Association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors with Graves' ophthalmopathy in European and Japanese populations.
OBJECTIVE
The development and severity of Graves' ophthalmopathy (GO) may result from a complex interplay of genetic and environmental factors. The aim of this study was to investigate the association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors (age, sex, cigarette smoking) with GO in two different populations, Polish-Caucasians and Japanese.


METHODS
We investigated the distribution of CTLA-4 A49G polymorphism in 264 Caucasian patients with Graves' disease (GD), of which 95 had clinically evident GO (NOSPECS class >or=3) and 319 Japanese patients with GD, of which 99 had ophthalmopathy. The control groups consisted of healthy Polish adults (n=194), Polish centenarians (n=51) and Japanese adults (n=112).


RESULTS
Allele G and G/G genotype were significantly increased in Caucasian patients with GD (48% and 25% respectively) and in Japanese patients with GD (69% and 47% respectively) compared with control groups. There were no significant differences in the G allele and G/G genotype frequencies in GO patients compared with GD patients without ophthalmopathy. Multiple logistic regression analysis demonstrated that cigarette smoking (P=0.03, odds ratio (OR)=1.7) and age of onset of GD over 42 Years (P=0.08; OR=1.6) were contributing factors associated with susceptibility to GO in Polish patients. In Japanese patients, a younger age of onset of GD had an effect on the development of GO (P=0.02, OR=1.8).


CONCLUSIONS
(i) Allele G and G/G genotype confer genetic susceptibility to GD; (ii) CTLA-4 A49G polymorphism is not associated with the development of GO; (iii) different non-genetic factors may contribute to GO in different populations.
Bednarczuk
Tomasz
T
Department of Endocrinology, Medical Research Center, Polish Academy of Science, Banacha 1A, 02-097 Warsaw, Poland. bednar@amwaw.edu.pl
Hiromatsu
Yuji
Y
Fukutani
Tomoka
T
Jazdzewski
Krystian
K
Miskiewicz
Piotr
P
Osikowska
Maria
M
Nauman
Janusz
J
D000069594:Abatacept; D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D044466:Asian People; D060908:CTLA-4 Antigen; D005060:Europe; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006111:Graves Disease / Q000208:ethnology* / Q000235:genetics*; D006801:Humans; D018796:Immunoconjugates; D007564:Japan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017678:Sex Distribution; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D044465:White People
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept