Allele-specific methylation of type 1 diabetes susceptibility genes

Alida S.D. Kindt; Rainer W. Fuerst; Jan Knoop; Michael Laimighofer; Tanja Telieps; Markus Hippich; Maria A. Woerheide; Simone Wahl; Rory Wilson; Eva Maria Sedlmeier; Angela Hommel; John A. Todd; Jan Krumsiek; Anette G. Ziegler; Ezio Bonifacio

doi:10.1016/j.jaut.2017.11.008

Allele-specific methylation of type 1 diabetes susceptibility genes

Alida S.D. Kindt, Rainer W. Fuerst, Jan Knoop, Michael Laimighofer, Tanja Telieps, Markus Hippich, Maria A. Woerheide, Simone Wahl, Rory Wilson, Eva Maria Sedlmeier, Angela Hommel, John A. Todd, Jan Krumsiek, Anette G. Ziegler, Ezio Bonifacio

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype. Extensive cis-metQTLs were identified in all 45 immune and non-immune type 1 diabetes susceptibility genes analyzed in this study. We observed and validated a novel association between the methylation status of CpG sites within the LDHC gene and the development of insulin autoantibodies in early childhood in children who are carriers of the highest type 1 diabetes risk genotype. Functionally relevant epigenetic changes in susceptibility genes may represent therapeutic targets for type 1 diabetes.

Original language	English
Pages (from-to)	63-74
Number of pages	12
Journal	Journal of Autoimmunity
Volume	89
DOIs	https://doi.org/10.1016/j.jaut.2017.11.008
State	Published - May 2018
Externally published	Yes

Keywords

Autoimmunity
Epigenetics
HLA
Insulin autoantibodies
Insulin gene
Lactate dehydrogenase C

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaut.2017.11.008

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Kindt, A. S. D., Fuerst, R. W., Knoop, J., Laimighofer, M., Telieps, T., Hippich, M., Woerheide, M. A., Wahl, S., Wilson, R., Sedlmeier, E. M., Hommel, A., Todd, J. A., Krumsiek, J., Ziegler, A. G., & Bonifacio, E. (2018). Allele-specific methylation of type 1 diabetes susceptibility genes. Journal of Autoimmunity, 89, 63-74. https://doi.org/10.1016/j.jaut.2017.11.008

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abstract = "The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype. Extensive cis-metQTLs were identified in all 45 immune and non-immune type 1 diabetes susceptibility genes analyzed in this study. We observed and validated a novel association between the methylation status of CpG sites within the LDHC gene and the development of insulin autoantibodies in early childhood in children who are carriers of the highest type 1 diabetes risk genotype. Functionally relevant epigenetic changes in susceptibility genes may represent therapeutic targets for type 1 diabetes.",

keywords = "Autoimmunity, Epigenetics, HLA, Insulin autoantibodies, Insulin gene, Lactate dehydrogenase C",

author = "Kindt, {Alida S.D.} and Fuerst, {Rainer W.} and Jan Knoop and Michael Laimighofer and Tanja Telieps and Markus Hippich and Woerheide, {Maria A.} and Simone Wahl and Rory Wilson and Sedlmeier, {Eva Maria} and Angela Hommel and Todd, {John A.} and Jan Krumsiek and Ziegler, {Anette G.} and Ezio Bonifacio",

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doi = "10.1016/j.jaut.2017.11.008",

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AU - Kindt, Alida S.D.

AU - Fuerst, Rainer W.

AU - Knoop, Jan

AU - Laimighofer, Michael

AU - Telieps, Tanja

AU - Hippich, Markus

AU - Woerheide, Maria A.

AU - Wahl, Simone

AU - Wilson, Rory

AU - Sedlmeier, Eva Maria

AU - Hommel, Angela

AU - Todd, John A.

AU - Krumsiek, Jan

AU - Ziegler, Anette G.

AU - Bonifacio, Ezio

PY - 2018/5

Y1 - 2018/5

N2 - The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype. Extensive cis-metQTLs were identified in all 45 immune and non-immune type 1 diabetes susceptibility genes analyzed in this study. We observed and validated a novel association between the methylation status of CpG sites within the LDHC gene and the development of insulin autoantibodies in early childhood in children who are carriers of the highest type 1 diabetes risk genotype. Functionally relevant epigenetic changes in susceptibility genes may represent therapeutic targets for type 1 diabetes.

AB - The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype. Extensive cis-metQTLs were identified in all 45 immune and non-immune type 1 diabetes susceptibility genes analyzed in this study. We observed and validated a novel association between the methylation status of CpG sites within the LDHC gene and the development of insulin autoantibodies in early childhood in children who are carriers of the highest type 1 diabetes risk genotype. Functionally relevant epigenetic changes in susceptibility genes may represent therapeutic targets for type 1 diabetes.

KW - Autoimmunity

KW - Epigenetics

KW - HLA

KW - Insulin autoantibodies

KW - Insulin gene

KW - Lactate dehydrogenase C

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ER -

Allele-specific methylation of type 1 diabetes susceptibility genes

Abstract

Keywords

UN SDGs

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