Yonago Acta medica 2006;49:49–58

Relationship between an Angiotensinogen Gene
Polymorphism (M235T) and Serum Lipids:
A Cross-Sectional Study among Japanese Workers
Akihiko Kaetsu, Takuji Kishimoto, Yoneatsu Osaki, Mikizoh Okamoto and Yoichi
Kurozawa*
Division of Environmental and Preventive Medicine and *Division of Health Administration andPromotion, Department of Social Medicine, School of Medicine, Tottori University Faculty of
Medicine, Yonago 683-8503 Japan

Angiotensinogen (AGT) is a component of the renin-angiotensin system, which plays acentral role in blood pressure regulation. Although it is controversial, the association
between AGT gene polymorphisms and hypertension, and coronary heart disease issuspected. In a case-control study on the metabolic syndrome, an association between
AGT M235T polymorphism and serum total cholesterol (TC) level was demonstrated byThomas et al. (2001). To reconﬁrm this relationship, a cross-sectional study among Japanese workers with 876 dyslipidemia and 1,158 non-dyslipidemia subjects was carriedout. To evaluate the AGT M235T polymorphism, a PCR-mutant allele speciﬁc ampliﬁcation (MASA) method was employed. No signiﬁcant difference in the distribution of genetic variance was observed between the two groups. Although it was not signiﬁcant, theT allele correlating to the lower TC of the present study occurred in a reversed mannerto the previous report. In our results, no signiﬁcant association between AGT M235T
and TC was observed.
Key words: angiotensinogen; polymorphism (genetics); cholesterol; cross-sectional study;
Japanese workers

phisms and hypertension have been investigatedsince 1992 (Jeunemaitre et al., 1992; Caulﬁeld etal., 1994; Hata et al., 1994; Tiret et al., 1995; Satoet al., 1997; Ishigami et al., 1997, 1999; Ishikawa
et al., 2001; Tiago et al., 2002; Vasku et al., 2002).
In particular, the AGT gene M235T polymorphism, with an amino acid substitution of methionine (M) to threonine (T) at codon 235, has been
demonstrated to be associated not only with hypertension, but also myocardial infarction (Tiret etEssential hypertension, a major part of hypertension, is a multifactorial disease and some candidate genes have been proposed. The renin-angiotensin system (RAS) has a central role in regulating blood pressure and sodium homeostasis.
Angiotensinogen (AGT) plays a role in RAS asa substrate of renin and a precursor of angiotensin II. For that reason, it was considered that theAGT gene polymorphism inﬂuenced blood pressure, and the relationship between some polymor-

Abbreviations: AGT, angiotensinogen; BMI, body mass index; CI, conﬁdence interval; DBP, diastolic blood pressure;
FBS, fasting blood sugar; HDL, high-density lipoprotein cholesterol; MASA, mutant allele speciﬁc ampliﬁcation; MM,
genotype M235M; MT, genotype M235T; M235T, mutation to the threonine of the methionine in amino acid codon 235;
OR, odds ratio; RAS, renin-angiotensin system; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; TT,
genotype T235T

49

A. Kaetsu et al.

consent of gene analysis was obtained from eachstudy subject.

al., 1995; Frossard et al., 1998; Fernandez-Arcaset al., 2001; Buraczynska et al., 2003). Although
the relationships are controversial (Fornage et al.,
1995; Hingorani et al., 1996; Ichihara et al., 1997;
Arnett et al., 1998; Fernandez-Llama et al., 1998;
Wang et al., 1999; Rodrigues-Perez et al., 2000;
Nair et al., 2003), a hypothesis that the T235 allele plays a role as a “thrifty gene” was proposedby comparing the genotype distribution of anthropoid and human ethnicities (Inoue et al., 1997).
In the current clinical situation, patients withboth hypertension and dyslipidemia were commonly observed. Moreover, the metabolic syndrome, in which hypertension is clustered together
with obesity, dyslipidemia and insulin resistancein an individual (WHO, 1999; NCEP ATP III,
2001), has reached epidemic proportions, even in
Japan.
In such situations, the association between
the AGT gene M235T polymorphism and serum
total cholesterol level (TC) was demonstrated in a
hospital-based case-control study on the metabolic syndrome (Thomas et al., 2001). The mechanism by which RAS inﬂuences the lipid metabolism directly has not been discovered (Nishimura
et al., 1995; Wierzbicki et al., 2000; Singh et al.,
2003; Strazzullo et al., 2004). However, this association is remarkable, whether or not AGT plays
any role as the candidate gene responsible for the
metabolic syndrome.
Therefore, we planned to evaluate the relationship between the AGT gene M235T polymorphism and serum lipids more closely to thegeneral population than the previous report. For
this purpose, a relatively large sample-size worksite based cross-sectional study was carried out.

