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Open Access 01-12-2008 | Research article

Methylation of class II transactivator gene promoter IV is not associated with susceptibility to Multiple Sclerosis

Authors: Sreeram V Ramagopalan, David A Dyment, Katie M Morrison, Blanca M Herrera, Gabriele C DeLuca, Matthew R Lincoln, Sarah M Orton, Lahiru Handunnetthi, Michael J Chao, A Dessa Sadovnick, George C Ebers

Published in: BMC Medical Genetics | Issue 1/2008

Abstract

Background

Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. The MHC class II transactivator (MHC2TA) is the master controller of expression of class II genes, and methylation of the promoter of this gene has been previously been shown to alter its function. In this study we sought to assess whether or not methylation of the MHC2TA promoter pIV could contribute to MS disease aetiology.

Methods

In DNA from peripheral blood mononuclear cells from a sample of 50 monozygotic disease discordant MS twins the MHC2TA promoter IV was sequenced and analysed by methylation specific PCR.

Results

No methylation or sequence variation of the MHC2TA promoter pIV was found.

Conclusion

The results of this study cannot support the notion that methylation of the pIV promoter of MHC2TA contributes to MS disease risk, although tissue and timing specific epigenetic modifications cannot be ruled out.

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Dyment DA, Ebers GC, Sadovnick AD: Genetics of multiple sclerosis. Lancet Neurol. 2004, 3 (2): 104-110. 10.1016/S1474-4422(03)00663-X.CrossRefPubMed

Zhang Z, Duvefelt K, Svensson F, Masterman T, Jonasdottir G, Salter H, Emahazion T, Hellgren D, Falk G, Olsson T, Hillert J, Anvret M: Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun. 2005, 6 (2): 145-152. 10.1038/sj.gene.6364171.CrossRefPubMed

Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL: Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007, 357 (9): 851-862. 10.1056/NEJMoa073493.CrossRefPubMed

Peltonen L: Old Suspects Found Guilty -- The First Genome Profile of Multiple Sclerosis. N Engl J Med. 2007

Fogdell A, Hillert J, Sachs C, Olerup O: The multiple sclerosis- and narcolepsy-associated HLA class II haplotype includes the DRB5*0101 allele. Tissue Antigens. 1995, 46 (4): 333-336.CrossRefPubMed

Lincoln MR, Montpetit A, Cader MZ, Saarela J, Dyment DA, Tiislar M, Ferretti V, Tienari PJ, Sadovnick AD, Peltonen L, Ebers GC, Hudson TJ: A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet. 2005, 37 (10): 1108-1112. 10.1038/ng1647.CrossRefPubMed

Chao MJ, Barnardo MC, Bu GZ, Lincoln MR, Ramagopalan SV, Herrera BM, Dyment DA, Sadovnick AD, Ebers GC: Transmission of class I/II multi-locus MHC haplotypes and multiple sclerosis susceptibility: accounting for linkage disequilibrium. Hum Mol Genet. 2007

Dyment DA, Herrera BM, Cader MZ, Willer CJ, Lincoln MR, Sadovnick AD, Risch N, Ebers GC: Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. Hum Mol Genet. 2005, 14 (14): 2019-2026. 10.1093/hmg/ddi206.CrossRefPubMed

Ramagopalan SV, Morris AP, Dyment DA, Herrera BM, Deluca GC, Lincoln MR, Orton SM, Chao MJ, Sadovnick AD, Ebers GC: The Inheritance of Resistance Alleles in Multiple Sclerosis. PLoS Genet. 2007, 3 (9): e150-10.1371/journal.pgen.0030150.CrossRefPubMedCentral

10.

Ting JP, Trowsdale J: Genetic control of MHC class II expression. Cell. 2002, 109 Suppl: S21-33. 10.1016/S0092-8674(02)00696-7.CrossRefPubMed

11.

Reith W, LeibundGut-Landmann S, Waldburger JM: Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol. 2005, 5 (10): 793-806. 10.1038/nri1708.CrossRefPubMed

12.

Morris AC, Spangler WE, Boss JM: Methylation of class II trans-activator promoter IV: a novel mechanism of MHC class II gene control. J Immunol. 2000, 164 (8): 4143-4149.CrossRefPubMed

13.

Swanberg M, Lidman O, Padyukov L, Eriksson P, Akesson E, Jagodic M, Lobell A, Khademi M, Borjesson O, Lindgren CM, Lundman P, Brookes AJ, Kere J, Luthman H, Alfredsson L, Hillert J, Klareskog L, Hamsten A, Piehl F, Olsson T: MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet. 2005, 37 (5): 486-494. 10.1038/ng1544.CrossRefPubMed

14.

Akkad DA, Jagiello P, Szyld P, Goedde R, Wieczorek S, Gross WL, Epplen JT: 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 (1): 59-61. 10.1111/j.1744-313X.2006.00568.x.CrossRefPubMed

15.

Sadovnick AD, Risch NJ, Ebers GC: Canadian collaborative project on genetic susceptibility to MS, phase 2: rationale and method. Canadian Collaborative Study Group. Can J Neurol Sci. 1998, 25 (3): 216-221.CrossRefPubMed

16.

Ramagopalan SV, Dyment DA, Valdar W, Herrera BM, Criscuoli M, Yee IM, Sadovnick AD, Ebers GC: Autoimmune disease in families with multiple sclerosis: a population-based study. Lancet Neurol. 2007, 6 (7): 604-610. 10.1016/S1474-4422(07)70132-1.CrossRefPubMed

17.

Bock C, Walter J, Paulsen M, Lengauer T: CpG island mapping by epigenome prediction. PLoS Comput Biol. 2007, 3 (6): e110-10.1371/journal.pcbi.0030110.CrossRefPubMedPubMedCentral

18.

Sambrook J, Russell DW: Molecular cloning : a laboratory manual. 2001, Cold Spring Harbor, New York , Cold Spring Harbor Laboratory Press, 3rd

19.

Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996, 93 (18): 9821-9826. 10.1073/pnas.93.18.9821.CrossRefPubMedPubMedCentral

20.

Bird AP: CpG-rich islands and the function of DNA methylation. Nature. 1986, 321 (6067): 209-213. 10.1038/321209a0.CrossRefPubMed

21.

Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC: Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A. 2003, 100 (22): 12877-12882. 10.1073/pnas.1932604100.CrossRefPubMedPubMedCentral

22.

Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M: Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005, 102 (30): 10604-10609. 10.1073/pnas.0500398102.CrossRefPubMedPubMedCentral

23.

Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC: Timing of birth and risk of multiple sclerosis: population based study. Bmj. 2005, 330 (7483): 120-10.1136/bmj.38301.686030.63.CrossRefPubMedPubMedCentral

24.

Dean G, Elian M: Age at immigration to England of Asian and Caribbean immigrants and the risk of developing multiple sclerosis. J Neurol Neurosurg Psychiatry. 1997, 63 (5): 565-568.CrossRefPubMedPubMedCentral

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/9/63/prepub

Title: Methylation of class II transactivator gene promoter IV is not associated with susceptibility to Multiple Sclerosis
Authors: Sreeram V Ramagopalan
David A Dyment
Katie M Morrison
Blanca M Herrera
Gabriele C DeLuca
Matthew R Lincoln
Sarah M Orton
Lahiru Handunnetthi
Michael J Chao
A Dessa Sadovnick
George C Ebers
Publication date: 01-12-2008
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2008
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-9-63

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Methylation of class II transactivator gene promoter IV is not associated with susceptibility to Multiple Sclerosis

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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