Yonago Acta medica 2012;55:29–40

Association of Gene Polymorphism of the Fat Mass andObesity Associated Gene with Metabolic Syndrome:
A Retrospective Cohort Study in Japanese Workers
Tomoka Kawajiri, Yoneatsu Osaki and Takuji Kishimoto
Division of Environmental and Preventive Medicine, Department of Social Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan

To investigate whether gene polymorphism of the fat mass and obesity associated gene
(FTO) is associated with metabolic syndrome (MS), we used two MS criteria, the National
Cholesterol Education Program-Adult Treatment panel III (NCEP-ATPIII) definition in2003 and the Japanese definition in 2005. Subjects were respectively 859 and 865 Japanese
workers at a company in Shimane Prefecture, Japan. They were non-MS individuals in1998 and had regular health checkups between 1998 and 2006. The Cox proportional hazard regression was used to predict MS. Three SNPs in the FTO, rs9939609, rs1121980 andrs1558902, were genotyped by the TaqMan PCR assay and a retrospective study was performed. The three SNPs in the FTO were significantly associated with body mass index,
and rs1121980 and rs1558902 were associated with fasting plasma glucose. MS definedby the NCEP-ATPIII definition was significantly associated with additive and dominantmodels of rs9939609 and rs1121980, and the dominant model of rs1558902, even after adjusting for confounding factors such as age, sex and lifestyle. MS defined by the Japanese
definition was significantly associated with the additive model of rs1121980 and additiveand dominant models of rs1558902 in multivariate analysis. These results suggested that
FTO gene polymorphisms, rs9939609, rs1121980 and rs1558902, were associated with anincreased risk of MS among Japanese workers.
Key words: cohort study; fat mass and obesity associated gene; Japanese worker; metabolic syndrome; single nucleotide polymorphism

namely lifestyles (Fappa et al., 2008), and genetic
factors are also related (Groop, 2000; Eckel et al.,2005).
Recently, part of a genome-wide association
study found that several single nucleotide polymorphisms (SNPs) of the fat mass and obesity associated gene (FTO) were strongly associated withobesity and T2DM (Hinney et al., 2007; Scuteri etal., 2007).

Metabolic syndrome (MS) is a cluster of risk factors
for developing cardiovascular disease such as type2 diabetes mellitus (T2DM), consisting of central
obesity, high blood pressure, abnormal glucose
tolerance and abnormal lipid profiles (Eckel et al.,2005; Grundy et al., 2005). The prevalence of MS
has become increasingly common not only in Japan,
but also in the world. It is because environmental fac-

tors contribute to the increased prevalence of MS,

Abbreviations: BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose; FTO, fat mass and obesity associated gene; HDL, high density lipoprotein; MS, metabolic syndrome; NCEP-ATPIII, National Cholesterol Education ProgramAdult Treatment panel III; SNP, single nucleotide polymorphism; T2DM, type 2 diabetes mellitus

29

T. Kawajiri et al.

The human FTO is located on chromosome no.16(16q12.2), which consists of 9 exons with an entire
length of 410 kb (410,507 bp). The FTO encodes a2-oxoglutarate-dependent nucleic acid demethylase
and is widely expressed in many tissues, especiallyin the hypothalamus, which controls energy balance(Dina et al., 2007; Frayling et al., 2007). Studies inmice indicated that FTO mRNA levels were regulated by feeding and fasting (Gerken et al., 2007),and FTO knockout mice had postnatal growth
delays, increased energy consumption and skinny
body shapes (Fischer et al., 2009). Thus, the FTO
may play an important role in controlling energy
expenditure and may also be involved in energy
homeostasis, but the exact function of the FTO andthe mechanisms by which the FTO involves biological pathways remain unknown.
In previous genetic analyses, SNPs rs9939609,
rs1121980 and rs1558902, located in intron1 of the
FTO were strongly associated with obesity, BMI
and MS in Caucasians and Hispanic Americans(Dina et al., 2007; Frayling et al., 2007; Hinney
et al., 2007; Scuteri et al., 2007; Al-Attar et al.,2008; Andreasen et al., 2008; Sjögren et al., 2008;
González-Sánchez et al., 2009), but not in African
American, Oceanic or Chinese populations (Ohashi
et al., 2007; Scuteri et al., 2007; Li et al., 2008).
These reports suggest that the FTO is a race-specificgene. Studies in the Japanese failed to establish consistency in the association between FTO SNPs andobesity (Horikoshi et al., 2007; Omori et al., 2008;
Hotta et al., 2010; Karasawa et al., 2010; Shimaoka
et al., 2010). Concerning the Japanese, few reports
indicated the association of FTO SNPs with MS,
and some denied (Tabara et al., 2009; Shimaoka etal., 2010).
Therefore, in the present study, we analyzed
the relationship between FTO SNPs, rs9939609,
rs1121980 and rs1558902, and MS diagnosed by
the NCEP-ATPIII and Japanese definitions among
Japanese workers. To investigate the association ina more detailed manner than previous reports, a retrospective cohort study enrolling lifestyle factors as
considerable variables was performed.

Materials and Methods
Subjects
Subjects consisted of 859 persons (486 males and
373 females) and 865 persons (498 males and 367
females) under the NCEP-ATPIII and Japanese
definitions for MS, respectively. They were employees of an industry in the Izumo region of Shimane
Prefecture in Japan who had consistently undergone
health check-ups between 1998 and 2006 and were
non-MS individuals in 1998. The average age (±SD) was 37.69 ± 8.74 years for the subjects under
NCEP-ATPIII and 37.75 ± 8.72 years for those under the Japanese definition. A retrospective cohort
study of the relationship between FTO polymorphism and the prevalence of MS for the period between 1998 and 2006 was performed. All subjects
gave written informed consent to participate in the
study. The study protocol was approved by the Ethics Committee of Tottori University (permission
number, G63).
Subjects completed health check-ups consisting of measurements of the height, weight, bodymass index (BMI), blood pressure (BP) and history taking (drinking, smoking, eating, exercise
and sleeping habits). The BMI was calculated as
the weight in kilogram divided by the square of
the height in meter. Obesity was defined as a BMI≥ 25.0 kg/m2, as defined by the Japan Society ofObesity. Blood pressure was measured once on thehealth-check day in a sitting position with a standard sphygmomanometer. The first and fifth Korotkoff sounds were used to determine systolic BP
and diastolic BP, respectively. Blood tests included
high-density lipoprotein (HDL) cholesterol, triglycerides and fasting plasma glucose (FPG). Plasma
glucose levels were determined by the hexokinaseG-6-PDH method (Wako, Tokyo, Japan.) We investigated lifestyles, alcohol drinking habits (nodrinking, occasionally, nearly every day), cigarettesmoking habits (no smoking, quit, smoking), eating
habits (eat various food, consider balance slightly,
rarely consider balance), exercise habits (frequently,
30

