title: Cytotoxic T lymphocyte antigen-4 Ala17 polymorphism is a genetic marker of autoimmune adrenal insufficiency: Italian association study and meta-analysis of European studies.
abstract: 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.
authors.affiliation: Section of Internal Medicine and Endocrine and Metabolic Sciences, Department of Internal Medicine, University of Perugia, Via Enrico Dal Pozzo, 06126 Perugia, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Brozzetti
authors.forename: Stefania
authors.initials: S
authors.lastname: Marzotti
authors.forename: Cristina
authors.initials: C
authors.lastname: Tortoioli
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bini
authors.forename: Roberta
authors.initials: R
authors.lastname: Giordano
authors.forename: Francesco
authors.initials: F
authors.lastname: Dotta
authors.forename: Corrado
authors.initials: C
authors.lastname: Betterle
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Bellis
authors.forename: Giorgio
authors.initials: G
authors.lastname: Arnaldi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Toscano
authors.forename: Emanuela
authors.initials: E
authors.lastname: Arvat
authors.forename: Antonio
authors.initials: A
authors.lastname: Bellastella
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
authors.forename: Alberto
authors.initials: A
authors.lastname: Falorni
mesh_terms: 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
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D005819:Genetic Markers; D000409:Alanine