Cytotoxic T lymphocyte antigen-4 Ala17 polymorphism is a genetic marker of autoimmune adrenal insufficiency: Italian association study and meta-analysis of European studies.
OBJECTIVE
Cytotoxic T lymphocyte antigen-4 (CTLA4) gene polymorphism has been associated with human autoimmune diseases, but discordant data are available on its association with autoimmune Addison's disease (AAD). We tested the human leukocyte antigen (HLA)-independent association of CTLA4+49 (A/G) (Ala 17) and/or CTLA4 CT60 (A/G) polymorphism with AAD.


METHODS
DNA samples from 180 AAD patients and 394 healthy control subjects from continental Italy were analyzed, and association statistical analyses and meta-analysis of published studies were performed. Methods TaqMan minor groove binder chemistry assays and PCR fragment length polymorphism assays were used.


RESULTS
Frequency of allele G of CTLA4+49 was significantly increased among AAD patients (40% alleles) than among healthy controls (27% alleles; P<0.0001). CTLA4 CT60 polymorphism was associated with AAD only in the heterozygous A/G individuals. The frequency of +49 AG+GG genotypes was significantly higher among AAD patients than among healthy control subjects, in both a co-dominant (P<0.0001) and G dominant model (P<0.0001). CTLA4+49 allele G was significantly associated with disease risk in both patients with isolated AAD and in patients with autoimmune polyendocrine syndrome. Multivariate logistic regression analysis showed that CTLA4+49 allele G was positively associated with AAD (P<0.0001, odds ratio (OR)=2.43, 95% confidence interval=1.54-3.86) also after correction for DRB1*03-DQA1*0501-DQB1*0201, DRB1*04-DQA1*0301-DQB1*0302, and sex. Meta-analysis of five studies revealed a significant association of CTLA4+49 allele G with AAD (P<0.0001) with an overall OR of 1.48 (1.28-1.71).


CONCLUSIONS
The CTLA4+49 polymorphism is strongly associated with genetic risk for AAD, independently from the well-known association with HLA class II genes.
Brozzetti
Annalisa
A
Section of Internal Medicine and Endocrine and Metabolic Sciences, Department of Internal Medicine, University of Perugia, Via Enrico Dal Pozzo, 06126 Perugia, Italy.
Marzotti
Stefania
S
Tortoioli
Cristina
C
Bini
Vittorio
V
Giordano
Roberta
R
Dotta
Francesco
F
Betterle
Corrado
C
De Bellis
Annamaria
A
Arnaldi
Giorgio
G
Toscano
Vincenzo
V
Arvat
Emanuela
E
Bellastella
Antonio
A
Mantero
Franco
F
Falorni
Alberto
A
D000224:Addison Disease / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D000409:Alanine / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D060908:CTLA-4 Antigen; D005819:Genetic Markers; D006801:Humans; D007558:Italy / Q000453:epidemiology; D011110:Polymorphism, Genetic; D012307:Risk Factors
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D005819:Genetic Markers; D000409:Alanine