Metabolic syndrome and FTO polymorphism

Table 1a. Clinical characteristics per genotype in rs9939609
TT
TA
AA
TT + TATA + AAAllPPP							value* value† value‡
NCEP-ATPIII
Number		570
251
38
821
570
859
Age
(yr) 37.76 ± 8.59 37.32 ± 9.13 39.07 ± 8.56 37.63 ± 8.75 37.55 ± 9.06 37.69 ± 8.74
BMI
(kg/m2) 22.09 ± 2.98 22.54 ± 3.22 23.32 ± 3.52 22.23 ± 3.06 22.64 ± 3.26 22.28 ± 3.09
SBP (mmHg) 115.29 ± 14.69 116.05 ± 15.58 116.95 ± 12.33 115.52 ± 14.96 116.17 ± 15.17 115.58 ± 14.85
DBP (mmHg) 71.61 ± 10.54 71.92 ± 10.71 72.32 ± 11.36 71.7 ± 10.58 71.97 ± 10.77 71.73 ± 10.61
HDL-C (mg/dL) 66.61 ± 17.26 65.39 ± 16.64 69.45 ± 14.38 66.24 ± 17.06 65.93 ± 16.39 66.38 ± 16.96
TG(mg/dL) 95.96 ± 66.78 93.98 ± 59.06 89.63 ± 50.89 95.36 ± 64.48 93.4 ± 57.99 95.1 ± 63.93
FPG(mg/dL) 95.66 ± 13.33 95.88 ± 17.28 96.55 ± 10.77 95.72 ± 14.64 95.97 ± 16.56 95.76 ± 14.49

0.487 0.740 0.318
0.018 0.015 0.034
0.672 0.411 0.563
0.874 0.636 0.728
0.335 0.580 0.254
0.795 0.580 0.590
0.924 0.768 0.730

Japanese definition
Number 		
573
253
39
826
292
865
Age
(yr) 37.79 ± 8.55 37.45 ± 9.13 39.1 ± 8.46 37.69 ± 8.73 37.67 ± 9.05 37.75 ± 8.72 0.533 0.841 0.322
BMI(kg/m2) 22.14 ± 2.98 22.56 ± 3.05 23.42 ± 3.52 22.27 ± 3.01 22.67 ± 3.12 22.32 ± 3.04 0.013 0.015 0.021
SBP (mmHg) 115.46 ± 14.72 116.08 ± 15.3 117.13 ± 12.22 115.65 ± 14.9 116.22 ± 14.91 115.71 ± 14.78 0.712 0.476 0.541
DBP (mmHg) 71.72 ± 10.6 72.04 ± 10.67 72.62 ± 11.36 71.82 ± 10.62 72.12 ± 10.75 71.85 ± 10.65 0.833 0.606 0.648
HDL-C (mg/dL) 66.16 ± 17.47 64.97 ± 16.98 68.64 ± 15.06 65.79 ± 17.32 65.46 ± 16.76 65.92 ± 17.23 0.396 0.573 0.313
TG(mg/dL) 98.91 ± 72.86 96.39 ± 61.41 93.69 ± 56.26 98.14 ± 69.52 96.03 ± 60.66 97.94 ± 68.96 0.823 0.561 0.694
FPG(mg/dL) 95.64 ± 13.17 95.99 ± 17.3 96.72 ± 10.68 95.75 ± 14.55 96.09 ± 16.56 95.79 ± 14.4 0.873 0.666 0.681
Data are numbers of subjects, divided into genotype groups, and values are mean ± SD.
BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL-C, high density lipoprotein-cholesterol;
NCEP-ATPIII, National Cholesterol Education Program-Adult Treatment panel III; SBP, systolic blood pressure; TG, triglyceride.
* Additive model (analysis of variance): comparison among 3 groups (TT versus TA versus AA).
† Dominant model (t-test): comparison of TT + TA with AA.
‡ Recessive model (t-test): comparison of TT with TA + AA.

definition includes: waist circumference ≥ 85 cm formales and ≥ 90 cm for females; systolic BP ≥ 130
mmHg or diastolic BP ≥ 85 mmHg; triglycerides≥ 150 mg/dL or HDL < 40 mg/dL in males and< 50 mg/dL in females; FPG ≥ 100 mg/dL. Central
obesity was defined as a BMI > 25 kg/m2, similar
to the NCEP-ATP III definition. Furthermore, theJapanese definition stipulates that all subjects receiving pharmacological treatment for hypertension
were considered to have elevated BP, all subjects
receiving fibrates were considered to have elevatedtriglycerides levels, and all subjects previously diagnosed with T2DM were considered to have raised
FPG.

sometimes, no exercise) and sleeping habits (sufficiency, usual, insufficiency).
Definition of metabolic syndrome
The NCEP-ATP III definition includes the presenceof three or more of the following five criteria: central obesity (waist circumference ≥ 90 cm for males,≥ 80 cm for females), elevated BP (systolic ≥ 130
mmHg or diastolic ≥ 85 mmHg), elevated triglycerides (≥ 150 mg/dL), reduced HDL cholesterol (< 40mg/dL for males, < 50 mg/dL for females), and elevated FPG (≥ 110 mg/dL). However, in this study,
central obesity was defined as a BMI > 25 kg/m2, as
defined by the Japan Society of Obesity. A previous
diagnosis of T2DM was considered to be evidenceof an elevated FPG.
The Japanese definition includes the same fivecriteria as the NCEP-ATPIII definition, but raised
triglycerides and/or reduced HDL cholesterol levels
are regarded as a single dyslipidemia criterion. In
addition, central obesity must be present as well as
two or more of the other four factors. The Japanese

Identification of FTO polymorphism
Peripheral blood samples, which had been collected
for the health check-up in 1998 and remained after blood tests, were used for the identification of
three SNPs rs9939609, rs1121980 and rs1558902
in the FTO. Genomic DNA was extracted fromthese samples using a QIAamp DNA Blood Kit
31

T. Kawajiri et al.

Table 1b. Lifestyle characteristics per genotypes in rs9939609
TT
TA
AA
TT + TATA + AAAllPPP							value* value† value‡
NCEP-ATPIII
Sex
Male
FemaleAlchol drinking habit
No drinking
Occasionally
Nearly every day
Smoking habit
Never smokedEx-smokers
Current smokers
Balance of food
Eat various foodConsider balance slightly
Rarely consider balance
Exercise habit
Frequently
Sometimes
No exercise
Sleeping habit
Sufficiently
NormalInsufficiently
Japanese definition
Sex
Male
FemaleAlchol drinking habit
No drinking
Occasionally
Nearly every day
Smoking habit
Never smokedEx-smokers
Current smokers
Balance of food
Eat various foodConsider balance slightly
Rarely consider balance
Exercise habit
Frequently
Sometimes
No exercise
Sleeping habit
Sufficiently
NormalInsufficiently

321 (56.3)
249 (43.7)

147 (58.6)
104 (41.4)

18 (47.4)
20 (52.6)

468 (57.0)
353 (43.0)

165 (57.1)
124 (42.9)

486 (56.6) 0.421 0.828 0.241
373 (43.4)

252 (44.4)
178 (31.4)
137 (24.2)

101 (40.6)
83 (33.3)
65 (26.1)

22 (59.5)
8 (21.6)
7 (18.9)353 (43.3)
261 (32.0)
202 (24.8)

123 (43.0)
91 (31.8)
72 (25.2)

375 (44.0) 0.300 0.914 0.149
269 (31.5)
209 (24.5)

343 (60.3)
23 (4.0)203 (35.7)

141 (56.2)
18 (7.2)
92 (36.7)

26 (68.4)
2 (5.3)10 (26.3)

484 (59.0)
41 (5.0)295 (36.0)

167 (57.8)
20 (6.9)102 (35.3)

510 (59.4) 0.245 0.185 0.473
43 (5.0)305 (35.5)

227 (40.0)
207 (36.4)
134 (23.6)

108 (43.0)
91 (36.3)
52 (20.7)

15 (39.5)
14 (36.8)
9 (23.7)335 (40.9)
298 (36.4)
186 (22.7)

123 (42.6)
105 (36.3)
61 (21.1)

350 (40.8) 0.899 0.658 0.982
312 (36.4)
195 (22.8)

38 (6.7)
172 (30.2)
359 (63.1)

20 (8.0)72 (28.7)
159 (63.3)

2 (5.3)
12 (31.6)
24 (63.2)

58 (7.1)
244 (29.8)
518 (63.2)

22 (7.6)
84 (29.1)
183 (63.3)

60 (7.0) 0.943 0.849 0.900
256 (29.8)
542 (63.2)

93 (16.3)
411 (72.2)
65 (11.4)

48 (19.2)
176 (70.4)
26 (10.4)

7 (18.4)
29 (76.3)
2 (5.3)141 (17.2)
587 (71.7)
91 (11.1)

55 (19.1)
205 (71.2)
28 (9.7)

148 (17.3) 0.671 0.502 0.526
616 (71.9)
93 (10.9)328 (57.2)
245 (42.8)

151 (59.7)
102 (40.3)

19 (48.7)
20 (51.3)

479 (58.0)
347 (42.0)

170 (55.8)
122 (44.2)

498 (57.6) 0.419 0.783 0.252367 (42.4)

251 (44.0)
178 (31.2)
141 (24.7)

103 (41.0)
83 (33.1)
65 (25.9)

22 (57.9)9 (23.7)
7 (18.4)354 (43.1)
261 (31.8)
206 (25.1)

125 (44.3)
92 (31.1)
72 (24.6)

376 (43.8) 0.425 0.975 0.200
270 (31.4)
213 (24.8)340 (59.4)
24 (4.2)
208 (36.4)

140 (55.3)
20 (7.9)
93 (36.8)

27 (69.2)
2 (5.1)
10 (25.6)

480 (58.2)
44 (5.3)
301 (36.5)

167 (60.4)
22 (3.9)103 (35.7)

507 (58.7) 0.134 0.118 0.369
46 (5.3)
311 (36.0)

230 (40.3)
207 (36.3)
134 (23.5)

110 (43.5)
91 (36.0)
52 (20.6)

16 (41.0)
14 (35.9)9 (23.1)

340 (41.3)
298 (36.2)
186 (22.6)

126 (43.2)
105 (37.8)
61 (19.0)356 (41.3) 0.894 0.619 0.997
312 (36.2)
195 (22.6)

39 (6.8)
171 (29.9)362 (63.3)

19 (7.5)
71 (28.1)
163 (64.4)

2 (5.1)
12 (30.8)
25 (64.1)

58 (7.0)242 (29.3)
525 (63.6)

21 (6.0)
83 (28.9)
188 (65.2)

60 (6.9) 0.965 0.897 0.895
254 (29.4)
550 (63.7)

93 (16.3)
413 (72.2)
66 (11.5)

49 (19.4)
178 (70.6)
25 (9.9)

7 (17.9)30 (76.9)
2 (5.1)142 (17.2)
591 (71.7)
91 (11.0)

56 (15.8)
208 (70.2)
27 (9.3)

149 (17.3) 0.579 0.382 0.507
621 (72.0)
93 (10.8)( ), %.
NCEP-ATPIII, National Cholesterol Education Program-Adult Treatment panel III.
* Additive model.
† Dominant model.
‡ Recessive model (c2 test).

(Qiagen, Hilden, Germany). These SNPs were
genotyped using TaqMan PCR methods with thefollowing probes: C_30090620_10 for rs9939609,

C_2031261_10 for rs1121980 and C_891711_10 for
rs1558902 (Applied Biosystems, Foster City, CA).

32

Metabolic syndrome and FTO polymorphism

Table 2a. Clinical characteristics per genotype in rs1121980
GG
GA
AA
GG + GA
GA + AAAllPPP							value* value† value‡
NCEP-ATPIII
Number		515
297
47
812
344
859
Age
(yr) 37.72 ± 8.64
37.46 ± 8.94
38.83 ± 8.73
37.63 ± 8.75
37.65 ± 8.91
37.69 ± 8.74
22.38 ± 3.15
23.6 ± 3.74
22.21 ± 3.03
22.55 ± 3.26
22.28 ± 3.08
BMI
(kg/m2) 22.11 ± 2.95
SBP
(mmHg) 115.56 ± 14.76 115.53 ± 15.46 116.13 ± 11.84 115.55 ± 15.01 115.62 ± 15115.58 ± 14.85
DBP(mmHg) 71.72 ± 10.47 71.89 ± 10.88 70.85 ± 10.53 71.78 ± 10.62 71.75 ± 10.83 71.73 ± 10.61
HDL-C (mg/dL) 66.57 ± 17.21 65.87 ± 16.89 67.43 ± 14.67 66.32 ± 17.09 66.08 ± 16.59 66.38 ± 16.96
TG(mg/dL) 95.15 ± 63.12 95.58 ± 66.43 91.64 ± 57.41 95.3 ± 64.31 95.04 ± 65.21 95.1 ± 63.93
FPG(mg/dL) 95.7 ± 13.54 95.1 ± 9.47 100.57 ± 35.5
95.48 ± 12.21 95.85 ± 15.81 95.76 ± 14.48

