Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.
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.
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge, CB2 2XY, UK.
Hironori
H
Ueda
Joanna M M
JM
Howson
Laura
L
Esposito
Joanne
J
Heward
Hywel
H
Snook
Giselle
G
Chamberlain
Daniel B
DB
Rainbow
Kara M D
KM
Hunter
Annabel N
AN
Smith
Gianfranco
G
Di Genova
Mathias H
MH
Herr
Ingrid
I
Dahlman
Felicity
F
Payne
Deborah
D
Smyth
Christopher
C
Lowe
Rebecca C J
RC
Twells
Sarah
S
Howlett
Barry
B
Healy
Sarah
S
Nutland
Helen E
HE
Rance
Vin
V
Everett
Luc J
LJ
Smink
Alex C
AC
Lam
Heather J
HJ
Cordell
Neil M
NM
Walker
Cristina
C
Bordin
John
J
Hulme
Costantino
C
Motzo
Francesco
F
Cucca
J Fred
JF
Hess
Michael L
ML
Metzker
Jane
J
Rogers
Simon
S
Gregory
Amit
A
Allahabadia
Ratnasingam
R
Nithiyananthan
Eva
E
Tuomilehto-Wolf
Jaakko
J
Tuomilehto
Polly
P
Bingley
Kathleen M
KM
Gillespie
Dag E
DE
Undlien
Kjersti S
KS
Rønningen
Cristian
C
Guja
Constantin
C
Ionescu-Tîrgovişte
David A
DA
Savage
A Peter
AP
Maxwell
Dennis J
DJ
Carson
Chris C
CC
Patterson
Jayne A
JA
Franklyn
David G
DG
Clayton
Laurence B
LB
Peterson
Linda S
LS
Wicker
John A
JA
Todd
Stephen C L
SC
Gough
D000069594:Abatacept; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D001483:Base Sequence; D060908:CTLA-4 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006111:Graves Disease / Q000235:genetics; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics; D018796:Immunoconjugates; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D020033:Protein Isoforms; D000069594:Abatacept