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Department of Medicine, University of Birmingham at Birmingham Heartlands (A.H.B., S.C.L.G., P.M.D.) and Queen Elizabeth Hospitals (J.M.H., A.A., J.C.-S., J.D., A.D., M.C.S., A.H.B., J.A.F., S.C.L.G.); the Department of Statistics, University of Birmingham (R.L.H.), Birmingham, United Kingdom B9 5SS; Royal Bournemouth Hospital (M.A.), Bournemouth, United Kingdom; and Royal Devon and Exeter Hospitals (A.H., K.M.), Exeter, United Kingdom
Address all correspondence and requests for reprints to: Dr. S. C. L. Gough, Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, United Kingdom B9 5SS. E-mail: s.c.gough{at}bham.ac.uk
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 (
2 = 21.7;
corrected P < 0.00003). Increased transmission of
the G allele was seen from heterozygous parents to affected offspring
compared to unaffected offspring (2 = 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.
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