Genetic analysis of the 2q33 region containing CD28-CTLA4-ICOS genes: association with non-Hodgkin's lymphoma.
There is strong evidence that altered immunological function entails an increased risk of lymphoma, although the current knowledge of aetiological factors for lymphomas is limited. The CTLA4 gene encodes a receptor that provides a negative signal to the T-cell once an immune response is initiated and completed. We analysed the 2q33 chromosomal region harbouring CD28, CTLA4 and ICOS genes, which are closely linked and have related functions in immune regulation, for association in 100 non-Hodgkin's lymphoma (NHL) patients and in 128 healthy controls; both groups originated from Sardinia. There was a strong association of the CTLA4 49A and the 3'-untranslated region (AT)(82) alleles with NHL [odds ratio (OR) = 2, 95% confidence interval (CI) = 1.2-3.2, and OR = 1.6, 95% CI = 1.1-2.4 respectively]. CTLA4-318C:49A:(AT)(82) was the most represented haplotype in the studied population and was associated with NHL (P = 0.0029, OR = 1.76, 95% CI = 1.2-2.5). Strong linkage disequilibrium was detected between CD28, CTLA4 and ICOS and a 'common' haplotype was found very frequently among NHLs. However, no independent association between CD28, ICOS, D2S72 markers and NHL was observed. Our findings enable CTLA4 from adjacent functionally related genes as the true causative risk gene for NHL susceptibility at least in Sardinian patients.
Piras
G
G
Haematology Division and Bone Marrow Transplantation Unit, San Francesco Hospital, Nuoro, Italy. labematologia.nuoro@tiscali.it
Monne
M
M
Uras
A
A
Palmas
A
A
Murineddu
M
M
Arru
L
L
Bianchi
A
A
Calvisi
A
A
Curreli
L
L
Gaviano
E
E
Lai
P
P
Murgia
A
A
Latte
G C
GC
Noli
A
A
Gabbas
A
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D015810:Linkage Disequilibrium; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000276:immunology; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein