Fig. 1. Body mass index, fasting insulin, total triglyceride and HDL-cholesterol levels according to the Pro12Ala substitution of the PPARg2 gene in study groups. Subjects with the Pro12Pro genotype are shown in white bars, subjects with the Pro12Ala genotype in shaded bars and subjects
with the Ala12Ala genotype in black bars. Number of cases summarized in each bar is shown in Table 2.
The frequencies between the study groups were com- pared with the chi-square test. The effect of the variants
on continuous variables was tested by ANCOVA in unrelated elderly subjects and by family-based associa-
tion analysis with the program ASSOC in FCHL families [38]. The ASSOC program uses linear regres-
sion analysis allowing the quantitative trait to have familial correlation among individuals. The likelihood
for the pedigree is computed with a linear regression model in which the quantitative trait is the dependent
variable and the genetic variation, discrete andor con- tinuous covariates are independent variables. Residual
variation is modeled assuming an additive polygenic pattern of correlation among relatives. Using this
model the likelihood for each pedigree was maximized twice, with and without the genetic variant in the
model. The difference in natural logarithms of these two maximized likelihoods follows chi-square distribu-
tion from which the corresponding P-value is taken with two degree of freedom three groups of genotypes
or with one degree of freedom subjects with or without a definite genotype. Gender was included as a discrete
covariate and age as a continuous covariate in all analyses. Insulin and triglyceride values were logarith-
mically transformed before analysis in order to achieve normal distribution. All data are presented as mean 9
SD.
P-value B 0.05 was
considered statistically
significant.
3. Results
Nondiabetic elderly subjects with dyslipidemia had higher BMI P = 0.002, adjusted for age and gender
and higher levels of glucose P = 0.005, insulin P B 0.001, total cholesterol P B 0.001, total triglycerides
P B 0.001 and apoB P B 0.001 and lower levels of HDL-cholesterol P B 0.001 than subjects without dys-
lipidemia. In addition to being more dyslipidemic higher total cholesterol, total triglycerides and apoB,
P B 0.001, FCHL family members were younger P B 0.001 and had higher gender- and age-adjusted insulin
levels P = 0.026 compared to elderly subjects without dyslipidemia Table 1.
Allele frequencies of the Pro12Ala polymorphism of the PPARg gene did not differ between elderly subjects
with 0.17 or without 0.14 dyslipidemia or probands with FCHL 0.15, P = ns. Genotype frequencies fol-
lowed the Hardy – Weinberg equilibrium in all study groups. The Pro113Gln substitution was not found in
any of the FCHL family members.
In FCHL family members, fasting insulin levels were associated with the Pro12Ala substitution of the
PPARg2 gene
72.6 9 72.0 in
subjects with
the Pro12Pro genotype vs. 83.4 9 59.4 in subjects with the
Pro12Ala genotype vs. 46.8 9 16.8 pmoll in subjects with the Ala12Ala genotype, P = 0.036 ANCOVA over
J .
Pihlajama ¨k
ie ta
l. Atherosclerosis
151 2000
567 –
574
571 Table 2
Body mass index, waist to hip ratio and fasting glucose, insulin and lipid and lipoprotein levels according to the Pro12Ala substitution of the PPARg2gene in the study groups
a
FCHL family members Elderly subjects with dyslipidemia
Elderly subjects without dyslipidemia ProAla
AlaAla ProPro
