title: CT60 single nucleotide polymorphisms of the cytotoxic T-lymphocyte-associated antigen-4 gene region is associated with Graves' disease in an Italian population.
abstract: Graves' disease (GD) is an autoimmune and polygenic disorder. Several studies have shown that human leukocyte antigen (HLA) class II and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene are involved in the genetic susceptibility. We performed a case control study on 150 patients with GD and 301 controls, matched for age and gender, to verify the association of three polymorphisms located in CTLA-4 region (A49G, [AT](n)-3'UTR, and CT60) and of HLA-DRB1 and DQB1 loci with the disease in an Italian population. The prevalence of patients with GD carrying the G allele of CT60 was significantly higher compared to control subjects (p = 0.02, odds ratio [OR] = 1.82). The allelic frequency of the G allele of CT60 was also significantly higher in patients with GD (p = 0.02). The G allele frequency of A49G in patients was significantly higher compared to control subjects (p = 0.04). The 280 allele phenotype frequency of (AT)(n)-3'UTR was also significantly higher in patients (p = 0.04). The G allele of A49G, the G allele of CT60, and the 280 allele of (AT)(n)-3'UTR microsatellite were significantly increased in patients with GD with thyroid-associated ophthalmopathy (TAO) compared to controls (p = 0.04, p = 0.03, and p = 0.02, respectively), however, we did not find any significant difference between TAO and non-TAO patients. We also found the HLA-DRB1*03 allele to be associated with GD; interestingly, the association of the CTLA-4 markers was independent from the HLA DRB1*03 status. These results highlight the role of the CTLA-4 locus, in addition to HLA, in the susceptibility to GD. Inside the CTLA-4 region, CT60 appears to be the most associated polymorphism to GD, however, further studies are needed to identify the etiologic variant.
authors.affiliation: Department of Clinical Science, University of Rome La Sapienza, 00161 Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Petrone
authors.forename: Gabriele
authors.initials: G
authors.lastname: Giorgi
authors.forename: Andrea
authors.initials: A
authors.lastname: Galgani
authors.forename: Irene
authors.initials: I
authors.lastname: Alemanno
authors.forename: Salvatore M
authors.initials: SM
authors.lastname: Corsello
authors.forename: Alberto
authors.initials: A
authors.lastname: Signore
authors.forename: Umberto
authors.initials: U
authors.lastname: Di Mario
authors.forename: Lorenza
authors.initials: L
authors.lastname: Nisticò
authors.forename: Isabella
authors.initials: I
authors.lastname: Cascino
authors.forename: Raffaella
authors.initials: R
authors.lastname: Buzzetti
mesh_terms: D020121:5' Untranslated Regions; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D017931:DNA Primers; D005787:Gene Frequency; D006111:Graves Disease / Q000235:genetics* / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D007558:Italy; D018895:Microsatellite Repeats; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D044465:White People
chemical_list: D020121:5' Untranslated Regions; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D017931:DNA Primers; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains