Rheumatology Advance Access originally published online on August 25, 2006
Rheumatology 2006 45(11):1442-1444; doi:10.1093/rheumatology/kel272
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LETTERS TO THE EDITOR |
Study of the role of a functional polymorphism of MHC2TA in rheumatoid arthritis in three ethnically different populations
1Instituto de Parasitología y Biomedicina López Neyra, Granada, Spain, 2Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, 3Servicio de Reumatología, Hospital Virgen de las Nieves, Granada, Spain, 4Servicio de Reumatologia e Inmunología, Hospital La Paz, Madrid, Spain, 5Servicio de Reumatología, Hospital Xeral-Calde, Lugo, Spain, 6Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina, 7Hospital José M. Cullen, Santa Fe, Argentina, 8Servicio de Reumatología, Hospital Interzonal General de Agudos "Dr. Oscar Alende", Mar del Plata, Argentina, 9Sanatorio Parque, Rosario, Argentina, 10Spenshult Hospital for Rheumatic Diseases, Halmstad, Sweden and 11for the BARFOT-study group, Sweden
Correspondence to: J. Martín, MD, PhD Instituto de Parasitología y Biomedicina "López Neyra", CSIC Parque Tecnológico Ciencias de la Salud. Avenida del Conocimiento s/n. 18100 Armilla, Granada, Spain. E-mail: martin{at}ipb.csic.es
SIR, Rheumatoid arthritis (RA) is a chronic complex inflammatory disease that is thought to have an autoimmune origin. Although the precise aetiology of RA is unknown, a strong genetic component is well-established. The strongest genetic association with RA has been found for particular alleles of HLA-DRB1. Furthermore, it has been reported that the differential expression of HLA class II genes is associated with both susceptibility and progression of RA [1]. Also, it has been recently reported about an association between the more severe forms of RA (extra-articular RA) and the presence of the HLA-DRB1*04 allele as well as between the HLA C3 allele and vasculitis in RA [2, 3]. Therefore, it seems that regulatory factors of the expression of major histocompatibility complex (MHC) class II molecules could play an important role in the pathogenesis of RA, and polymorphisms in these genes might confer susceptibility to the disease.
The MHC class II transactivator (CIITA), encoded by the MHC II transactivator (MHC2TA) gene, is a major physiological regulator of the expression of MHC class II genes, and it maps to chromosome 16p13, a region which has shown linkage with RA [4]. Therefore, it is an attractive functional and positional candidate gene for RA. It has been recently reported that the –168A
G polymorphism (rs3087456) in MHC2TA is associated with RA, multiple sclerosis (MS) and myocardial infarction in a Nordic population [5]. In addition, the single nucleotide polymorphism (SNP) leads to reduced MHC2TA expression, and hence reduced production of MHC II molecules. Our aim was to replicate the reported association of the MHC2TA –168AG SNP with RA in three ethnically different populations from Spain, Argentina and Sweden.
MHC2TA genotypes were in Hardy–Weinberg equilibrium in cases and controls for the three populations under study. An association was found when we compared allele frequencies between Spanish RA patients and healthy controls, with a higher frequency of the MHC2TA–168A allele in the RA group [P = 0.01, odds ratio (OR) 1.23 (95% confidence intervals (CI) 1.04–1.47)] (Table 1). In addition, the MHC2TA–168 AA genotype was more frequent among RA patients than in healthy controls [P = 0.01, OR 1.31 (95% CI 1.06–1.63)]. Next, we analysed the demographic and clinical characteristics of Spanish RA patients (gender, age at disease-onset, presence of shared epitope, rheumatoid factor, rheumatic nodules and extra-articular disease) according to the MHC2TA–168AG genotype; however, no statistically differences were observed (data not shown). Additionally, we sought to replicate the association of the MHC2TA–168AG SNP with RA in two ethnically different population from Argentina and Sweden. No evidence of association was observed in the RA Argentinean and Swedish sets (Table 1). Finally, the three independent cohorts were pooled in order to carry out a meta-analysis, showing that MHC2TA–168AG SNP is not associated with RA (pooled OR 1.08, 95% CI 0.96–1.21, P = 0.206).
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In an attempt to replicate the reported association of the MHC2TA–168A
G polymorphism with RA in three different cohorts, we found that, in contrast to the original study by Swanberg et al. [5], the A allele is the susceptibility allele in the Spanish population, not the G allele, while a lack of association was observed in the Argentinean and Swedish cohort. Notably, Akkad et al. [6] were not able to replicate the association of MHC2TA–168AG polymorphism and RA in a German population. Lack of replication of a previous association is a common event in the search for genetic determinant of complex human traits that may be due to a number of factors. The effects of genetic, population and clinical heterogeneity must be considered when attempting to detect susceptibility genes for RA in different populations. In this regard, we have found striking differences in allele frequencies for healthy controls between the Spanish and Argentinean populations, and those found in the Nordic population (P = 5x10–5 and P < 10–7, respectively) [5]. Furthermore, these allele frequencies are statistically different between Spanish and Argentinean subjects (P = 2x10–6). Interestingly, Spanish allele frequencies were similar to those found in Germans [6]. However, allele frequencies for the Argentinean population were different from the German population (P = 3x10–6). It is worth mentioning that we have found genetic heterogeneity between the Swedish population from the original study by Swanberg et al. [5] and the Swedish population tested in the present study. Although the frequency of the RA patients was similar for the two Nordic populations, they differ in the allele frequency of the SNP in healthy controls (P = 0.006). Surprisingly, the frequencies in RA patients and controls for the Swedish population that we studied are comparable with those found in the Spanish population.
In light of this evidence, it seems possible that a cause of discrepancy could be genetic heterogeneity, which can be explained by differences in the haplotype structure of the MHC2TA locus across populations. However, the association found in the Spanish population between RA and MHC2TA –168A allele is possibly due to a type I error (false positive). The lack of replication of the original finding in two cohorts from Argentina and Sweden, and the results from the meta-analysis carried out pooling the three RA cohorts, also points to this hypothesis.
Other groups have evaluated the possible role of MHC2TA SNPs in autoimmune disease, but none of them have reached robust conclusions. MHC2TA–168AG polymorphism is weakly associated with MS in an English population [7]. In a Japanese study a trend of association was found only between 485(AA/G) MHC2TA and systemic lupus erythematosus [8].
In conclusion, it appears that this genetic variation on MHC2TA does not play a role in the susceptibility to RA. Inherent genetic differences in the allele frequencies and haplotype structure in the MHC2TA region in the populations studied can explain the lack of confirmation of the initial positive finding. This could be avoided using a gene-based replication approach, not allele-based, in which all genetic variants in the MHC2TA gene are re-examined for association with autoimmune diseases.
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This work was supported by Plan Nacional de I+D (grant SAF03-3460) and in part by Junta de Andalucía, grupo CTS-180. We also thank the Swedish Research Council and the Swedish Association against Rheumatisms for support. We thank Ma Paz Ruiz Blas and Hong Yin for excellent technical assistance, the rheumatologist for providing the DNA samples and patients for their essential collaboration.
The authors have declared no conflicts of interest.
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* These authors have contributed equally to this study.
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TopAcknowledgementsReferences |
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- Akkad DA, Jagiello P, Szyld P, et al. (2006) 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 33:59–61.[CrossRef][Web of Science][Medline]
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[Abstract/Free Full Text]
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