Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease.
The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G single-nucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P=0.01, OR=1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.
Ban
Y
Y
Division of Endocrinology, Diabetes, and Bone Diseases, Mount Sinai School of Medicine Box 1055, New York, NY 10029, USA. Yoshiyuki_Ban@mssm.edu
Davies
T F
TF
Greenberg
D A
DA
Kissin
A
A
Marder
B
B
Murphy
B
B
Concepcion
E S
ES
Villanueva
R B
RB
Barbesino
G
G
Ling
V
V
Tomer
Y
Y
D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D016013:Likelihood Functions; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000235:genetics* / Q000276:immunology; D044465:White People
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