0.607
0.005
0.967
0.822
0.773
0.926
0.055

0.910
0.040
0.960
0.967
0.676
0.981
0.884

0.360
0.003
0.796
0.559
0.663
0.703
0.019

Japanese definition
Number		517
300
48
817
348
865
Age
(yr) 37.75 ± 8.61
37.57 ± 8.93
38.85 ± 8.64
37.69 ± 8.72
37.75 ± 8.89
37.75 ± 8.72
23.67 ± 3.73
22.24 ± 2.98
22.57 ± 3.15
22.32 ± 3.04
BMI
(kg/m2) 22.15 ± 2.96 22.4 ± 3.01
SBP
(mmHg) 115.76 ± 14.8 115.54 ± 15.22 116.29 ± 11.78 115.68 ± 14.95 115.64 ± 14.78 115.71 ± 14.78
DBP(mmHg) 71.84 ± 10.56 72 ± 10.84 71.13 ± 10.6
71.9 ± 10.66 71.88 ± 10.8
71.85 ± 10.65
HDL-C (mg/dL) 66.14 ± 17.41 65.4 ± 17.26 66.81 ± 15.13 65.87 ± 17.35 65.59 ± 16.97 65.92 ± 17.23
TG(mg/dL) 97.86 ± 69.19 98.55 ± 69.94 94.9 ± 61.12 98.12 ± 69.42 98.05 ± 68.72 97.94 ± 68.96
FPG(mg/dL) 95.64 ± 13.36 95.27 ± 9.64 100.63 ± 35.12 95.51 ± 12.12 96.01 ± 15.83 95.79 ± 14.4

0.640
0.003
0.942
0.869
0.782
0.943
0.053

0.997
0.044
0.910
0.955
0.645
0.970
0.717

0.368
0.001
0.781
0.626
0.713
0.753
0.017

Data are numbers of subjects, divided into genotype groups, and values are mean ± SD.
BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL-C, high density lipoprotein-cholesterol;
NCEP-ATPIII, National Cholesterol Education Program-Adult Treatment panel III; SBP, systolic blood pressure; TG, triglyceride.
* Additive model (analysis of variance): comparison among 3 groups (GG versus GA versus AA).
† Dominant model (t-test): comparison of GG + GA with AA.
‡ Recessive model (t-test): comparison of GG with GA + AA.

erozygote and AA homozygote in rs9939609 were
66.4%, 29.2%, 4.4% and 66.2%, 29.3%, 4.5% according to the NCEP-ATP III and Japanese definitions, respectively. Those of GG, GA and AA in
rs1121980 were 60.0%, 34.6%, 5.4% and 59.8%,
34.7%, 5.5% according to the NCEP-ATP III andJapanese definitions, respectively. Those of TT, TA
and AA in rs1558902 were 66.6%, 29.1%, 4.3% and66.5%, 29.1%, 4.4% according to the NCEP-ATP III
and Japanese definitions, respectively.
In both the NCEP-ATP III and Japanese definitions, the three SNPs, rs9939609, rs1121980 andrs1558902, were significantly associated with the
BMI, as shown in Tables 1a, 2a and 3a, but there
was no association between genotypes and lifestyles, such as drinking, smoking, eating, exercise
and sleeping habits. Moreover, for rs1121980 andrs1558902, there were significant differences on
FPG (Tables 1b, 2b and 3b).
Results of univariate analyses of the hazard
ratios for MS of gene polymorphism and the indices
are shown in Table 4. According to the NCEP-ATP
III definition, the hazard ratios of sex, age, additive

Statistical analysis
We used Student’s t-test and analysis of varianceto compare continuous variables and the c2 test tocompare categorical variables. Quantitative variables were expressed as the mean ± SD. The hazard
ratio and 95% confidence interval of each factor
for incidence of MS were estimated by univariate
and multivariate Cox proportional-hazards models
adjusted for sex, age, smoking, drinking, exercise,eating and sleeping habits. The onset of metabolic
syndrome was defined as the day of health checkup when an employee had a diagnosis of metabolic
syndrome. Analysis was performed using PASW
Statistics 18 (SPSS Japan, Tokyo). The significancelevel was set to P values of less than 0.05.

Results
The distributions of genotype and characteristics
of study subjects are shown in Tables 1 to 3. The
relative frequencies of TT homozygote, TA het33

T. Kawajiri et al.

Table 2b. Lifestyle characteristics per genotypes in rs1121980
GG
GA
AA
GG + GA
GA + AAAllPPP							value* value† value‡
NCEP-ATPIII
Sex
Male
FemaleAlchol drinking habit
No drinking
Occasionally
Nearly every day
Smoking habit
Never smokedEx-smokers
Current smokers
Balance of food
Eat various foodConsider balance slightly
Rarely consider balance
Exercise habit
Frequently
Sometimes
No exercise
Sleeping habit
Sufficiently
NormalInsufficiently
Japanese definition
Sex
Male
FemaleAlchol drinking habit
No drinking
Occasionally
Nearly every day
Smoking habit
Never smokedEx-smokers
Current smokers
Balance of food
Eat various foodConsider balance slightly
Rarely consider balance
Exercise habit
Frequently
Sometimes
No exercise
Sleeping habit
Sufficiently
NormalInsufficiently

297 (57.7)
218 (42.3)

165 (55.6)
132 (44.4)

24 (51.1)
23 (48.9)

462 (56.9)
350 (43.1)

189 (54.9)
155 (45.1)

486 (56.6) 0.619 0.429 0.433
373 (43.4)

216 (42.2)
160 (31.3)
136 (26.6)

132 (44.7)
100 (33.9)
63 (21.4)

27 (58.7)
9 (19.6)
10 (21.7)

348 (43.1)
260 (32.2)
199 (24.7)

159 (46.6)
109 (32.0)
73 (21.4)375 (44.0) 0.111 0.205 0.092
269 (31.5)
209 (24.5)

301 (58.6)
25 (4.9)
188 (36.6)

179 (60.3)
14 (4.7)
104 (35.0)

30 (63.8)
4 (8.5)13 (27.7)

480 (59.2)
39 (4.8)292 (36.0)

209 (60.8)
18 (5.2)
117 (34.0)510 (59.4)
43 (5.0)305 (35.5)