Study population and eligible subjects
The study population was recruited from workers
of a company who received annual health checkups in 1998, in Shimane Prefecture in WesternJapan. Among the study population of our study,
individuals who gave informed consent were chosen as eligible subjects for the present study.
Various measurements
The body mass index (BMI), body weight in kilograms divided by height in meters squared, wasused as a measure of body composition. Obesity
was defined as a BMI of 25 and over. Bloodpressure was measured using a standard mercury
sphygmomanometer. Hypertension was defined
as a systolic blood pressure (SBP) of 140 mmHg
and over and/or a diastolic blood pressure (DBP)of 90 mmHg and over. Blood samples were collected from a peripheral vein. Serum total cholesterol (TC), high-density lipoprotein cholesterol(HDL), triglyceride (TG) and fasting blood sugar(FBS) were measured using an autoanalyzer(Model 7150 Autoanalyzer, Hitachi). TC, HDL,TG and FBS were determined enzymatically using commercial enzyme kits (cholesterol oxidase
method, direct method, free glycerol without
blank method, Kyowa Medex, Tokyo, Japan; andthe hexokinase glucose-6-phosphatedehydrogenase method, Wako, Tokyo, Japan, respectively).
Details of these measurements have been described previously (Kaetsu et al., 2004).
In the present study, dyslipidemia was deﬁned as at least one of the following three criteria:
TC 220 mg/dL and over, HDL less than 40 mg/
dL, or TG 150 mg and over. Hyperglycemia wasdeﬁned as FBS 110 mg/dL and over, as a substitute for insulin resistance.
Alcohol drinking and smoking habits wereassessed using a questionnaire on lifestyle factors
at annual health checkups. Drinkers were deﬁned

Subjects and Methods
Ethical issues
The present study was approved by the Ethics
Committee of the Faculty of Medicine, Tottori
University (No. 81, 2000). Written informed
50

AGT M235T and dyslipidemia

AGT M235T genotype and the prevalence of abnormalities in each serum lipid.

as daily drinkers, and occasional and never drinkers were assessed as non-drinkers. Smokers were
defined as current smokers, and past and neversmokers were assessed as non-smokers.

Results
Identification of the AGT gene M235T
polymorphism and genotyping

The total number of eligible subjects was 2,034,
with 1,137 male and 897 female subjects, respectively. The descriptive characteristics of the subjects are shown in Table 1. Of the 2,034 subjects,
876 were assigned to the dyslipidemia group and
1,158 to the non-dyslipidemia group (Control
group). In the dyslipidemia group, a higher meanage, higher proportion of male subjects, obesity,
hypertension, hyperglycemia, alcohol drinkers,
and smokers were observed than in the control
group.
The distributions of genotype and allele
frequency are shown in Table 2. The relative
frequencies of MM, MT and TT genotypes were4%, 31% and 65%, respectively. The allele frequencies were 19% and 81% for M and T alleles,
respectively. These results are consistent with
the Hardy-Weinberg equilibrium, not only forthe total subjects, but also when divided according to the presence of dyslipidemia. Neither the
genotype nor the allele frequency showed statistic
signiﬁcance between the dyslipidemia and control
groups.
The differences of quantitative variables between genotypes are shown in Table 3. Although
it was not signiﬁcant, the subjects carrying the M
allele had higher TC. On the other hand, no suchdifferences were seen in either HDL or TG.
The relationships between genotype and dyslipidemia and its components estimated by unconditional logistic regression analysis are shown in
Table 4. No signiﬁcant relationship was observed,
both in univariate and multivariate analysis.

Genome DNA was extracted using a fully automatic nucleic acid extractor (MagExtractor Genome, Toyobo, Osaka, Japan). The PCR mutant
allele specific amplification (MASA) method
was employed to analyze the AGT gene M235T
polymorphism and genotyping, M235M (MM),
M235T (MT) and T235T (TT), respectively.
Details of the molecular approach of this study
have been described previously (Kishimoto et al.,2001a, 2001b).
Because there was quite a small proportionof the MM genotype (3.8, 30.6 and 65.6% for
MM, MT and TT, respectively), genotype speciﬁc
evaluation was performed in three genotypes, andMM and MT were combined against TT.
Statistical analysis
The software SAS (SAS Institute, Cary, NC) was
employed for all statistical analysis. The eligible
subjects were divided into two groups according
to dyslipidemia to compare the AGT gene M235T
genotype distribution using a Mantel-Haenszel
chi-square test. The unpaired analysis of results
using a Kruskal-Wallis test was performed to assess whether the differences of the quantitative
variables between genotypes were significant.
These analyses were performed on all the subjects, sex and age speciﬁcally. According to the“Guidelines for Diagnosis and Treatment of Atherosclerotic Cardiovascular Disease 2002” of theJapan Atherosclerosis Society (Saito, 2004), eligible subjects were divided into younger and older
groups with cutoff ages of 45 for males and 55
for females. Moreover, univariate and multivariate unconditional logistic regression analysis was
employed to evaluate the relationship between the

Discussion
The relative frequencies of the AGT gene M235T
polymorphism in all eligible subjects were 4, 31
51

A. Kaetsu et al.

Table 1. Descriptive characteristics
Control

Dyslipidemia

Number of subjects
1158
Male subjects
(%)
48.3%
Older subjects; age ≥ 45 in males, ≥ 55 in females
Ratio
(%)
24.9%
Age, mean ± SD
(year)
40.3 ± 11.6
Obese subjects; BMI > 25
Ratio
(%)
16.3%
BMI, mean ± SD
22.1 ± 3.1
Hypertension; SBP ≥ 140 and/or DBP ≥ 90 mmHg
Occurence ratio
(%)
13.7%
SBP ≥ 140 mmHg
Occurence ratio
(%)
10.2%
Mean ± SD(mmHg)
116.8 ± 16.6
DBP ≥ 90 mmHg
Occurence ratio(%)
9.8%
Mean ± SD(mmHg)
72.6 ± 11.5
Dyslipidemia
Occurence ratio(%)
0.0%
TC ≥ 220 mg/dL
Occurence ratio(%)–
Mean ± SD(mg/dL)184.0 ± 22.4
HDL < 40 mg/dL
Occurence ratio(%)–
Mean ± SD(mg/dL)
66.7 ± 14.7
TG ≥ 150 mg/dL
Occurence ratio(%)–
Mean ± SD(mg/dL)74.5 ± 29.7
Hyperglycemia; FBS ≥ 110 mg/dL
Occurence ratio(%)
8.9%
Mean ± SD(mg/dL)96.5 ± 13.7
Alcohol drinking
Current ratio
(%)
23.9%
Smoking
Current ratio
(%)
30.1%

