Rheumatology Advance Access originally published online on October 23, 2007
Rheumatology 2008 47(1):102-103; doi:10.1093/rheumatology/kem242
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LETTERS TO THE EDITOR |
Study of two polymorphisms of the MHC2TA gene with systemic lupus erythematosus
Consejo Superior de Investigaciones Científicas, CSIC, 1Servicio de Medicina Interna, Hospital Virgen de las Nieves, 2Servicio de Medicina Interna, Hospital Clínico San Cecilio, Granada, 3Servicio de Medicina Interna, Hospital Carlos-Haya, Malaga, 4Servicio de Reumatología, Hospital Virgen de la Victoria, Málaga and 5Servicio de Inmunología, Hospital Virgen de las Nieves, Granada, Spain
Correspondence to: E. Sánchez, Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, Parque Tecnológico de Ciencias de la Salud., Avenida del Conocimiento s/n 18100-Armilla (Granada), Spain. E-mail: elena{at}ipb.csic.es
SIR, Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with a complex pathogenesis which involves multiple genetic and environmental factors. Although the pathogenesis of SLE is unknown, a strong genetic component is well established. Among the genetic factors believed to influence susceptibility to SLE, the major histocompatibility complex (MHC) alleles show the most significant association. The mechanism by which these alleles increase the risk of SLE is unknown. However, it seems that regulatory factors of expression of MHC class II molecules could play an important role in the pathogenesis of SLE, and polymorphisms in these genes might confer susceptibility to the disease.
The class II transactivator CIITA, encoded by the MHC2TA gene, maps in the chromosomal region 16p13, which has shown evidences of linkage with SLE [1]. Therefore, the MHC2TA gene is essential for the expression of genes encoding MHC class II [2]. This gene expression is controlled by four different promoters, resulting in different CIITA isoforms. A -168A/G polymorphism (rs3087456) was reported to be associated with susceptibility to rheumatoid arthritis (RA), multiple sclerosis (MS) and myocardial infarction in a Nordic population [3]. In addition, this genetic variant has been associated with lower expression of MHC2TA after the stimulation of leukocytes with interferon-
. Subsequent studies have failed to replicate that association within one German and two Spanish populations [4–6]. Martinez et al. [6] recently reported that the -168G allele is not an aetiological variant itself, but a haplotype pattern of -168A/G. This together with another variant located in exon 11 (1614G/C, rs4774) are associated with the risk of RA and MS [6]. To clarify this controversial data, we aimed to determine the potential role of MHC2TA gene polymorphisms with SLE in a Spanish population.
Our study includes 394 SLE patients meeting the American College of Rheumatology criteria [7] and 514 matched healthy controls. Demographic characteristics of the subjects have been described previously [8]. The two polymorphisms tested were genotyped by pre-development TaqMan allelic discrimination assay. All patients were included in the study after informed consent was obtained, and the study was approved by the hospitals’ Ethics Committee.
MHC2TA genotypes were in Hardy–Weinberg equilibrium in cases and controls for both polymorphisms studied. The -168AA genotype was more frequent among SLE patients compared with controls [57.1 vs 50.4%, P = 0.04, odds ratio (OR) = 1.51, 95% confidence interval (CI) 1.00–1.72]. However, the difference in the allele frequencies was not statistically significant (P = 0.2). No significant differences were observed between SLE patients and controls for the 1614G/C polymorphism. In addition, the haplotype defined by the two markers tested was also analysed. Although a significantly higher frequency of the GC haplotype was found among the controls (P = 0.04, OR = 0.68, 95% CI 0.46–0.99) that turned out to be non-significant after the Bonferroni test was applied (Pcorr = 0.1; Table 1). Next, we analysed the demographic and clinical characteristics of SLE patients according to MHC2TA -168A/G and 1614G/C genotypes; however, no statistical differences were observed (data not shown).
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In an attempt to determine the possible role of two variants on the MHC2TA gene with SLE within a Caucasian population, we failed to detect any association. Noticeably, most replication studies in other populations did not reproduce the original finding by Swanberg and colleagues. [5, 6, 9]. The possibility that the lack of association found in our study could have arisen due to a type II error (false negative) seems to be unlikely, since we estimated that our cohort had enough power (>80% for both polymorphisms) to detect the effect of polymorphisms considering an OR of 1.5 at the 5% significance level. In addition, this lack of concordance does not seem to be due to differences in the genetic background, since the allele and genotype frequencies observed in our control group were similar to those previously described within other populations [3–5, 9]. Although a primary role for the MHC2TA gene polymorphisms in RA and MS has been proposed [3], several studies have failed to replicate the association between these variants and a range of autoimmune diseases, such as RA, MS, juvenile idiopathic arthritis or inflammatory bowel disease, which suggest that the MHC2TA gene has a negligible effect on the susceptibility to autoimmune diseases.
In conclusion, it appears that these genetic variants on MHC2TA do not play a role in the susceptibility to SLE in a Spanish population. Nevertheless, in a Japanese study a trend of association was found between the 485A/G MHC2TA variant and SLE [10]. The fact that other MHC2TA polymorphisms or other genes in the MHC class II pathway may contribute to the development of SLE cannot be ruled out. Further studies in larger cohorts, in which all the genetic variants in the MHC2TA gene are included, will be necessary to define the role of this gene in autoimmunity.
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We thank all SLE patients and controls for making this study possible. This work was supported by grant SAF2006-00398 from Plan Nacional de I+D+I and by the Junta de Andalucía, grupo CTS-180.
Disclosure statement: The authors have declared no conflicts of interest.
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TopAcknowledgementsReferences |
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- Akkad DA, Jagiello P, Szyld P, et al. Promoter polymorphism rs3087456 in the MHC class II transactivator gene is not associated with susceptibility for selected autoimmune diseases in German patient groups. Int J Immunogenet (2006) 33:59–61.[CrossRef][Web of Science][Medline]
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- Koizumi K, Okamoto H, Iikuni N, et al. Single nucleotide polymorphisms in the gene encoding the major histocompatibility complex class II transactivator (CIITA) in systemic lupus erythematosus. Ann Rheum Dis (2005) 64:947–50.
[Abstract/Free Full Text]
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