Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease.
Susceptibility to coeliac disease involves HLA and non-HLA-linked genes. The CTLA4/CD28 gene region encodes immune regulatory T-cell surface molecules and is a strong candidate as a susceptibility locus. We evaluated CTLA4/CD28 in coeliac disease by genetic linkage and association and combined our findings with published studies through a meta-analysis. 116 multiplex families were genotyped across CTLA4/CD28 using eight markers. The contribution of CTLA4/CD28 to coeliac disease was assessed by non-parametric linkage and association analyses. Seven studies were identified that had evaluated the relationship between CTLA4/CD28 and coeliac disease and a pooled analysis of data undertaken. In our study there was evidence for a relationship between variation in the CTLA4/CD28 region and coeliac disease by linkage and association analyses. However, the findings did not attain formal statistical significance (p = 0.004 and 0.039, respectively). Pooling findings with published results showed significant evidence for linkage (504 families) and association (940 families): p values, 0.0001 and 0.0014 at D2S2214, respectively, and 0.0008 and 0.0006 at D2S116, respectively. These findings suggest that variation in the CD28/CTLA4 gene region is a determinant of coeliac disease susceptibility. Dissecting the sequence variation underlying this relationship will depend on further analyses utilising denser sets of markers.
Popat
S
S
Section of Cancer Genetics, Institute of Cancer Research, Surrey, UK. sanjay@icr.ac.uk
Hearle
N
N
Hogberg
L
L
Braegger
C P
CP
O'Donoghue
D
D
Falth-Magnusson
K
K
Holmes
G K T
GK
Howdle
P D
PD
Jenkins
H
H
Johnston
S
S
Kennedy
N P
NP
Kumar
P J
PJ
Logan
R F A
RF
Marsh
M N
MN
Mulder
C J
CJ
Torinsson Naluai
A
A
Sjoberg
K
K
Stenhammar
L
L
Walters
J R F
JR
Jewell
D P
DP
Houlston
R S
RS
D000069594:Abatacept; D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen; D002446:Celiac Disease / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D018796:Immunoconjugates; D007223:Infant; D008297:Male; D008875:Middle Aged; D012306:Risk; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D005819:Genetic Markers; D018796:Immunoconjugates; D000069594:Abatacept