ProAla ProPro
AlaAla AlaAla
ProAla ProPro
n = 157 n = 58
n = 457 n = 6
n = 57 n = 16
n = 3 n = 176
n = 164 48109
1542 03
8381 2731
42 7898
Gender MF 511
181276 75.7 9 4.0
51.5 9 15.4 52.3 9 15.1
53.7 9 16.0 73.2 9 2.8
72.6 9 2.8 Age years
73.0 9 2.9 72.8 9 2.8
73.1 9 3.3 28.2 9 4.0
23.3 9 2.8
b
26.1 9 4.2 27.4 9 5.0
24.4 9 1.7 Body mass index
26.7 9 3.9 27.3 9 4.4
26.1 9 4.5 27.0 9 4.4
kgm
2
0.92 9 0.08 0.91 9 0.10
0.92 9 0.09 0.91 9 0.05
0.93 9 0.09 0.95 9 0.08
0.93 9 0.08 0.94 9 0.08
0.94 9 0.08 Waist-to-hip ratio
159 9 27 151 9 22
135 9 19 139 9 21
Systolic BP 134 9 14
153 9 22 153 9 22
160 9 18 155 9 23
mmHg 83 9 9
77 9 16 84 9 11
82 9 12 83 9 11
82 9 8 81 9 10
82 9 10 Diastolic BP
82 9 9 mmHg
5.7 9 1.1 5.9 9 0.9
5.8 9 0.8 5.9 9 1.0
5.6 9 1.1 5.6 9 0.7
5.6 9 0.5 5.6 9 0.8
Fasting glucose 5.5 9 0.5
mmoll 68.4 9 33.6
85.2 9 54.6 102.0 9 65.4
54.6 9 10.8
c
72.6 9 72.0 83.4 9 59.4
46.8 9 16.8
d
65.4 9 42.7 Fasting insulin
55.2 9 22.2 pmoll
7.02 9 1.15 8.48 9 0.75
6.81 9 1.34 6.70 9 1.19
6.30 9 0.83 6.77 9 1.18
7.10 9 1.31 6.09 9 0.88
6.20 9 0.99 Total cholesterol
mmoll 1.18 9 0.32
2.09 9 1.34 2.26 9 1.28
1.07 9 0.35
e
1.97 9 1.33 2.05 9 1.32
1.85 9 0.96 1.37 9 0.50
Total triglycerides 1.33 9 0.45
mmoll 1.23 9 0.33
2.24 9 0.41
f
1.36 9 0.30 1.29 9 0.29
1.50 9 0.30 1.31 9 0.30
1.38 9 0.30 1.33 9 0.39
HDL-cholesterol 1.40 9 0.35
mmoll 1.42 9 0.25
1.34 9 0.34 Apolipoprotein B
1.17 9 0.26 1.04 9 0.18
1.23 9 0.30 1.13 9 0.26
1.05 9 0.18 1.05 9 0.15
1.37 9 0.27 gl
a
All values are mean 9 SD. HDL indicates high-density lipoprotein.
b
P = 0.034,
c
P = 0.050,
d
P = 0.036,
e
P = 0.027,
f
PB0.001 over the three genotypes after adjustment for gender, age.
the three genotypes Fig. 1, Table 2. Subjects with the Ala12Ala genotype had lower levels of fasting insulin
than subjects with the Pro12Pro and Pro12Ala geno- types P = 0.021. However, BMI, waist to hip ratio,
blood pressure, fasting glucose and serum lipids and lipoproteins were not associated with this polymor-
phism in FCHL family members.
In the pooled group of elderly nondiabetic subjects with and without dyslipidemias BMI P = 0.010, fast-
ing insulin P = 0.034, HDL-cholesterol P = 0.002 and total triglycerides P = 0.007 were associated with
the Pro12Ala substitution of the PPARg gene. No associations between the Pro12Ala substitution and
these parameters could be shown in the subgroup of elderly subjects without dyslipidemia n = 649, Table 2.
However, in dyslipidemic elderly subjects n = 217 BMI 27.0 9 4.4 vs. 28.2 9 4.0 vs. 23.3 9 2.8 kgm
2
, P = 0.034,
fasting insulin
levels 85.2 9 54.6
vs. 102.0 9 65.4 vs. 54.6 9 10.8 pmoll, P = 0.050, total
triglyceride levels 2.09 9 1.34 vs. 2.26 9 1.28 vs. 1.07 9 0.35 mmoll, P = 0.027 and HDL-cholesterol levels
1.33 9 0.39 vs. 1.23 9 0.33 vs. 2.24 9 0.41 mmoll, P B 0.001 differed among the three genotypes Fig. 1,
Table 2. No differences were seen between subjects with Pro12Pro and Pro12Ala genotypes. However, the
subjects with the Ala12Ala genotype had higher HDL- cholesterol P B 0.001 levels than subjects with other
genotypes. Still, BMI P = 0.097, fasting insulin P = 0.200 or total triglycerides levels P = 0.088 did not
differ significantly between dyslipidemic elderly subjects with or without the Ala12Ala genotype. We did not
find any association between the Pro12Ala substitution and waist-to-hip ratio, blood pressure, fasting glucose,
total cholesterol or apoB levels in elderly subjects Table 2.
4. Discussion
