Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

H Ueda; Joanne King; JMM Howson; L Esposito; H Snook; G Chamberlain; DB Rainbow; KMD Hunter; A Smith; G Di Genova; MH Herr; I Dahlman; F Payne; D Smyth; D Lowe; RC Twells; S Howlett; B Healy; S Nutland; HE Rance; V Everett; LJ Smink; Alison Lam; HJ Cordell; NM Walker; C Bordin; Jonathan Hulme; C Motzo; F Cucca; JF Hess; ML Metzker; J Rogers; S Gregory; Amit Allahabadia; Ratnasingam Nithiyananthan; E Tuomilehto-Wolf; J Tuomilehto; P Bingley; KM Gillespie; DE Undlien; KS Ronningen; C Guja; C Ionescu-Tirgoviste; DA Savage; AP Maxwell; DJ Carson; CC Patterson; Jayne Franklyn; DG Clayton; LB Peterson; LS Wicker; JA Todd; Stephen Gough

doi:10.1038/nature01621

Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

H Ueda, Joanne King, JMM Howson, L Esposito, H Snook, G Chamberlain, DB Rainbow, KMD Hunter, A Smith, G Di Genova, MH Herr, I Dahlman, F Payne, D Smyth, D Lowe, RC Twells, S Howlett, B Healy, S Nutland, HE RanceV Everett, LJ Smink, Alison Lam, HJ Cordell, NM Walker, C Bordin, Jonathan Hulme, C Motzo, F Cucca, JF Hess, ML Metzker, J Rogers, S Gregory, Amit Allahabadia, Ratnasingam Nithiyananthan, E Tuomilehto-Wolf, J Tuomilehto, P Bingley, KM Gillespie, DE Undlien, KS Ronningen, C Guja, C Ionescu-Tirgoviste, DA Savage, AP Maxwell, DJ Carson, CC Patterson, Jayne Franklyn, DG Clayton, LB Peterson, LS Wicker, JA Todd, Stephen Gough

Birmingham Medical School

Research output: Contribution to journal › Article

1738 Citations (Scopus)

Abstract

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

Original language	English
Pages (from-to)	506-511
Number of pages	6
Journal	Nature
Volume	423
Issue number	6939
Early online date	30 Apr 2003
DOIs	https://doi.org/10.1038/nature01621
Publication status	Published - 29 May 2003

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Ueda, H., King, J., Howson, JMM., Esposito, L., Snook, H., Chamberlain, G., Rainbow, DB., Hunter, KMD., Smith, A., Di Genova, G., Herr, MH., Dahlman, I., Payne, F., Smyth, D., Lowe, D., Twells, RC., Howlett, S., Healy, B., Nutland, S., ... Gough, S. (2003). Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature, 423(6939), 506-511. https://doi.org/10.1038/nature01621

@article{1a4b198e25d34b82a41e07d4d6205607,

title = "Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease",

abstract = "Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.",

author = "H Ueda and Joanne King and JMM Howson and L Esposito and H Snook and G Chamberlain and DB Rainbow and KMD Hunter and A Smith and {Di Genova}, G and MH Herr and I Dahlman and F Payne and D Smyth and D Lowe and RC Twells and S Howlett and B Healy and S Nutland and HE Rance and V Everett and LJ Smink and Alison Lam and HJ Cordell and NM Walker and C Bordin and Jonathan Hulme and C Motzo and F Cucca and JF Hess and ML Metzker and J Rogers and S Gregory and Amit Allahabadia and Ratnasingam Nithiyananthan and E Tuomilehto-Wolf and J Tuomilehto and P Bingley and KM Gillespie and DE Undlien and KS Ronningen and C Guja and C Ionescu-Tirgoviste and DA Savage and AP Maxwell and DJ Carson and CC Patterson and Jayne Franklyn and DG Clayton and LB Peterson and LS Wicker and JA Todd and Stephen Gough",

year = "2003",

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doi = "10.1038/nature01621",

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Ueda, H, King, J, Howson, JMM, Esposito, L, Snook, H, Chamberlain, G, Rainbow, DB, Hunter, KMD, Smith, A, Di Genova, G, Herr, MH, Dahlman, I, Payne, F, Smyth, D, Lowe, D, Twells, RC, Howlett, S, Healy, B, Nutland, S, Rance, HE, Everett, V, Smink, LJ, Lam, A, Cordell, HJ, Walker, NM, Bordin, C, Hulme, J, Motzo, C, Cucca, F, Hess, JF, Metzker, ML, Rogers, J, Gregory, S, Allahabadia, A, Nithiyananthan, R, Tuomilehto-Wolf, E, Tuomilehto, J, Bingley, P, Gillespie, KM, Undlien, DE, Ronningen, KS, Guja, C, Ionescu-Tirgoviste, C, Savage, DA, Maxwell, AP, Carson, DJ, Patterson, CC, Franklyn, J, Clayton, DG, Peterson, LB, Wicker, LS, Todd, JA & Gough, S 2003, 'Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease', Nature, vol. 423, no. 6939, pp. 506-511. https://doi.org/10.1038/nature01621

TY - JOUR

T1 - Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

AU - Ueda, H

AU - King, Joanne

AU - Howson, JMM

AU - Esposito, L

AU - Snook, H

AU - Chamberlain, G

AU - Rainbow, DB

AU - Hunter, KMD

AU - Smith, A

AU - Di Genova, G

AU - Herr, MH

AU - Dahlman, I

AU - Payne, F

AU - Smyth, D

AU - Lowe, D

AU - Twells, RC

AU - Howlett, S

AU - Healy, B

AU - Nutland, S

AU - Rance, HE

AU - Everett, V

AU - Smink, LJ

AU - Lam, Alison

AU - Cordell, HJ

AU - Walker, NM

AU - Bordin, C

AU - Hulme, Jonathan

AU - Motzo, C

AU - Cucca, F

AU - Hess, JF

AU - Metzker, ML

AU - Rogers, J

AU - Gregory, S

AU - Allahabadia, Amit

AU - Nithiyananthan, Ratnasingam

AU - Tuomilehto-Wolf, E

AU - Tuomilehto, J

AU - Bingley, P

AU - Gillespie, KM

AU - Undlien, DE

AU - Ronningen, KS

AU - Guja, C

AU - Ionescu-Tirgoviste, C

AU - Savage, DA

AU - Maxwell, AP

AU - Carson, DJ

AU - Patterson, CC

AU - Franklyn, Jayne

AU - Clayton, DG

AU - Peterson, LB

AU - Wicker, LS

AU - Todd, JA

AU - Gough, Stephen

PY - 2003/5/29

Y1 - 2003/5/29

N2 - Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

AB - Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

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U2 - 10.1038/nature01621

DO - 10.1038/nature01621

M3 - Article

C2 - 12724780

VL - 423

SP - 506

EP - 511

JO - Nature

JF - Nature

IS - 6939

ER -

Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Abstract

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