CpG Methylation Changes Within the IL2RA Promoter in Type 1 Diabetes of Childhood Onset

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Jul 23

PMID 23874506

Citations 19

Authors

Marie-Pierre Belot

Delphine Fradin

Nga Mai

Sophie Le Fur

Diana Zelenika

Julie Kerr-Conte

Francois Pattou

Bruno Lucas

Pierre Bougneres

Affiliations

Soon will be listed here.

Abstract

None of the polymorphic variants of the IL2RA gene found associated with Type 1 Diabetes (T1D) was shown to have a functional effect. To test if the epigenetic variation could play a role at this locus, we studied the methylation of 6 CpGs located within the proximal promoter of IL2RA gene in 252 T1D patients compared with 286 age-matched controls. We found that DNA methylation at CpGs -373 and -456 was slightly but significantly higher in patients than in controls (40.4 ± 4.6 vs 38.3 ± 5.4, p=1.4E4; 91.4 ± 2.8 vs 89.5 ± 5.3, p=1.8E-6), while other CpG showed a strictly comparable methylation. Among 106 single nucleotide polymorphisms (SNPs) located in the neighboring 180 kb region, we found that 28 SNPs were associated with DNA methylation at CpG -373. Sixteen of these SNPs were known to be associated with T1D. Our findings suggest that the effect of IL2RA risk alleles on T1D may be partially mediated through epigenetic changes.

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References

Caligiuri M, Zmuidzinas A, Manley T, Levine H, Smith K, Ritz J . Functional consequences of interleukin 2 receptor expression on resting human lymphocytes. Identification of a novel natural killer cell subset with high affinity receptors. J Exp Med. 1990; 171(5):1509-26. PMC: 2187895. DOI: 10.1084/jem.171.5.1509. View

Barrett J, Clayton D, Concannon P, Akolkar B, Cooper J, Erlich H . Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet. 2009; 41(6):703-7. PMC: 2889014. DOI: 10.1038/ng.381. View

Imamura T, Ohgane J, Ito S, Ogawa T, Hattori N, Tanaka S . CpG island of rat sphingosine kinase-1 gene: tissue-dependent DNA methylation status and multiple alternative first exons. Genomics. 2001; 76(1-3):117-25. DOI: 10.1006/geno.2001.6607. View

Kerkel K, Spadola A, Yuan E, Kosek J, Jiang L, Hod E . Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet. 2008; 40(7):904-8. DOI: 10.1038/ng.174. View

Velten F, Rambow F, Metharom P, Goerdt S . Enhanced T-cell activation and T-cell-dependent IL-2 production by CD83+, CD25high, CD43high human monocyte-derived dendritic cells. Mol Immunol. 2006; 44(7):1544-50. DOI: 10.1016/j.molimm.2006.08.020. View

Shen S, Sandoval J, Swiss V, Li J, Dupree J, Franklin R . Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci. 2009; 11(9):1024-34. PMC: 2656679. DOI: 10.1038/nn.2172. View

Cui H, Cruz-Correa M, Giardiello F, Hutcheon D, Kafonek D, Brandenburg S . Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science. 2003; 299(5613):1753-5. DOI: 10.1126/science.1080902. View

Byun H, Siegmund K, Pan F, Weisenberger D, Kanel G, Laird P . Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. Hum Mol Genet. 2009; 18(24):4808-17. PMC: 4481584. DOI: 10.1093/hmg/ddp445. View

Fehniger T, Cooper M, Nuovo G, Cella M, Facchetti F, Colonna M . CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood. 2002; 101(8):3052-7. DOI: 10.1182/blood-2002-09-2876. View

10.

Caligiuri M, Murray C, Robertson M, Wang E, Cochran K, Cameron C . Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J Clin Invest. 1993; 91(1):123-32. PMC: 330005. DOI: 10.1172/JCI116161. View

11.

. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447(7145):661-78. PMC: 2719288. DOI: 10.1038/nature05911. View

12.

Nishino K, Hattori N, Tanaka S, Shiota K . DNA methylation-mediated control of Sry gene expression in mouse gonadal development. J Biol Chem. 2004; 279(21):22306-13. DOI: 10.1074/jbc.M309513200. View

13.

Hafler D, Compston A, Sawcer S, Lander E, Daly M, De Jager P . Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007; 357(9):851-62. DOI: 10.1056/NEJMoa073493. View

14.

Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M . Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995; 155(3):1151-64. View

15.

Furtado G, Curotto de Lafaille M, Kutchukhidze N, Lafaille J . Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med. 2002; 196(6):851-7. PMC: 2194060. DOI: 10.1084/jem.20020190. View

16.

Vella A, Cooper J, Lowe C, Walker N, Nutland S, Widmer B . Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet. 2005; 76(5):773-9. PMC: 1199367. DOI: 10.1086/429843. View

17.

Zhang D, Cheng L, Badner J, Chen C, Chen Q, Luo W . Genetic control of individual differences in gene-specific methylation in human brain. Am J Hum Genet. 2010; 86(3):411-9. PMC: 2833385. DOI: 10.1016/j.ajhg.2010.02.005. View

18.

Yagi S, Hirabayashi K, Sato S, Li W, Takahashi Y, Hirakawa T . DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression. Genome Res. 2008; 18(12):1969-78. PMC: 2593572. DOI: 10.1101/gr.074070.107. View

19.

Stahl E, Raychaudhuri S, Remmers E, Xie G, Eyre S, Thomson B . Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010; 42(6):508-14. PMC: 4243840. DOI: 10.1038/ng.582. View

20.

Kim H, Imbert J, Leonard W . Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev. 2006; 17(5):349-66. DOI: 10.1016/j.cytogfr.2006.07.003. View