209 (40.7)
188 (36.6)
116 (22.6)

123 (41.4)
110 (37.0)
64 (21.5)

18 (38.3)
14 (29.8)
15 (31.9)332 (41.0)
298 (36.8)
180 (22.2)

141 (41.0)
124 (36.0)
79 (23.0)350 (40.8) 0.621 0.983 0.285
312 (36.4)
195 (22.8)

35 (6.8)
156 (30.4)
323 (62.8)

23 (7.7)
84 (28.3)
190 (64.0)

2 (4.3)16 (34.0)
29 (61.7)

58 (7.2)
240 (29.6)
513 (63.3)

25 (7.3)
100 (29.1)
219 (63.7)

60 (7.0)
256 (29.8)
542 (63.2)

0.846 0.906 0.656

87 (16.9)
371 (72.2)
56 (10.9)51 (17.2)
210 (70.9)
35 (11.8)

10 (21.3)
35 (74.5)
2 (4.3)138 (17.0)
581 (71.7)
91 (11.2)

61 (17.8)
245 (71.4)
37 (10.8)

148 (17.3)
616 (71.9)
93 (10.9)

0.609 0.948 0.286

303 (58.6)
214 (41.4)

170 (56.7)
130 (43.3)

25 (52.1)
23 (47.9)473 (57.9)344 (42.1)

195 (56.0)
153 (44.0)

498 (57.6)
367 (42.4)

0.631 0.453 0.429

214 (41.6)
160 (31.1)
140 (27.2)

135 (45.3)
100 (33.6)
63 (21.1)

27 (57.4)
10 (21.3)
10 (21.3)

349 (43.0)
260 (32.0)
203 (25.0)

162 (47.0)
110 (31.9)
73 (21.2)

376 (43.8) 0.101 0.108 0.135
270 (31.4)
213 (24.8)

298 (57.8)
26 (5.0)
192 (37.2)

178 (59.3)
16 (5.3)
106 (35.3)

31 (64.6)
4 (8.3)
13 (27.1)

476 (58.3)
42 (5.1)
298 (36.5)

209 (60.1)
20 (5.7)
119 (34.2)

507 (58.7)
46 (5.3)
311 (36.0)

211 (41.0)
188 (36.5)
116 (22.5)

126 (42.0)
110 (36.7)
64 (21.3)

19 (39.6)
14 (29.2)
15 (31.3)

337 (41.3)
298 (36.6)
180 (22.1)

145 (41.7)
124 (35.6)
79 (22.7)356 (41.3) 0.631 0.965 0.300
312 (36.2)
195 (22.6)

36 (7.0)155 (30.0)
325 (63.0)

22 (7.3)
83 (27.7)
195 (65.0)

2 (4.2)16 (33.3)
30 (62.5)

58 (7.1)
238 (29.2)
520 (63.7)

24 (6.9)99 (28.4)
225 (64.7)

60 (6.9)254 (29.4)
550 (63.7)

87 (16.9)
372 (72.1)
57 (11.0)

52 (17.4)
213 (71.2)
34 (11.4)

10 (20.8)
36 (75.0)
2 (4.2)139 (17.1)
585 (71.8)
91 (11.2)

62 (17.9)
249 (71.8)
36 (10.4)

149 (17.3) 0.632 0.899 0.286
621 (72.0)
93 (10.8)

0.649 0.739 0.325

0.630 0.635 0.319

0.851 0.873 0.656( ), %.
NCEP-ATPIII, National Cholesterol Education Program-Adult Treatment panel III.
* Additive model.
† Dominant model.
‡ Recessive model (c2 test).

and dominant models of rs9939609 and rs1121980
and the dominant model of rs1558902 were significantly high. According to the Japanese definition,that of only sex was significantly high. In both definitions, drinking and smoking habits showed significantly high risks, but regarding balance of food,34

Metabolic syndrome and FTO polymorphism

Table 3a. Clinical characteristics per genotype in rs1558902
TT
TA
AA
TT + TATA + AAAllPPP							value* value† value‡
NCEP-ATPIII
Number		572
250
37
822
287
859
Age
(yr) 37.73 ± 8.58
37.36 ± 9.14
39.41 ± 8.54
37.62 ± 8.75
37.62 ± 9.08
37.69 ± 8.74
23.58 ± 3.95
22.22 ± 3.03
22.68 ± 3.36
22.28 ± 3.08
BMI
(kg/m2) 22.08 ± 2.92 22.55 ± 3.25
SBP
(mmHg) 115.37 ± 14.78 115.86 ± 15.41 117.03 ± 12.14 115.52 ± 14.96 116.01 ± 15.01 115.58 ± 14.85
DBP(mmHg) 71.62 ± 10.59 71.93 ± 10.6
72.16 ± 11.17 71.71 ± 10.59 71.96 ± 10.65 71.73 ± 10.61
HDL-C (mg/dL) 66.73 ± 17.3
65.14 ± 16.45 69.3 ± 14.69 66.25 ± 17.05 65.67 ± 16.27 66.38 ± 16.96
TG(mg/dL) 95.08 ± 63.8
95.72 ± 66.03 91.35 ± 51.67 95.27 ± 64.45 95.16 ± 64.29 95.1 ± 63.93
FPG(mg/dL) 95.47 ± 13.07 95.36 ± 9.79 102.95 ± 39.64 95.44 ± 12.16 96.34 ± 16.96 95.76 ± 14.48

0.407
0.005
0.757
0.899
0.262
0.928
0.008

0.864
0.008
0.548
0.658
0.389
0.986
0.405

0.224
0.009
0.546
0.801
0.285
0.715
0.002

Japanese definition
Number		575
252
38
827
290
865
Age
(yr) 37.76 ± 8.55
37.48 ± 9.15
39.42 ± 8.43
37.67 ± 8.73
37.73 ± 9.06
37.75 ± 8.72
23.67 ± 3.94
22.26 ± 2.98
22.71 ± 3.23
22.32 ± 3.04
BMI
(kg/m2) 22.12 ± 2.92 22.56 ± 3.09
SBP
(mmHg) 115.54 ± 14.81 115.89 ± 15.14 117.21 ± 12.03 115.64 ± 14.9 116.06 ± 14.76 115.71 ± 14.78
DBP(mmHg) 71.73 ± 10.66 72.05 ± 10.57 72.47 ± 11.19 71.83 ± 10.63 72.1 ± 10.63 71.85 ± 10.65
HDL-C (mg/dL) 66.28 ± 17.52 64.71 ± 16.79 68.47 ± 15.36 65.8 ± 17.31 65.2 ± 16.63 65.92 ± 17.23
TG(mg/dL) 98.02 ± 70.18 98.13 ± 68.03 95.47 ± 56.95 98.05 ± 69.49 97.78 ± 66.6
97.94 ± 68.96
FPG(mg/dL) 95.45 ± 12.92 95.48 ± 9.92 102.95 ± 39.11 95.46 ± 12.08 96.46 ± 16.96 95.79 ± 14.4

0.441
0.003
0.777
0.865
0.312
0.975
0.007

0.968
0.008
0.622
0.625
0.384
0.962
0.332

0.228
0.005
0.523
0.714
0.351
0.822
0.002

Data are numbers of subjects, divided into genotype groups, and values are mean ± SD.
BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL-C, high density lipoprotein-cholesterol;
NCEP-ATPIII, National Cholesterol Education Program-Adult Treatment panel III; SBP, systolic blood pressure; TG, triglyceride.
* Additive model (analysis of variance): comparison among 3 groups (TT versus TA versus AA).
† Dominant model (t-test): comparison of TT + TA with AA.
‡ Recessive model (t-test): comparison of TT with TA + AA.

considering balance showed a significantly low risk.
After adjusting for age, sex and lifestyle(drinking, smoking, eating, exercise and sleeping
habit), results of multivariate analysis are shown in
Table 5. According to the NCEP-ATP III definition,
results were almost the same as single variant analysis. But the hazard ratio was significantly higher
in the additive model of rs1558902. In the Japanese
definition, the additive model of rs1558902 was asignificant high risk for MS.

contrast, those of genotypes and alleles in other ethnic groups were remarkably different from those inJapanese. By the HapMap database (http://hapmap.
ncbi.nlm.nih.gov/), the frequencies of the rs9939609
A allele were 0.14 in Chinese and Japanese, 0.45 in
CEPH Europeans and 0.52 in Yorubans. Therefore,
the effect and importance of genetic factors makes
differences among ethnic groups.
According to the NCEP-ATPIII definition, thethree SNPs in the FTO were significantly associatedwith BMI. Moreover, rs1121980 and rs1558902 wereassociated with FPG. These results were consistent
with previous studies (Horikoshi et al., 2007; Hottaet al., 2008; Tabara et al., 2009; Hotta et al., 2010;
Shimaoka et al., 2010). However, in both the NCEPATPIII and Japanese definitions, none of the three
SNPs were associated with sex and lifestyle (drinking, smoking, eating, exercise and sleeping habit).
The three SNPs clarified by not only univariate, butalso multivariate analysis adjusting for age, sex andlifestyle were significantly associated with the incidence of MS diagnosed by the NCEP-ATPIII definition. By the Japanese definition, only rs1558902

Discussion
In the present study, a retrospective cohort study
over 9 years was performed in Japanese workers to investigate the association of three SNPs,
rs9939609, rs1121980 and rs1558902, in the FTO
with the incidence of MS diagnosed by the NCEPATPIII and Japanese definitions.
The frequencies of genotypes and alleles in the
FTO were similar to those in other studies in Japanese (Hotta et al., 2008; Shimaoka et al., 2010). In
35

T. Kawajiri et al.

Table 3b. Lifestyle characteristics per genotypes in rs1558902
TT
TA
AA
TT + TATA + AAAllPPP							value* value† value‡
NCEP-ATPIII
Sex
Male
FemaleAlcohol drinking habit
No drinking
Occasionally
Nearly every day
Smoking habit
Never smokedEx-smokers
Current smokers
Balance of food
Eat various foodConsider balance slightly
Rarely consider balance
Exercise habit
Frequently
Sometimes
No exercise
Sleeping habit
Sufficiently
NormalInsufficiently
Japanese definition
Sex
Male
FemaleAlcohol drinking habit
No drinking
Occasionally
Nearly every day
Smoking habit
Never smokedEx-smokers
Current smokers
Balance of food
Eat various foodConsider balance slightly
Rarely consider balance
Exercise habit
Frequently
Sometimes
No exercise
Sleeping habit
Sufficiently
NormalInsufficiently

327 (57.2)
245 (42.8)

142 (56.8)
108 (43.2)

17 (45.9)
20 (54.1)

469 (57.1)
353 (42.9)

159 (55.4)
128 (44.6)

486 (56.6) 0.409 0.622 0.182
373 (43.4)

246 (43.2)
179 (31.5)
144 (25.3)

107 (43.1)
83 (33.5)
58 (23.4)

22 (61.1)
7 (19.4)
7 (19.4)353 (43.2)
262 (32.1)
202 (24.7)

129 (45.4)
90 (31.7)
65 (22.9)375 (44.0) 0.274 0.718 0.098
269 (31.5)
209 (24.5)

340 (59.5)
28 (4.9)203 (35.6)

144 (57.6)
13 (5.2)
93 (37.2)

26 (70.3)
2 (5.4)9 (24.3)

484 (59.0)
41 (5.0)296 (36.1)

170 (59.2)
15 (5.2)
102 (35.5)510 (59.4)
43 (5.0)305 (35.5)

227 (39.8)
209 (36.7)
134 (23.5)

108 (43.2)
90 (36.0)
52 (20.8)

15 (40.5)
13 (35.1)
9 (24.3)

335 (40.9)
299 (36.5)
186 (22.7)

123 (42.9)
103 (35.9)
61 (21.3)

350 (40.8) 0.890 0.641 0.970
312 (36.4)
195 (22.8)

39 (6.8)
174 (30.5)
358 (62.7)

19 (7.6)
70 (28.0)
161 (64.4)

2 (5.4)
12 (32.4)
23 (62.2)

58 (7.1)
244 (29.7)
519 (63.2)

21 (7.3)
82 (28.6)
184 (64.1)

60 (7.0)
256 (29.8)
542 (63.2)

0.936 0.837 0.890

94 (16.5)
414 (72.5)
63 (11.0)

48 (19.3)
173 (69.5)
28 (11.2)

6 (16.2)
29 (78.4)
2 (5.4)142 (17.3)
587 (71.6)
91 (11.1)

54 (18.9)
202 (70.6)
30 (10.5)

148 (17.3)
616 (71.9)
93 (10.9)

0.675 0.673 0.520

334 (58.1)
241 (41.9)

146 (57.9)
106 (42.1)

18 (47.4)
20 (52.6)

480 (58.0)
347 (42.0)

164 (56.6)
126 (43.4)

498 (57.6)
367 (42.4)

0.428 0.666 0.193

245 (42.8)
179 (31.3)
148 (25.9)

109 (43.6)
83 (33.2)
58 (23.2)

