Associations between autoimmune thyroid disease prognosis and functional polymorphisms of susceptibility genes, CTLA4, PTPN22, CD40, FCRL3, and ZFAT, previously revealed in genome-wide association studies.
OBJECTIVE
Genome-wide association studies have revealed several susceptibility genes among patients with autoimmune thyroid disease (AITD), including CTLA4, PTPN22, FCRL3, and ZFAT. However, any possible association between these genes and AITD prognosis remains unknown. The objective of this study was to identify associations between polymorphisms of these genes and AITD prognosis.


METHODS
We genotyped functional polymorphisms, including CTLA4 CT60, CTLA4 +49A/G, CTLA4 -1147C/T, CTLA4 -318C/T, PTPN22 -1123C/G, PTPN22 SNP37, CD40 -1C/T, FCRL3 -169C/T, ZFAT Ex9b-SNP10, and ZFAT Ex9b-SNP2, in 197 AITD patients carefully selected from 456 registered AITD patients, and 86 control subjects. The restriction fragment length polymorphism method was used for genotyping.


RESULTS
The CD40 -1CC genotype and C allele were significantly more frequent in patients with Graves' disease (GD) in remission than in those with intractable GD (P = 0.041 and P = 0.031, respectively). The FCRL3 -169TT genotype was significantly less frequent in patients with intractable GD than in those with GD in remission (P = 0.0324). For a ZFAT Ex9b-SNP10 polymorphism, the TT genotype and T allele were significantly more frequent in patients with severe Hashimoto's disease (HD) than in those with mild HD (P = 0.0029 and P = 0.0049, respectively). For a CTLA4 CT60 polymorphism, the antithyrotropin receptor antibody levels at the onset of GD were significantly higher in those with the GG genotype than in those with other genotypes (P = 0.0117).


CONCLUSIONS
CD40 and FCRL3 gene polymorphisms were associated with GD intractability, and ZFAT polymorphism was associated with HD severity but not its development.
Department of Biomedical Informatics, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka, Japan.
Naoya
N
Inoue
Mikio
M
Watanabe
Hiroya
H
Yamada
Kazuya
K
Takemura
Fumiaki
F
Hayashi
Noriko
N
Yamakawa
Maiko
M
Akahane
Yu
Y
Shimizuishi
Yoh
Y
Hidaka
Yoshinori
Y
Iwatani
D000328:Adult; D000483:Alleles; D019013:CD40 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006111:Graves Disease / Q000175:diagnosis / Q000235:genetics*; D050031:Hashimoto Disease / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D011379:Prognosis; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D012720:Severity of Illness Index; D014157:Transcription Factors / Q000235:genetics*
D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C457775:FCRL3 protein, human; D011971:Receptors, Immunologic; D014157:Transcription Factors; C529572:ZFAT protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22