The Multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis

Kaushal S. Gandhi, Fiona C. McKay, Patrick Danoy, Graeme J. Stewart, Simon A. Broadley, Pablo Moscato, Jeanette Lechner-Scott, Rodney J. Scott, David R. Booth, Lyn Griffiths, Mark Slee, Sharon Browning, Matthew Cox, Brian L. Browning, Trevor Kilpatrick, Justin Rubio, Victoria Perreau, Helmut Butzkeuven, Mary Tanner, Jim Wiley & 12 others Simon Foote, Bruce Taylor, Allan Kermode, Carlos Riveros, Bill Carroll, Melanie Bahlo, Nicola Armstrong, Robert N. Heard, Steve Vucic, David W. Williams, Jim Stankovich, Matthew Brown

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P <10−12) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P <0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P <10⁻¹⁴). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.
LanguageEnglish
Pages2134-2143
Number of pages10
JournalHuman molecular genetics
Volume19
Issue number11
DOIs
Publication statusPublished - 2010
Externally publishedYes

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Transcriptome
Multiple Sclerosis
T-Lymphocytes
Messenger RNA
Chronic Progressive Multiple Sclerosis
Haplotypes
Genome
Genes
Gene Expression
Chromosomes, Human, Pair 14
Relapsing-Remitting Multiple Sclerosis
Oxidative Phosphorylation
Linkage Disequilibrium
Antigen Presentation
Cell- and Tissue-Based Therapy
Synapses
Autoimmune Diseases
Single Nucleotide Polymorphism
Leukocytes
Lymphocytes

Cite this

Gandhi, Kaushal S. ; McKay, Fiona C. ; Danoy, Patrick ; Stewart, Graeme J. ; Broadley, Simon A. ; Moscato, Pablo ; Lechner-Scott, Jeanette ; Scott, Rodney J. ; Booth, David R. ; Griffiths, Lyn ; Slee, Mark ; Browning, Sharon ; Cox, Matthew ; Browning, Brian L. ; Kilpatrick, Trevor ; Rubio, Justin ; Perreau, Victoria ; Butzkeuven, Helmut ; Tanner, Mary ; Wiley, Jim ; Foote, Simon ; Taylor, Bruce ; Kermode, Allan ; Riveros, Carlos ; Carroll, Bill ; Bahlo, Melanie ; Armstrong, Nicola ; Heard, Robert N. ; Vucic, Steve ; Williams, David W. ; Stankovich, Jim ; Brown, Matthew. / The Multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis. In: Human molecular genetics. 2010 ; Vol. 19, No. 11. pp. 2134-2143.
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abstract = "Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P <10−12) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P <0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P <10⁻¹⁴). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.",
author = "Gandhi, {Kaushal S.} and McKay, {Fiona C.} and Patrick Danoy and Stewart, {Graeme J.} and Broadley, {Simon A.} and Pablo Moscato and Jeanette Lechner-Scott and Scott, {Rodney J.} and Booth, {David R.} and Lyn Griffiths and Mark Slee and Sharon Browning and Matthew Cox and Browning, {Brian L.} and Trevor Kilpatrick and Justin Rubio and Victoria Perreau and Helmut Butzkeuven and Mary Tanner and Jim Wiley and Simon Foote and Bruce Taylor and Allan Kermode and Carlos Riveros and Bill Carroll and Melanie Bahlo and Nicola Armstrong and Heard, {Robert N.} and Steve Vucic and Williams, {David W.} and Jim Stankovich and Matthew Brown",
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Gandhi, KS, McKay, FC, Danoy, P, Stewart, GJ, Broadley, SA, Moscato, P, Lechner-Scott, J, Scott, RJ, Booth, DR, Griffiths, L, Slee, M, Browning, S, Cox, M, Browning, BL, Kilpatrick, T, Rubio, J, Perreau, V, Butzkeuven, H, Tanner, M, Wiley, J, Foote, S, Taylor, B, Kermode, A, Riveros, C, Carroll, B, Bahlo, M, Armstrong, N, Heard, RN, Vucic, S, Williams, DW, Stankovich, J & Brown, M 2010, 'The Multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis', Human molecular genetics, vol. 19, no. 11, pp. 2134-2143. https://doi.org/10.1093/hmg/ddq090

The Multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis. / Gandhi, Kaushal S.; McKay, Fiona C.; Danoy, Patrick; Stewart, Graeme J.; Broadley, Simon A.; Moscato, Pablo; Lechner-Scott, Jeanette; Scott, Rodney J.; Booth, David R.; Griffiths, Lyn; Slee, Mark; Browning, Sharon; Cox, Matthew; Browning, Brian L.; Kilpatrick, Trevor; Rubio, Justin; Perreau, Victoria; Butzkeuven, Helmut; Tanner, Mary; Wiley, Jim; Foote, Simon; Taylor, Bruce; Kermode, Allan; Riveros, Carlos; Carroll, Bill; Bahlo, Melanie; Armstrong, Nicola; Heard, Robert N.; Vucic, Steve; Williams, David W.; Stankovich, Jim; Brown, Matthew.

In: Human molecular genetics, Vol. 19, No. 11, 2010, p. 2134-2143.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The Multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis

AU - Gandhi, Kaushal S.

AU - McKay, Fiona C.

AU - Danoy, Patrick

AU - Stewart, Graeme J.

AU - Broadley, Simon A.

AU - Moscato, Pablo

AU - Lechner-Scott, Jeanette

AU - Scott, Rodney J.

AU - Booth, David R.

AU - Griffiths, Lyn

AU - Slee, Mark

AU - Browning, Sharon

AU - Cox, Matthew

AU - Browning, Brian L.

AU - Kilpatrick, Trevor

AU - Rubio, Justin

AU - Perreau, Victoria

AU - Butzkeuven, Helmut

AU - Tanner, Mary

AU - Wiley, Jim

AU - Foote, Simon

AU - Taylor, Bruce

AU - Kermode, Allan

AU - Riveros, Carlos

AU - Carroll, Bill

AU - Bahlo, Melanie

AU - Armstrong, Nicola

AU - Heard, Robert N.

AU - Vucic, Steve

AU - Williams, David W.

AU - Stankovich, Jim

AU - Brown, Matthew

PY - 2010

Y1 - 2010

N2 - Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P <10−12) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P <0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P <10⁻¹⁴). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.

AB - Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P <10−12) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P <0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P <10⁻¹⁴). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.

U2 - 10.1093/hmg/ddq090

DO - 10.1093/hmg/ddq090

M3 - Article

VL - 19

SP - 2134

EP - 2143

JO - Human molecular genetics

T2 - Human molecular genetics

JF - Human molecular genetics

SN - 0964-6906

IS - 11

ER -