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Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases

Genes & Immunity volume 7, pages 625–631 (2006)Cite this article

Abstract

The telomeric class III region of the major histocompatibility complex is gene dense, but apart from the three tumour necrosis factor (TNF) superfamily members (TNF, lymphotoxin alpha and lymphotoxin beta) little is known of the expression and function of the majority of the genes. Recent genetic studies in autoimmune diseases, particularly rheumatoid arthritis (RA), have suggested a human leukocyte antigen (HLA)-DR-independent disease effect in this region. To gain further insights into these associations, we used lipopolysaccharide-stimulated human macrophages to examine inducible mRNA expression and genotype–phenotype relationships for genes in this region. Following stimulation in addition to the expected induction of TNF mRNA, a 14-fold increase of ATP6V1G2 at 18 h (P<0.001) was seen, whereas B-associated transcript (BAT)2 (P<0.001) and leucocyte-specific transcript (LST)1 (P<0.001) were both downregulated. By genotyping single-nucleotide polymorphisms spanning a 70 kb interval centred on the TNF locus, we constructed haplotypes and determined associated expression profiles for 10 genes in the cluster using quantitative real-time polymerase chain reaction. Overexpression of BAT1 mRNA was associated with carriers of a haplotype containing the LST1 marker transmitted to RA cases in a family study and also DRB1*15 associated with susceptibility to nephritis in systemic lupus erythematosus. The implications of our findings for the understanding of genetic associations with disease susceptibility in this region are discussed.

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References

  1. Mulcahy B, Waldron-Lynch F, McDermott MF, Adams C, Amos CI, Zhu DK et al. Genetic variability in the tumor necrosis factor–lymphotoxin region influences susceptibility to rheumatoid arthritis. Am J Hum Genet 1996; 59: 676–683.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Martinez A, Fernandez-Arquero M, Pascual-Salcedo D, Conejero L, Alves H, Balsa A et al. Primary association of tumor necrosis factor-region genetic markers with susceptibility to rheumatoid arthritis. Arthritis Rheum 2000; 43: 1366–1370.

    Article  CAS  Google Scholar 

  3. Hajeer AH, Dababneh A, Makki RF, Thomson W, Poulton K, Gonzalez-Gay MA et al. Different gene loci within the HLA-DR and TNF regions are independently associated with susceptibility and severity in Spanish rheumatoid arthritis patients. Tissue Antigens 2000; 55: 319–325.

    Article  CAS  Google Scholar 

  4. Singal DP, Li J, Lei K . Genetics of rheumatoid arthritis (RA): two separate regions in the major histocompatibility complex contribute to susceptibility to RA. Immunol Lett 1999; 69: 301–306.

    Article  CAS  Google Scholar 

  5. Castro F, Acevedo E, Ciusani E, Angulo JA, Wollheim FA, Sandberg-Wollheim M . Tumour necrosis factor microsatellites and HLA-DRB1*, HLA-DQA1*, and HLA-DQB1*alleles in Peruvian patients with rheumatoid arthritis. Ann Rheum Dis 2001; 60: 791–795.

    Article  CAS  Google Scholar 

  6. Mattey DL, Hassell AB, Dawes PT, Ollier WE, Hajeer A . Interaction between tumor necrosis factor microsatellite polymorphisms and the HLA-DRB1 shared epitope in rheumatoid arthritis: influence on disease outcome. Arthritis Rheum 1999; 42: 2698–2704.

    Article  CAS  Google Scholar 

  7. Brinkman BM, Huizinga TW, Kurban SS, van der Velde EA, Schreuder GM, Hazes JM et al. Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease? Br J Rheumatol 1997; 36: 516–521.

    Article  CAS  Google Scholar 

  8. van Krugten MV, Huizinga TW, Kaijzel EL, Zanelli E, Drossaers-Bakker KW, van de Linde P et al. Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis. Genes Immun 1999; 1: 91–96.

    Article  CAS  Google Scholar 

  9. Ota M, Katsuyama Y, Kimura A, Tsuchiya K, Kondo M, Naruse T et al. A second susceptibility gene for developing rheumatoid arthritis in the human MHC is localized within a 70-kb interval telomeric of the TNF genes in the HLA class III region. Genomics 2001; 71: 263–270.

    Article  CAS  Google Scholar 

  10. Zanelli E, Jones G, Pascual M, Eerligh P, van der Slik AR, Zwinderman AH et al. The telomeric part of the HLA region predisposes to rheumatoid arthritis independently of the class II loci. Hum Immunol 2001; 62: 75–84.

    Article  CAS  Google Scholar 

  11. Jawaheer D, Li W, Graham RR, Chen W, Damle A, Xiao X et al. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet 2002; 71: 585–594.

    Article  CAS  Google Scholar 

  12. Kilding R, Iles MM, Timms JM, Worthington J, Wilson AG . Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1 locus. Arthritis Rheum 2004; 50: 763–769.

    Article  CAS  Google Scholar 

  13. Kochi Y, Yamada R, Kobayashi K, Takahashi A, Suzuki A, Sekine A et al. Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences. Arthritis Rheum 2004; 50: 63–71.

    Article  CAS  Google Scholar 

  14. Tamiya G, Shinya M, Imanishi T, Ikuta T, Makino S, Okamoto K et al. Whole genome association study of rheumatoid arthritis using 27 039 microsatellites. Hum Mol Genet 2005; 14: 2305–2321.

    Article  CAS  Google Scholar 

  15. Newton JL, Harney SM, Timms AE, Sims AM, Rockett K, Darke C et al. Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis. Arthritis Rheum 2004; 50: 2122–2129.

