Genetic susceptibility to Graves' ophthalmopathy: the role of polymorphisms in proinflammatory cytokine genes.
OBJECTIVE
In order to investigate the underlying genetic mechanisms of Graves' ophthalmopathy (GO), we examined the association between single-nucleotide polymorphisms in five important proinflammatory cytokines, namely IL-12, TNF-alpha, IFN-gamma, IL-2, and IL-6, with GO in a sample of Iranian adults.


METHODS
A total of 57 patients with Graves' disease without GO, 50 patients with GO, and 140 healthy controls were enrolled. Patients were recruited consecutively from the outpatient endocrine clinic of a large university general hospital. Genotype and allele frequencies of the following proinflammatory cytokines were compared between the groups: IL-12 (-1188A/C), TNF-alpha (-308A/G, -238A/G), INF-gamma (UTR 5644A/T), IL-2 (-330T/G, 166G/T), and IL-6 (-174C/G, nt565A/G). A corrected (for multiple testing) P-value (Pc) less than 0.05 was considered statistically significant.


RESULTS
The IL-12 -1188C allele (odds ratio (OR)=2.65, Pc<0.01) and CC genotype (OR=7.58, Pc<0.01) were significantly more common in patients with GO than in patients without GO. The TNF-alpha-238A allele was more frequent in patients with GO than in patients without GO (OR=2.99, Pc<0.05). The frequency of the IFN-gamma UTR 5644T allele (OR=2.67, Pc<0.05), AT genotype (OR=13.33, Pc<0.05), and TT genotype (OR=18.46, Pc<0.01) was significantly higher among patients with GO than patients without GO. No significant association was found for other polymorphisms.


CONCLUSIONS
We demonstrated that specific polymorphisms in IL-12, IFN- gamma, and TNF-alpha genes are associated with susceptibility to GO in the Iranian population. Our results open a new perspective to genetic correlates of GO.
Anvari
M
M
Molecular Immunology and Immunogenetics Research Center, Tehran University of Medical Sciences, and Endocrinology and Metabolism Research Center, Vali-Asr Hospital, Tehran, Iran.
Khalilzadeh
O
O
Esteghamati
A
A
Esfahani
S A
SA
Rashidi
A
A
Etemadi
A
A
Mahmoudi
M
M
Amirzargar
A A
AA
D000328:Adult; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics*; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D049970:Graves Ophthalmopathy / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007492:Iran; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016207:Cytokines; D007376:Interleukin-2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma