The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.
Case-control studies suggest that the CTLA-4 gene may be a susceptibility locus for Graves' disease. The previously reported A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene was, therefore, investigated in a case-control (n = 743) and family-based (n = 179) dataset of white Caucasian subjects with Graves' disease. The relationship between CTLA-4 genotype and severity of thyroid dysfunction at diagnosis was also investigated. An increase in frequency of the G (alanine) allele was seen in Graves' patients compared with control subjects (42% vs. 31.5%, respectively; corrected P<0.0002; odds ratio = 1.58), and a significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (chi2 = 21.7; corrected P<0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (chi2 = 5.7; P = 0.025). Circulating free T4 concentrations at diagnosis were significantly associated with CTLA-4 genotype (F = 3.26; P = 0.04). These results support the hypothesis that CTLA-4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves' disease.
Queen Elizabeth Hospitals, Birmingham, United Kingdom.
J M
JM
Heward
A
A
Allahabadia
M
M
Armitage
A
A
Hattersley
P M
PM
Dodson
K
K
Macleod
J
J
Carr-Smith
J
J
Daykin
A
A
Daly
M C
MC
Sheppard
R L
RL
Holder
A H
AH
Barnett
J A
JA
Franklyn
S C
SC
Gough
D000069594:Abatacept; D000409:Alanine / Q000235:genetics; D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D002889:Chromosomes, Human, Pair 2; D005091:Exons; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D018796:Immunoconjugates; D011110:Polymorphism, Genetic; D013974:Thyroxine / Q000097:blood
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept; D000409:Alanine; D013974:Thyroxine