FTO Gene Polymorphism Is Associated with Type 2 Diabetes through Its Effect on Increasing the Maximum BMI in Japanese Men.
OBJECTIVE
Several studies have demonstrated that polymorphisms within the fat-mass and obesity-associated gene (FTO) are associated with type 2 diabetes (T2D). However, whether the effects of the FTO locus on T2D susceptibility are independent of fat-mass increases remains controversial. To investigate this issue, we examined the association of FTO variants with T2D and various aspects of BMI history during adult life in a Japanese population.


METHODS
We genotyped SNPs within FTO (rs1121980 and rs1558902) in 760 Japanese patients with T2D who had reached a lifetime maximum BMI (BMImax) before or at the time of diagnosis and 693 control individuals with information regarding their BMImax.


RESULTS
The BMImax showed the strongest association with T2D risk among the BMIs evaluated in this study. In the sex-combined analysis, FTO SNPs were not associated with any of the BMI variables or with T2D, but in sex-stratified analyses, both SNPs were significantly associated with the BMImax and rs1558902 was associated with T2D in men. The association of the SNPs with T2D remained significant after adjustments for the current BMI and age, whereas the T2D association of the SNP was no longer significant after adjustments for BMImax and age.


CONCLUSIONS
These results suggest that the effects of FTO polymorphisms on T2D susceptibility in Japanese men are mediated through their effect on increasing the BMImax before or at the time of diagnosis.
First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
Yutaka
Y
Kamura
First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.|Health Administration Center, University of Toyama, Toyama, Japan.
Minoru
M
Iwata
Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan.|Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.|Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Okinawa, Japan.
Shiro
S
Maeda
First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
Satomi
S
Shinmura
First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
Yukiko
Y
Koshimizu
First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
Hisae
H
Honoki
First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
Kazuhito
K
Fukuda
First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
Manabu
M
Ishiki
First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
Isao
I
Usui
Department of Internal Medicine, Asahi General Hospital, Asahi-machi, Toyama, Japan.
Yasuo
Y
Fukushima
Division of Endocrinology and Metabolism, Department of Internal Medicine, Saiseikai Takaoka Hospital, Takaoka, Toyama, Japan.
Atsuko
A
Takano
Division of Endocrinology and Metabolism, Department of Internal Medicine, Japan Community Health care Organization Takaoka Fushiki Hospital, Takaoka, Toyama, Japan.
Hiromi
H
Kato
Division of Endocrinology and Metabolism, Department of Internal Medicine, Toyama Rosai Hospital, Uozu, Toyama, Japan.
Shihou
S
Murakami
Department of Internal Medicine, Kouseiren Itoigawa General Hospital, Itoigawa, Niigata, Japan.
Kiyohiro
K
Higuchi
Department of Internal Medicine, Kamiichi General Hospital, Kamiichi-machi, Toyama, Japan.
Chikaaki
C
Kobashi
First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
Kazuyuki
K
Tobe
D000368:Aged; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human