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

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

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.

Autoimmune Diseases, DNA Primers, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lipopolysaccharides, Major Histocompatibility Complex, Multigene Family, Phenotype, Polymorphism, Single Nucleotide, RNA, Messenger, Telomere, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
1466-4879
625-631
Mewar, D.
9485f0d2-a9cb-4331-a1ff-d2bb647efeae
Marinou, I.
56b7d835-e5fe-4ca2-83ed-0c7209c84f4f
Lee, M.E.
cc9ac703-7b07-40ae-8778-e0e5df37c9f8
Timms, J.M.
4c480af8-7dd7-404f-b051-edf13b64f112
Kilding, R.
9f855fdd-9459-451e-a542-b52936992987
Teare, M.D.
a1107526-ed90-40bf-b11c-010260bef7cb
Read, R.C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Wilson, A.G.
91a85e27-8876-498a-a543-114d6e993d94
Mewar, D.
9485f0d2-a9cb-4331-a1ff-d2bb647efeae
Marinou, I.
56b7d835-e5fe-4ca2-83ed-0c7209c84f4f
Lee, M.E.
cc9ac703-7b07-40ae-8778-e0e5df37c9f8
Timms, J.M.
4c480af8-7dd7-404f-b051-edf13b64f112
Kilding, R.
9f855fdd-9459-451e-a542-b52936992987
Teare, M.D.
a1107526-ed90-40bf-b11c-010260bef7cb
Read, R.C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Wilson, A.G.
91a85e27-8876-498a-a543-114d6e993d94

Mewar, D., Marinou, I., Lee, M.E., Timms, J.M., Kilding, R., Teare, M.D., Read, R.C. and Wilson, A.G. (2006) Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases. Genes and Immunity, 7 (8), 625-631. (doi:10.1038/sj.gene.6364339).

Record type: 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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More information

Accepted/In Press date: 10 August 2006
e-pub ahead of print date: 14 September 2006
Published date: December 2006
Keywords: Autoimmune Diseases, DNA Primers, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lipopolysaccharides, Major Histocompatibility Complex, Multigene Family, Phenotype, Polymorphism, Single Nucleotide, RNA, Messenger, Telomere, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 416313
URI: http://eprints.soton.ac.uk/id/eprint/416313
ISSN: 1466-4879
PURE UUID: 47b857f0-dac2-4de1-85c2-60e502ff9bdc
ORCID for R.C. Read: ORCID iD orcid.org/0000-0002-4297-6728

Catalogue record

Date deposited: 12 Dec 2017 17:30
Last modified: 26 Nov 2021 02:58

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Contributors

Author: D. Mewar
Author: I. Marinou
Author: M.E. Lee
Author: J.M. Timms
Author: R. Kilding
Author: M.D. Teare
Author: R.C. Read ORCID iD
Author: A.G. Wilson

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