
Taking into account that genetic factors have been involved in the pathogenesis of AS, and that T cells could play an important role because of their implication in peripheral tolerance, we analyze the possible association of the +49-A/G polymorphism of CTLA4 with AS. Thirty one consecutive patients with AS, diagnosed according to the New York criteria (14), and 67 healthy controls were included in the study. DNA was extracted from a peripheral blood sample, and the +46-A/G genotype was determined by allele-specific PCR, by using previously reported primers (9). As internal control, Human Growth Hormone fragment was amplified by using the reported primers (15). Frequencies for each genotype were obtained, and odds ratio, and 95%CI, and Chi square were calculated.
Our results (Table 1) showed that 13/31 (41.94%) patients with AS and 12/67 (17.91%) healthy subjects have the AA genotype (OR= 3.3102, IC95%= 1.2826, 8.5430, p=0.011), 15/31 (48.3%) patients with AS, and 46/67 (68.66%) healthy controls have the AG genotype (OR=0.4280; IC95%=0.1787-1.0229, p= 0.054). Three out of 31 (9.67%) patients with AS, and 9/67 (13.4%) healthy controls have the GG genotype OR= 0.6905, IC95%= 0.1733, 2.7510, p=0.598). The allele A frequency was 41/62 and 70/134, and for allele G 21/62 and 70/134, for patients and controls respectively.
Our results showed no statistically differences in the frequencies of GG, and AG genotypes between patients and controls. However, the frequencies of the AA genotype could be considered as a candidate to be a risk factor (OR = 3.3102, 95%CI = 1.3068-8.3849). However, these data should be considered as preliminary, because of the small sample size, but it is a strong candidate gene to be associated with AS.
Acknowledgements
Financial support: This work was supported in part by the Programa Integral de Fortalecimiento Institucional (PIFI)-2003-19-01 and 2010-18-MSU0019M-04.
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Keywords:
ankylosing spondylitis,
CTLA-4,
Polymorphism, Single Nucleotide,
+49-A/G,
Association
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune-mediated disease pathogenesis
Citation:
Zambrano-Zaragoza
J,
Gutiérrez-Franco
J,
Durán-Avelar
M,
De León-Amaral
B,
Peña-Virgen
S and
Vibanco-Pérez
N
(2013). Association of the +49-A/G polymorphism of CTLA-4 in Mexican patients with ankylosing spondylitis.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00605
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Received:
13 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Jose Francisco Zambrano-Zaragoza, Universidad Autonoma de Nayarit, Unidad Académica de Ciencias Químico Biológicas y Farmacéuticas, Tepic, Mexico, jzambran44@gmail.com