22 (59.5)
8 (21.6)
7 (18.9)354 (43.1)
262 (31.9)
206 (25.1)

131 (45.6)
91 (31.7)
65 (22.6)

376 (43.8) 0.328 0.560 0.143
270 (31.4)
213 (24.8)

337 (58.7)
29 (5.1)
208 (36.2)

143 (56.7)
15 (6.0)
94 (37.3)

27 (71.1)
2 (5.3)9 (23.7)

480 (58.1)
44 (5.3)
302 (36.6)

170 (58.6)
17 (5.9)103 (35.5)

507 (58.7)
46 (5.3)
311 (36.0)

230 (40.1)
209 (36.5)
134 (23.4)

110 (43.7)
90 (35.7)
52 (20.6)

16 (42.1)
13 (34.2)
9 (23.7)340 (41.2)
299 (36.2)
186 (22.5)

230 (40.1)
209 (36.5)
134 (23.4)

356 (41.3) 0.877 0.597 0.966
312 (36.2)
195 (22.6)

40 (7.0)
173 (30.1)
361 (62.9)

18 (7.1)
69 (27.4)
165 (65.5)

2 (5.3)
12 (31.6)
24 (63.2)

58 (7.0)242 (29.3)
526 (63.7)

20 (6.9)81 (27.9)
189 (65.2)

60 (6.9)254 (29.4)
550 (63.7)

94 (16.4)
416 (72.5)
64 (11.1)

49 (19.5)
175 (69.7)
27 (10.8)

6 (15.8)
30 (78.9)
2 (5.3)143 (17.3)
591 (71.6)
91 (11.0)55 (19.0)
205 (70.9)
29 (10.0)

149 (17.3) 0.618 0.586 0.486
621 (72.0)
93 (10.8)

0.659 0.979 0.342

0.533 0.876 0.258

0.929 0.787 0.892( ), %.
NCEP-ATPIII, National Cholesterol Education Program-Adult Treatment panel III.
* Additive model.
† Dominant model.
‡ Recessive model (c2 test).

was significantly associated with MS. Moreover, in
rs1121980 and rs1558902, the hazard ratio for MS
by the NCEP-ATPIII definition became higher as

the number of risk alleles increased. Thus, it wassuggested that the A allele at three SNPs is a risk
allele and is at substantially increased risk of MS.
36

Metabolic syndrome and FTO polymorphism

Table 4. Hazard ratios of gender, age and lifestyle for MS by genotype (univariate analysis)
Hazardratio
SexFemale		
Male		
Age			
rs9939609
Additive model
TT
		
TA
		
AA
Dominant modelTT		
TA + AA
Recessive model
TT + TA		AA
rs1121980
Additive model
GG
		
GA
		
AA
Dominant modelGG		GA + AA
Recessive model
GG + GA		AA
rs1558902
Additive model
TT
		
TA
		
AA
Dominant modelTT		
TA + AA
Recessive model
AT + TT		AA
Alchol drinking habit
No drinking		Occasionally		
Nearly every day		
Smoking habit
Never smoked		
Ex-smokers		Current smokers		
Balance of food
Eat various food		Consider balance slightly
Rarely consider balance
Exercise habit
Frequently		
Sometimes		
No exercise		
Sleeping habit
Sufficiently		
Normal		Insufficiently		

NCEP-ATPIII
95%
P
CI
value

1.00 			4.462.95–6.74
0.00
1.02
1.00–1.04
0.02
1.00 			1.521.10–2.08
0.01
1.31
0.63–2.70
0.46
1.00 			1.491.09–2.02
0.01
1.00 			1.140 0.56–2.32
0.72
1.00 			1.571.14–2.16
0.01
1.78
0.92–3.41
0.08
1.00 			1.601.17–2.16
0.00
1.00 			1.520 0.80–2.89
0.20
1.00 			1.330.97–1.83
0.08
1.76
0.98–3.15
0.06
1.00 			1.391.02–1.88
0.04
1.00 			1.570.89–2.77
0.12
1.00 			1.701.16–2.49
0.01
2.36
1.62–3.45
0.00
1.00 			1.300.59–2.83
0.51
2.81
2.05–3.85
0.00
1.00 			0.570.39–0.83
0.00
1.01
0.70–1.45
0.97
1.00 			1.010.54–1.90
0.96
0.94
0.52–1.71
0.84
1.00 			0.750.52–1.10
0.14
0.68
0.38–1.22
0.20

Japanese definition
Hazard
95%
P
ratio
CI
value
1.00
7.01
1.01
1.00
1.38
1.33
1.00
1.37
1.00
1.19
1.00
1.19
1.82
1.00
1.27
1.00
1.7
1.00
1.37
1.88
1.00
1.44
1.00
1.69
1.00
1.37
1.99
1.00
1.92
2.92
1.00
0.62
0.99
1.00
1.05
0.8
1.00
0.96
0.83

3.86–12.75
0.99–1.03

0
0.53

0.93–2.03
0.58–3.05

0.10
0.51

0.95–1.99

0.09

0.52–2.71

0.68

0.80–1.74
0.93–3.55

0.39
0.07

0.88–1.83

0.2

0.89–3.26

0.11

0.93–2.03
0.9–3.91

0.11
0.09

0.99–2.08

0.05

0.82–3.47

0.15

0.87–2.15
1.28–3.10

0.18
00.86–4.28
1.98–4.30

0.11
00.39–0.96
0.64–1.55

0.03
0.97

0.51–2.17
0.4–1.61

0.89
0.53

0.60–1.55
0.40–1.71

0.88
0.6

CI, confidence interval; MS, metabolic syndrome; NCEP-ATPIII, National Cholesterol Education Program-Adult Treatment panel III.