876
66.0%

Total
2034
55.9%

P
< 0.0001

42.2%
45.3 ± 10.3

31.9%
42.4 ± 11.3

< 0.0001< 0.0001

34.7%
23.8 ± 3.0

23.9%
22.9 ± 3.2< 0.0001< 0.0001

28.5%

19.8%

< 0.0001

20.5%
125.2 ± 17.5

14.5%
120.4 ± 17.5

< 0.0001< 0.0001

21.5%
78.8 ± 12.2

14.7%
75.2 ± 12.2

< 0.0001< 0.0001

100.0%

43.1%

74.3%
232.5 ± 36.9

32.0%
204.9 ± 38.1

< 0.0001

11.2%
62.0 ± 19.3

4.8%
64.7 ± 17.0

< 0.0001

43.7%
158.7 ± 108.1

18.8%
110.8 ± 85.3

< 0.0001

16.7%
102.0 ± 21.8

12.2%
98.8 ± 17.8

< 0.0001< 0.0001

34.7%

28.6%

< 0.0001

42.1%

35.3%

< 0.0001

Dyslipidemia: at least one of the following features: TC ≥ 220, HDL < 40 and TG ≥ 150 mg/dL.
BMI, body mass index; DBP, diastolic blood pressure; FBS, fasting blood sugar; HDL, high density lipoprotein-colesterol;
SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride.
P: P value for difference between dyslipidemia and control subjects.
P values were determined by chi-square (sex, older, obese, hypertension, dyslipidemia, hyperglycemia, alcohol drinking
and smoking) and Wilcoxon rank sum test (age, BMI, TC, HDL, TG and FBS).

and 65% for the MM, MT and TT genotypes,
respectively. Although it was not signiﬁcant, thesubjects carrying the M allele had higher TCs.
No signiﬁcant relationship was observed, both inunivariate and multivariate unconditional logistic
regression analysis.
The genotype distribution of this polymorphism of the present study was close to the result

reported by Thomas et al. (2001). Since the ethnically different genotype distribution of this polymorphism has been reported (Rodriguez-Perez etal., 2000), it may represent the ethnic proximity
in the genetic backgrounds between the two study
populations. On the other hand, the relationshipbetween the polymorphism and TC occurred in areversed manner. They reported that the subjects
52

AGT M235T and dyslipidemia

Table 2. Angiotensinogen M235T genotypes and allele frequencies with dyslipidemia
Control
All subjects
Number
Genotype

1158
T/T
770 ( 66.5)
M/T
344 ( 29.7)
M/M
44 ( 3.8)
M/T + M/M
388 ( 33.5)
Allele frequency T allele
1884 ( 81.3)
M allele
432 ( 18.7)
Male subjects
Number
559
Genotype
T/T
389 ( 69.6)
M/T
150 ( 26.8)
M/M
20 ( 3.6)
M/T + M/M
170 ( 30.4)
Allele frequency T allele
928 ( 83.0)
M allele
190 ( 17.0 )Female subjects
Number
599
Genotype
T/T
381 ( 63.6)
M/T
194 ( 32.4)
M/M
24 ( 4.0)
M/T + M/M
218 ( 36.4)
Allele frequency T allele
956 ( 79.8)
M allele
242 ( 20.2)
Younger subjects; age < 45 in males, < 55 in females
Number879
Genotype
T/T
572 ( 65.1)
M/T
271 ( 30.8)
M/M
36 ( 4.1)
M/T + M/M
307 ( 34.9)
Allele frequency T allele
1415 ( 80.5)
M allele
343 ( 19.5)
Older subjects; age < 45 in males, < 55 in females
Number
279
Genotype
T/T
98 ( 71.0)
M/T
73 ( 26.2)
M/M
8 ( 2.9)
M/T + M/M
81 ( 29.0)
Allele frequency T allele
469 ( 84.1)
M allele89 ( 15.9)

Dyslipidemia

Total

876
564 ( 64.4)
278 ( 31.7)
34 ( 3.9)
312 ( 35.6)
1406 ( 80.3)
346 ( 19.7)

2034
1334 ( 65.6)
622 ( 30.6)
78 ( 3.8)700 ( 34.4)
3290 ( 80.9)778 ( 19.1)

578
374 ( 64.7)
191 ( 33.1)
13 ( 2.2)
204 ( 35.3)
939 ( 81.2)
217 ( 18.8)

1137
763 ( 67.1)
341 ( 30.0)
33 ( 2.9)374 ( 32.9)
1867 ( 82.1)
407 ( 17.9)

298
190 ( 63.8)
87 ( 29.2)
21 ( 7.0)
108 ( 36.2)
467 ( 78.4)
129 ( 21.6)

897
571 ( 63.7)
281 ( 31.3)
45 ( 5.0)326 ( 36.3)
1423 ( 79.3)
371 ( 20.7)506
326 ( 64.4)
161 ( 31.8)
19 ( 3.8)
180 ( 35.6)
813 ( 80.3)
199 ( 19.7)

1385
898 ( 64.8)
432 ( 31.2)
55 ( 4.0)
487 ( 35.2)
2228 ( 80.4)
542 ( 19.6)

370
238 ( 64.3)
117 ( 31.6)
15 ( 4.1)
132 ( 35.7)
593 ( 80.1)
147 ( 19.9)649
436 ( 67.2)
190 ( 29.3)
23 ( 3.5)
213 ( 32.8)
1062 ( 81.8)
236 ( 18.2)

P

0.3816
0.3447†0.37880.92240.0913†0.27780.48681.0000†0.47690.92240.8537†0.92200.07270.0891†0.0702

P: P value for difference between dyslipidemia and control subjects.
P values were determined by chi-square test.
† Compared to T/T.

carrying the M allele of the AGT gene M235T
polymorphism (MM/MT) had signiﬁcantly lower
TC than those with the TT genotype. Furthermore, a linear dose-dependent relationship between the genotypes for TC was demonstrated.
However, our result showed that the M allele hadhigher TC, though it was not significant. According to other investigations, which described
the relationship between the AGT gene M235T
polymorphism and TC, some reported the M allele had lower TC, equivalent to Thomas et al.
(Iwai et al., 1995; Nishimura et al., 1995; Batalla
53

A. Kaetsu et al.

Table 3. Mean value of serum lipids and other variables according to AGT M235T genotype
TT

MT

MM

MT + MMPP†

All subjects
NumberTC(mg/dL)HDL (mg/dL)TG(mg/dL)BMI (kg/m2)
SBP (mmHg)
DBP (mmHg)
FBS (mg/dL)

1334
203.6 ± 36.2
64.7 ± 17.2
108.7 ± 79.5
23.0 ± 3.2
120.8 ± 17.3
75.5 ± 12.0
99.0 ± 18.1

622
206.6 ± 41.6
64.6 ± 16.6
116.1 ± 97.8
22.6 ± 3.2
120.1 ± 17.9
72.0 ± 12.6
98.7 ± 17.7

78
213.2 ± 39.3
65.1 ± 16.7
102.7 ± 70.9
22.7 ± 3.1
116.0 ± 17.9
73.4 ± 11.9
97.7 ± 13.5

700
207.4 ± 41.4
64.7 ± 16.6
114.6 ± 95.2
22.6 ± 3.2
119.7 ± 17.9
74.8 ± 12.5
98.6 ± 17.2

0.18160.99980.5886
0.06870.04640.2767
0.66350.26270.98550.38530.02190.09920.23110.3669Male subjects
NumberTC(mg/dL)HDL (mg/dL)TG(mg/dL)BMI (kg/m2)
SBP (mmHg)
DBP (mmHg)
FBS (mg/dL)

763
203.0 ± 36.0
59.6 ± 16.4
132.8 ± 91.1
23.6 ± 3.1
124.8 ± 16.5
78.6 ± 11.9
101.9 ± 20.6

341
210.6 ± 41.5
60.0 ± 15.6
146.3 ± 112.7
23.3 ± 3.1
124.8 ± 16.1
78.6 ± 12.1
101.8 ± 20.0

33
204.5 ± 35.5
62.1 ± 17.2
117.6 ± 94.9
23.1 ± 2.6
119.4 ± 18.8
76.1 ± 13.1
97.7 ± 9.9374210.1 ± 41.0
60.2 ± 15.8
143.8 ± 111.5
23.3 ± 3.1
124.3 ± 16.4
78.3 ± 12.2
101.5 ± 19.4

0.04930.67890.03040.43470.20260.45100.50620.01990.44190.16510.2227
0.63680.85680.3140Femle subjects
NumberTC(mg/dL)HDL (mg/dL)TG(mg/dL)BMI (kg/m2)
SBP (mmHg)
DBP (mmHg)
FBS (mg/dL)

571
204.4 ± 36.4
71.4 ± 15.9
76.6 ± 43.3
22.2 ± 3.2
115.5 ± 16.9
71.2 ± 10.8
95.1 ± 13.2

281
201.8 ± 41.3
70.3 ± 16.1
79.4 ± 57.5
21.8 ± 3.1
114.5 ± 18.4
70.7 ± 11.9
94.8 ± 13.3

45
219.6 ± 41.0
67.3 ± 16.1
91.8 ± 44.2
22.4 ± 3.5
113.5 ± 17.0
71.4 ± 10.6
97.8 ± 15.7

326
204.3 ± 41.7
69.9 ± 16.1
81.1 ± 56.0
21.9 ± 3.2
114.4 ± 18.2
70.8 ± 11.7
95.2 ± 13.7

0.01120.10770.02380.18900.30180.50970.65070.38790.10300.39630.13280.12250.37880.5979Younger subjects; age < 45 in males, < 55 in females
Number898
432
TC(mg/dL)200.3 ± 35.9
201.2 ± 40.7
HDL (mg/dL)
66.7 ± 17.2
66.1 ± 16.8
TG
(mg/dL)98.3 ± 76.4
101.6 ± 83.0
BMI (kg/m2)
22.6 ± 3.2
22.2 ± 3.2
SBP (mmHg)
116.5 ± 15.3
115.6 ± 15.7
DBP (mmHg)
72.2 ± 10.7
71.5 ± 11.5
FBS (mg/dL)
95.9 ± 12.1
95.3 ± 12.6

55
205.5 ± 38.1
64.5 ± 15.8
96.8 ± 80.8
22.2 ± 3.1
111.9 ± 15.1
70.7 ± 10.7
93.8 ± 8.3

487
201.7 ± 40.4
65.9 ± 16.6
101.0 ± 82.7
22.2 ± 3.2
115.2 ± 15.7
71.4 ± 11.4
95.1 ± 12.2

0.70190.50440.92110.10280.08430.21030.34500.8596
0.36830.72870.03310.11410.08690.1565

Older subjects; age ≥ 45 in males, ≥ 55 in females
Number436
190
TC(mg/dL)210.3 ± 35.8
219.0 ± 40.9
HDL (mg/dL)
60.4 ± 16.3
61.4 ± 15.9TG
(mg/dL)130.3 ± 81.5
149.2 ± 118.9
BMI (kg/m2)
23.7 ± 3.0
23.5 ± 3.0
SBP (mmHg)
129.7 ± 17.7
130.3 ± 18.4
DBP (mmHg)
82.1 ± 11.9
83.0 ± 11.3
FBS (mg/dL)
105.4 ± 25.4
106.5 ± 24.0

23231.7 ± 36.4
66.5 ± 18.8
116.9 ± 35.7
23.9 ± 2.9
125.7 ± 20.4
79.9 ± 12.1
107.2 ± 18.3

213
220.4 ± 40.6
62.0 ± 16.3
145.7 ± 113.3
23.6 ± 3.0
129.8 ± 18.6
82.7 ± 11.4
106.5 ± 23.4

0.0066
0.38990.18010.51980.73070.36350.36940.00610.32780.07200.5649‡0.91900.40730.2070

P: P value for difference between TT versus MT versus MM by Kruskal-Wallis test.
P†: P value for differences between TT versus MT + MM by Wilcoxon rank sum test.
‡ P value for differences between TT versus MT + MM by Student’s t-test

54

AGT M235T and dyslipidemia

Table 4. Odds ratios of AGT M235T genotype for dyslipidemia

Dyslipidemia
TT
MT
MM
P‡
0.3816TT
MT + TTP‡
0.3447TC, ≥ 220 mg/dL
TT
MT
MM
P‡
0.1742TT
MT + TTP‡
0.2730
HDL, < 40 mg/dL
TT
MT
MM
P‡
0.3101TT
MT + TTP‡
0.4168TG, ≥ 150 mg/dL
TT
MT
MM
P‡
0.8794TT
MT + TTP‡
0.7033OR

