A polymorphism of the 5' flanking region of tumour necrosis factor alpha gene is associated with thyroid-associated ophthalmopathy in Japanese.
OBJECTIVE
We have studied the polymorphism of the 5' flanking region of the tumour necrosis factor (TNF)-alpha gene in order to better understand the genetic background of autoimmune thyroid disorders and thyroid-associated ophthalmopathy.


METHODS
We studied the polymorphism of the 5' flanking region of the TNF-alpha gene at positions - 1031 (T to C change, termed as - 1031C), - 863 (C to A, - 863 A), - 857 (C to T, - 857T), - 308 (G to A, - 308 A) and - 238 (G to A, - 238 A) in Japanese patients with Graves' disease [n = 173, 62 of whom had associated ophthalmopathy (American Thyroid Association (ATA) class III or greater)] and healthy control subjects (n = 575), using a polymerase chain reaction sequence-specific oligonucleotide probe method.


RESULTS
The allele frequency of - 857T in the Graves' disease patients (22. 5% vs. 17.7%, OR = 1.35, P = 0.045, corrected P = 0.23) was slightly greater than in the Japanese healthy subjects, respectively. However, the difference was not statistically significant. In Graves' disease patients with evident ophthalmopathy (ATA class III or greater), the allele frequencies of - 1031C and - 863 A were significantly greater than those with no or mild ophthalmopathy (ATA class 0-II) (31.5% vs. 13.5%, OR =2.94, P < 0.0001, corrected P < 0. 0005; 23.4% vs. 11.7%, OR =2.30, P = 0.0044, corrected P = 0.022, respectively) and in control subjects. The strength of the association of the polymorphism - 1031C increased with the severity of ophthalmopathy, with odds ratios of 2.36 for ATA class III, and 5. 43 for ATA class IV-VI, respectively, compared with Graves' disease with no or mild ophthalmopathy (ATA class 0-II). Although the phenotype frequency of DRB1*0901 was not different among Graves' disease patients with or without ophthalmopathy and control subjects, the phenotype frequency of DRB1*0901(-)/-1031C(+) was significantly increased in Graves' disease patients with ophthalmopathy compared to those with no or mild ophthalmopathy (OR = 4.91, P = 0.0005) or control subjects (OR = 4.59, P < 0.0001).


CONCLUSIONS
These results suggest that the - 1031C or - 863 A alleles, or a gene in linkage disequilibrium with the TNF-alpha gene, predispose to the development of ophthalmopathy in Japanese patients with Graves' disease.
Kamizono
S
S
Department of Immunology, Kurume University School of Medicine, Japan.
Hiromatsu
Y
Y
Seki
N
N
Bednarczuk
T
T
Matsumoto
H
H
Kimura
A
A
Itoh
K
K
D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006111:Graves Disease / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D020121:5' Untranslated Regions; D014409:Tumor Necrosis Factor-alpha