The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease: a multicenter collaborative study in Japan.
BACKGROUND
Transracial studies are a powerful tool for genetic association studies of multifactorial diseases, such as type 1 diabetes. The low incidence of type 1 diabetes in Asian countries, however, makes it difficult to perform large-scale studies in Asia.


OBJECTIVE
To overcome this, we have assembled a multicenter study group in Japan and studied the association of CTLA4 polymorphisms with type 1 diabetes relative to autoimmune thyroid disease (AITD) phenotypes.


METHODS
Subjects included a total of 1837 samples, including 1114 cases (769 with type 1 diabetes and 345 with AITD) and 723 control subjects.


METHODS
The +6230G>A and +49G>A polymorphisms of CTLA4 as well as HLA-DRB1 and -DQB1 were genotyped.


RESULTS
The +6230G>A polymorphism was significantly associated with type 1 diabetes complicated with AITD (odds ratio, 1.54; P = 0.027) and with AITD alone (odds ratio, 1.31; P = 0.045) but not with type 1 diabetes without AITD. The association with type 1 diabetes positive for autoantibodies to both pancreatic islets and thyroid was particularly strong (odds ratio, 1.87; P = 0.001). Type 1 diabetic patients with the disease-associated GG genotype were characterized by a significantly higher frequency of AITD (P = 0.013), of positivity for both AITD and antiislet autoantibody (P = 0.00086), and of high-risk HLA genotypes (P = 0.034).


CONCLUSIONS
Given the high frequency of AITD in patients with type 1 diabetes, these data suggest the possibility that the association of CTLA4 with type 1 diabetes in previous studies may have been secondary to AITD, suggesting the importance of subclassification of type 1 diabetes relative to AITD in genetic studies.
Ikegami
Hiroshi
H
Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka 565-0871, Japan. ikegami@geriat.med.osaka-u.ac.jp
Awata
Takuya
T
Kawasaki
Eiji
E
Kobayashi
Tetsuro
T
Maruyama
Taro
T
Nakanishi
Koji
K
Shimada
Akira
A
Amemiya
Shin
S
Kawabata
Yumiko
Y
Kurihara
Susumu
S
Tanaka
Shoichiro
S
Kanazawa
Yasuhiko
Y
Mochizuki
Mie
M
Ogihara
Toshio
T
D000328:Adult; D017668:Age of Onset; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D044466:Asian People; D060908:CTLA-4 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000145:classification / Q000150:complications* / Q000235:genetics* / Q000276:immunology; D005260:Female; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D007564:Japan; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013967:Thyroiditis, Autoimmune / Q000145:classification / Q000150:complications* / Q000235:genetics* / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains