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.
Ueda
Hironori
H
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.
Howson
Joanna M M
JM
Esposito
Laura
L
Heward
Joanne
J
Snook
Hywel
H
Chamberlain
Giselle
G
Rainbow
Daniel B
DB
Hunter
Kara M D
KM
Smith
Annabel N
AN
Di Genova
Gianfranco
G
Herr
Mathias H
MH
Dahlman
Ingrid
I
Payne
Felicity
F
Smyth
Deborah
D
Lowe
Christopher
C
Twells
Rebecca C J
RC
Howlett
Sarah
S
Healy
Barry
B
Nutland
Sarah
S
Rance
Helen E
HE
Everett
Vin
V
Smink
Luc J
LJ
Lam
Alex C
AC
Cordell
Heather J
HJ
Walker
Neil M
NM
Bordin
Cristina
C
Hulme
John
J
Motzo
Costantino
C
Cucca
Francesco
F
Hess
J Fred
JF
Metzker
Michael L
ML
Rogers
Jane
J
Gregory
Simon
S
Allahabadia
Amit
A
Nithiyananthan
Ratnasingam
R
Tuomilehto-Wolf
Eva
E
Tuomilehto
Jaakko
J
Bingley
Polly
P
Gillespie
Kathleen M
KM
Undlien
Dag E
DE
Rønningen
Kjersti S
KS
Guja
Cristian
C
Ionescu-Tîrgovişte
Constantin
C
Savage
David A
DA
Maxwell
A Peter
AP
Carson
Dennis J
DJ
Patterson
Chris C
CC
Franklyn
Jayne A
JA
Clayton
David G
DG
Peterson
Laurence B
LB
Wicker
Linda S
LS
Todd
John A
JA
Gough
Stephen C L
SC
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