Univariate
95% CIP

OR

Multivariate†
95% CI

770
344
44

1.00
1.10
1.06

0.91 – 1.34
0.67 – 1.67

0.31400.8200

1.00
1.22
1.20

0.99 – 1.50
0.74 – 1.97

0.05850.4609

564
312

770
388

1.00
1.10

0.91 – 1.32

0.32041.00
1.22

1.00 – 1.49

0.0508

416
205
30

918
417
48

1.00
1.09
1.38

0.89 – 1.33
0.86 – 2.21

0.43260.1806

1.00
1.16
1.42

0.94 – 1.43
0.87 – 2.31

0.17580.1633

416
235

918
465

1.00
1.12

0.92 – 1.36

0.27301.00
1.18

0.97 – 1.45

0.101768 1266
28 594
2
76

1.00
0.88
0.49

0.56 – 1.38
0.12 – 2.04

0.57020.3265

1.00
0.95
0.66

0.60 – 1.50
0.16 – 2.82

0.81920.5781

68 1266
30 6701.00
0.83

0.54 – 1.29

0.41731.00
0.92

0.59 – 1.44

0.7191

248 1086
125 497
10
68

1.00
1.10
0.64

0.87 – 1.40
0.33 – 1.27

0.43000.2033

1.00
1.21
0.89

0.93 – 1.57
0.43 – 1.82

0.16310.7415

248 1086
135 565

1.00
1.05

0.83 – 1.32

0.70201.00
1.17

0.91 – 1.52

0.2238

+

–

564
278
34

P

Dyslipidemia: at least one of the following features: TC ≥ 220, HDL < 40 and TG ≥150 mg/dL.
CI, conﬁdence interval; OR, ddds ratio.
† Adjusted for sex, age, BMI, FBS, alcohol and smoking.
‡ P for chi-square.

al., 2004), the relationship may in fact be weak oreven nonexistent.
Although this work-site cross-sectional study
was employed to investigate the relationship between the AGT gene M235T polymorphism andserum lipids more closely to general population
than a hospital-based case-control study, some
limitations remain in this study. First, the presence of the healthy worker’s effect was suspected.
The possibility that the exclusion of unhealthy
subjects from the study population inﬂuenced theet al., 2000), and some reported the M allele hadhigher TC, equivalent to our ﬁndings (Matsubara
et al., 2003), others still showed no relationship(Iwai et al., 1994; Katsuya et al., 1995; Hingorani
et al., 1996; Fujiwara et al., 2002; Robinson etal., 2004). Because the relationship between thispolymorphism and TC was not stable among theinvestigations, and the mechanism by which RAS
influences the lipid metabolism directly has notbeen discovered (Nishimura et al., 1995; Wierzbicki et al., 2000; Singh et al., 2003; Strazzullo et55

A. Kaetsu et al.

result cannot be denied. Second, the relationships among study subjects were not conﬁrmed.
The possibility that relatives and siblings showedsimilar characteristics and inﬂuenced the resultscannot be denied. Third, the present and pastillnesses of each subject were not evaluated. Because our data originated from the work-site, thehistory of each subject was not obtained in moredetail than the hospital-based data. However, inthe current clinical situation of Japanese hypertension therapy, medication is administered subsequent to lifestyle modification (Saruta, 2005).
That lifestyle modification improves cardiovascular risk factors, including serum lipids among
general population, has been reported (Okazaki
et al., 2001). Furthermore, it was reported thatthe subjects with the TT homozygote of the AGT
M235T genotype had a higher prevalence of antihypertension medication among middle-aged
Japanese men (Nishimura et al., 1995). By notconsidering the present and past history of eachsubject, the possibility that the underestimation of
the serum lipids of the subjects carrying the T allele cannot be denied. A prospective cohort study
should be performed for a more conclusive evaluation.

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from the Ministry of Education, Science, Sports and Culture of Japan.

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Received December 22, 2005; accepted January 10, 2006
Corresponding author: Akihiko Kaetsu, MD, PhD

58