In the present study, we showed an association between SNPs FTO and MS diagnosed by
the NCEP-ATP III and Japanese definitions which
disagreed with the results of Shimaoka et al. (2010)
and Tabara et al. (2009). However, according to the
NCEP-ATP III definition used internationally, thisstudy were consistent with the results of Sjögren
et al. (2008) and Al-Attar et al. (2008) in Swedish,French, Inuit, and Chinese specific ethnic groups(Table 6). To investigate the importance of FTO
SNPs in Japanese populations, further studies should

be carried out in more extensive Japanese subjects.
The average of BMI in subjects was 22.3 ±3.1 kg/m2, which is close to the Japanese average ofaround 30 years of age. The hazard ratios of lifestyle for MS in univariate analysis were not significantly associated with food, exercise and sleeping
habits. Lifestyle is known as a risk factor of MS,
but an association with these habits was not found;however, we performed the investigation in 1998
and as for these lifestyles, we speculate the index
easily changed during the 9 years between 1998 and
37

T. Kawajiri et al.

Table 5. Hazard ratios of gender, age and lifestyle for MS by genotype (multivariate analysis)
Genotype		rs9939609
Additive model				Dominant model		
Recessive model		rs1121980
Additive model				Dominant model		
Recessive model		
rs1558902
Additive model				Dominant model		
Recessive model		

NCEP-ATPIII			 Japanese definition
Hazard ratio 95% CI
P value
Hazard ratio 95% CI P value
TT
TA
AA
TT
TA + AA
TT + TA
AA
GG
GA
AA
GG
GA + AA
GG + GA
AA
TT
TA
AA
TT
TA + AA
AT + TTAA

1.00			1.481.07–2.04
0.02
1.48
0.72–3.07
0.29
1.00			1.481.08–2.02
0.01
1.00			1.290.63–2.63
0.49
1.00			1.551.12–2.14
0.01
2.06
1.07–3.99
0.03
1.00			1.601.18–2.19
0.00
1.00			1.760.93–3.37
0.08
1.00			1.350.98–1.86
0.07
1.88
1.04–3.40
0.04
1.00			1.411.04–1.92
0.03
1.00			1.670.94–2.97
0.08

1.00
1.35
1.54
1.00
1.37
1.00
1.38
1.00
1.19
1.99
1.00
1.29
1.00
1.86
1.00
1.37
2.24
1.00
1.47
1.00
2.01

0.91–2.00
0.66–3.57

0.13
0.32

0.94–2.00

0.10

0.60–3.18

0.44

0.81–1.76
1.00–3.94

0.38
0.05

0.89–1.86

0.18

0.96–3.61

0.07

0.93–2.04
1.07–4.72

0.12
0.03

1.01–2.13

0.05

0.97–4.17

0.06

Adjusted for sex, age and lifestyle (drinking, smoking, eating, exercise and sleeping habits).
CI, confidence interval; MS, metabolic syndrome; NCEP-ATPIII, National Cholesterol Education Program-Adult Treatment panel III.

2006. Thus, lifestyles varied with the incidence ofMS. According to alcohol and smoking habits, there
were significant associations with MS. Lifestyle isthe factor that is hard to be changed and it strongly
affects the onset of MS.
It was reported that risk allele carriers were 3 kg
heavier than non-carriers (Dina et al., 2007; Frayling
et al., 2007). It has been reported that lifestyle alterations can reduce the risk of MS (Fappa et al., 2008),
even in individuals carrying the MS-susceptibility
variant of FTO. Therefore, genotyping SNPs of FTO
in an individual may be effective for personalized
preventive medicine in Japanese populations.
In the present study, we could not determine
the mechanism of FTO SNPs affecting the prevalence of MS. So far, the function of the FTO wasrevealed gradually, and there was evidence that
the FTO was involved in the development of obesity. FTO mRNA was widely expressed in fetal
and adult tissues, especially in the brain, and inparticular the hypothalamus, which is involved inenergy balance (Dina et al., 2007; Frayling et al.,2007; Gerken et al., 2007). Moreover, several stud-ies suggested that risk-allele carriers had greater
food intake in human subjects (Cecil et al., 2008;
Speakman et al., 2008), but not all (Tanofsky-Kraff
et al., 2009). The risk-allele in human FTO may
enhance the expression and/or activity of the FTO(Church et al., 2010). Thus, overexpression of the
FTO may lead to increased food intake, resulting
in obesity. However, the precise mechanism of how
the FTO affects obesity and MS is not clear yet.
Most reports which have studied the relationship between polymorphism in the FTO and MS
were analyzed using case-control or cross-sectional
studies (Al-Attar et al., 2008; Tabara et al., 2009;
Shimaoka et al., 2010) (Table 6). A retrospective cohort study among workers, not hospital-based, wasemployed in the present study. Although a cohort
study was employed to reduce the effect of biases
compared to the case-control study, some limitations
remain. First, the relatively young subject populationand healthy-worker effect due to selection of subjects
after medical checkups at the time of employment
may have decreased subjects with MS and affected
the results of the study. Second, regarding the sam-38

Metabolic syndrome and FTO polymorphism

Table 6. Association of FTO genotype with MS
MethodSubject

Definition of MS

SNP

Association

Present study
Cohort study
JapaneseJapanese definition
rs9939609–
		(Izumo region, Shimane)		
rs1121980–				
rs1558902+
			
NCEP-ATPIII
rs9939609+
				rs1121980+				
rs1558902+
Shimaoka et al., 2010 Cross-sectional study JapaneseJapanese definition
rs9939609–
		(Tanno-Sobetsu, Hokkaido)		
rs1121980–				
rs1558902–
Tabara et al., 2009
Case-control study
Japanese
NCEP-ATPIII
rs9939609–
		(Ehime)
Sjögren et al., 2008
Cohort study
SwedishOrdinalrs9939609+
			(reference to NCEP-ATPIII, IDF)
Al-Attar et al., 2008 Meta-analysis
South AsianIDF
rs9939609+
		
Chinese			–		Oji-Cree			–		Greenland Inuit			–		South Asian
NCEP-ATPIII
rs9939609–
		
Chinese			–		Oji-Cree			–		Greenland Inuit			+
FTO, fat mass and obesity associated gene; IDF, International Diabetes Federation; MS, metabolic syndrome; NCEP-ATPIII, National
Cholesterol Education Program-Adult Treatment panel III; SNP, single nucleotide polymorphism.

ple size, we could not recruit enough numbers of therisk A-allele homozygous genotype. Results presented above need to be further verified with increased
numbers. Because we did not have the data of abdominal circumference of subjects, we used BMI
for classification of Japanese metabolic syndromein substitution for abdominal circumference. Since
BMI ≥ 25 is a good surrogate measure of abdominal
obesity among the Japanese population (Otsuka and
Kawada, 2010), the effect of misclassification of theabdominal obesity to the study results is consideredsmall.
In our results, we indicated that rs9939609,
rs1121980 and rs1558902 in the FTO may be significantly associated with the incidence of MS diagnosed by the NCEP-ATP III in Japanese subjects,
and by the Japanese definition the association applied to rs1558902. It is considered that there is thelinkage disequilibrium between three SNPs assessedin the present study; however, we did not assessed
statistically. SNPs may be an important risk factor for the future incidence of MS in the Japanese.
Therefore, knowing earlier whether individuals arerisk allele carriers may be useful in preventing MS
in the future.

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Received March 23, 2012; accepted May 7, 2012
Corresponding author: Yoneatsu Osaki, MD, PhD

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