MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction

Abstract

Antigen presentation to T cells by MHC molecules is essential for adaptive immune responses. To determine the exact position of a gene affecting expression of MHC molecules, we finely mapped a previously defined rat quantitative trait locus regulating MHC class II on microglia in an advanced intercross line. We identified a small interval including the gene MHC class II transactivator (Mhc2ta) and, using a map over six inbred strains combined with gene sequencing and expression analysis, two conserved Mhc2ta haplotypes segregating with MHC class II levels. In humans, a –168A → G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction, as well as lower expression of MHC2TA after stimulation of leukocytes with interferon-γ. We conclude that polymorphisms in Mhc2ta and MHC2TA result in differential MHC molecule expression and are associated with susceptibility to common complex diseases with inflammatory components.

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Figure 1: Fine mapping of the Vra4 locus in the AIL F8 generation.
Figure 2: VRA-induced expression of MHC class II molecules in the spinal cord.
Figure 3: Haplotype map over Vra4 in rat strains examined for expression of MHC class II molecules.
Figure 4: RT-PCR analysis of Mhc2ta and Cd74 transcript levels in ipsilateral L3 segments from F8 rats 14 d after VRA stratified for marker D10Mgh25.
Figure 5: Expression of MHC class II molecules in the striatum after intracerebral injections of IFN-γ or LPS.
Figure 6: Effect of −168A → G polymorphism on class II associated transcript levels.
Figure 7: Correlation between MHC2TA and MHC class II associated transcripts in human PBMCs stimulated with 50 U ml−1 recombinant IFN-γ (rIFNγ).

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Acknowledgements

L.P., P.E. and E.Å. contributed equally to the human genetic part of the study. We thank K. Becanovic, J. Lorentzen, L. Bäckdahl and E. Wallström for expert advice in genetics and practical help with breeding of the AIL; K. Duvefelt for collaboration on microarray analysis; and the EIRA group, E. Jemseby, the MI group and B. Burt for their contributions. This study was supported by grants from the Wadsworth Foundation, Torsten and Ragnar Söderbergs Foundation, The Swedish Heart-Lung Foundation, the Petrus and Augusta Hedlunds Foundation, Björklunds Foundation, Nils and Bibbi Jenssens Foundation, the Swedish Foundation for Neurologically Disabled, Montel Williams Foundation, Svenska Läkaresällskapet, Max and Edit Follins Foundation, the King Gustaf V and Queen Victoria foundation, AFA insurance and the Swedish Research Council, af Ugglas Foundation, Novartis Foundation, Royal Physiographic Society and The Swedish Medical Research Council.

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Correspondence to Tomas Olsson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Genotype and allele frequencies for SNP2 (rs2229320plus27bp) and SNP3 (rs4774). (PDF 57 kb)

Supplementary Table 2

Primers and probes used for RT-PCR. (XLS 20 kb)

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Swanberg, M., Lidman, O., Padyukov, L. et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet 37, 486–494 (2005) doi:10.1038/ng1544

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