    Article  CAS  Google Scholar 

  16. Deininger MH, Meyermann R, Schluesener HJ . The allograft inflammatory factor-1 family of proteins. FEBS Lett 2002; 514: 115–121.

    Article  CAS  Google Scholar 

  17. Rollinger-Holzinger I, Eibl B, Pauly M, Griesser U, Hentges F, Auer B et al. LST1: a gene with extensive alternative splicing and immunomodulatory function. J Immunol 2000; 164: 3169–3176.

    Article  CAS  Google Scholar 

  18. Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L et al. Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med 1999; 190: 1505–1516.

    Article  CAS  Google Scholar 

  19. Okamoto K, Makino S, Yoshikawa Y, Takaki A, Nagatsuka Y, Ota M et al. Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am J Hum Genet 2003; 72: 303–312.

    Article  CAS  Google Scholar 

  20. Collado L, Rueda B, Caliz R, Torres B, Garcia A, Nunez-Roldan A et al. Lack of association between the I kappa BL promoter polymorphism and rheumatoid arthritis. Arthritis Rheum 2004; 50: 2032–2033.

    Article  CAS  Google Scholar 

  21. Finbow ME, Harrison MA . The vacuolar H+-ATPase: a universal proton pump of eukaryotes. Biochem J 1997; 324 (Part 3): 697–712.

    Article  CAS  Google Scholar 

  22. Low R, Rockel B, Kirsch M, Ratajczak R, Hortensteiner S, Martinoia E et al. Early salt stress effects on the differential expression of vacuolar H(+)-ATPase genes in roots and leaves of Mesembryanthemum crystallinum. Plant Physiol 1996; 110: 259–265.

    Article  CAS  Google Scholar 

  23. Nanda A, Gukovskaya A, Tseng J, Grinstein S . Activation of vacuolar-type proton pumps by protein kinase C. Role in neutrophil pH regulation. J Biol Chem 1992; 267: 22740–22746.

    CAS  PubMed  Google Scholar 

  24. Bidani A, Wang CZ, Saggi SJ, Heming TA . Evidence for pH sensitivity of tumor necrosis factor-alpha release by alveolar macrophages. Lung 1998; 176: 111–121.

    Article  CAS  Google Scholar 

  25. Bidani A, Reisner BS, Haque AK, Wen J, Helmer RE, Tuazon DM et al. Bactericidal activity of alveolar macrophages is suppressed by V-ATPase inhibition. Lung 2000; 178: 91–104.

    Article  CAS  Google Scholar 

  26. Trombetta ES, Ebersold M, Garrett W, Pypaert M, Mellman I . Activation of lysosomal function during dendritic cell maturation. Science 2003; 299: 1400–1403.

    Article  CAS  Google Scholar 

  27. Sato K, Shikano S, Xia G, Takao J, Chung JS, Cruz Jr PD et al. Selective expression of vacuolar H(+)-ATPase subunit d2 by particular subsets of dendritic cells among leukocytes. Mol Immunol 2006; 43: 1443–1453.

    Article  CAS  Google Scholar 

  28. Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T et al. Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA 2002; 99: 4465–4470.

    Article  CAS  Google Scholar 

  29. de Baey A, Fellerhoff B, Maier S, Martinozzi S, Weidle U, Weiss EH . Complex expression pattern of the TNF region gene LST1 through differential regulation, initiation, and alternative splicing. Genomics 1997; 45: 591–600.

    Article  CAS  Google Scholar 

  30. Fronek Z, Timmerman LA, Alper CA, Hahn BH, Kalunian K, Peterlin BM et al. Major histocompatibility complex associations with systemic lupus erythematosus. Am J Med 1988; 85: 42–44.

    Article  CAS  Google Scholar 

  31. Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO . Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 1990; 87: 1233–1237.

    Article  CAS  Google Scholar 

  32. Jacob CO, McDevitt HO . Tumour necrosis factor-alpha in murine autoimmune ‘lupus’ nephritis. Nature 1988; 331: 356–358.

    Article  CAS  Google Scholar 

  33. Luo ML, Zhou Z, Magni K, Christoforides C, Rappsilber J, Mann M et al. Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 2001; 413: 644–647.

    Article  CAS  Google Scholar 

  34. Allcock RJ, Williams JH, Price P . The central MHC gene, BAT1, may encode a protein that down-regulates cytokine production. Genes Cells 2001; 6: 487–494.

    Article  CAS  Google Scholar 

  35. Kwiatkowski D, Hill AV, Sambou I, Twumasi P, Castracane J, Manogue KR et al. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet 1990; 336: 1201–1204.

    Article  CAS  Google Scholar 

  36. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D . Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 1994; 371: 508–510.

    Article  CAS  Google Scholar 

  37. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997; 94: 3195–3199.

    Article  CAS  Google Scholar 

  38. Bunce M, O'Neill CM, Barnardo MC, Krausa P, Browning MJ, Morris PJ et al. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens 1995; 46: 355–367.

    Article  CAS  Google Scholar 

  39. http://www-gene.cimr.cam.ac.uk/clayton/software/snphap.txt.

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Acknowledgements

This work was supported in part by the Sheffield Hospitals Charitable Trust and arc, the Arthritis Research Campaign of the UK.

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Authors and Affiliations

  1. School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK

    D Mewar, I Marinou, M E Lee, J M Timms, R Kilding, M D Teare, R C Read & A G Wilson

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  1. D Mewar
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  2. I Marinou
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  3. M E Lee
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  4. J M Timms
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  5. R Kilding
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  8. A G Wilson
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Correspondence to D Mewar.

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Mewar, D., Marinou, I., Lee, M. et al. Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases. Genes Immun 7, 625–631 (2006). https://doi.org/10.1038/sj.gene.6364339

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