Rheumatology Advance Access originally published online on February 5, 2008
Rheumatology 2008 47(4):547-548; doi:10.1093/rheumatology/kem382
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LETTERS TO THE EDITOR |
Promoter activity of A/G at position –168 in the type III promoter of MHCIITA gene
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
Correspondence to: H. Okamoto, Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku, Tokyo 162-0054, Japan. E-mail: hokamoto{at}ior.twmu.ac.jp
SIR, The MHC class II transactivator (MHCIITA) gene was originally identified as a defective gene associated with bare lymphocyte syndrome (BLS) [1]. Transcription of the human MHCIITA gene is controlled by alternative promoters [2]. Promoter III (pIII) is responsible for constitutive CIITA expression in B cells.
The recent paper by Swanberg et al. [3] described that a—168A 
G polymorphism in the type III promoter of the MHCIITA was associated with increased susceptibility to RA, multiple sclerosis and myocardial infarction, as well as lower expression of MHCIITA after stimulation of leucocytes with IFN-
. Although similar studies in three other European populations did not find this association [4–6], our study in the Japanese population supported this association [7]. We recently found that –168 A dominance is protective against SLE [8]. In this current report, we studied the effect of the A/G polymorphism at position –168 on the type III promoter activity of MHCIITA gene to evaluate the functional importance.
We amplified the type III promoter of MHCIITA, which includes the –168 A/G polymorphism and cloned products upstream of the luciferase reporter gene of pGL4 (Promega, Madison, WI, USA). Single-nucleotide polymorphisms (SNPs) containing reporter plasmids were constructed by using PCR. The 5'-end primer was flanked by a NheI restriction enzyme site and the 3'-end primer was flanked by a Hind III restriction enzyme site and the PCR products were purified by phenol/chloroform extraction and cleaved with NheI and HindIII restriction endonucleases. The resulting products were purified from agarose gels and ligated into the NheI and HindIII sites of pGL4.11 (Promega). The role of the promoter region that contains the two functionally relevant SNPs was investigated by generating two constructs and comparing their promoter activity. Constructs were verified by sequencing and transiently transfected into Raji cells and 293T cells, as described previously [9]. Luciferase activity was assessed in three independent samples and all experiments were repeated in triplicate.
As shown in Fig. 1, we found a significant difference in the transcriptional activity between the type III promoter of MHCIITA with –168A and that with –168G by reporter gene assay. The type III promoter of MHCIITA containing –168G had higher transcriptional activity than that containing –168A. IFN- responsive potential was found in both types of promoter. Our findings contradicted the results reported by Swanberg et al. [3] as they have shown that expression of MHCIITA mRNA was lower in cells from individuals with genotype GG than in cells from individuals with other genotypes by the activation with IFN-. This discrepancy might be explained by the presence of the additional SNP around position –168. In supporting this speculation, Martinez et al. [10] recently reported that haplotype pattern of 1614G/C together with –168A/G was associated with a greater risk of RA, although SNP alone did not show significant association with the risk of RA. Further studies are needed to confirm biological effects of SNP (–168A G) in association with other SNPs including 1614G/C in the setting of haplotype classification, especially whether transcriptional activation in each haplotype is prerequisite for the better understanding of the contribution of SNPs in MHCIITA gene in human diseases.
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Disclosure statement: The authors have declared no conflicts of interest.
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