PGC1alpha Gly482Ser Polymorphism is Associated with Habitual Levels

of Physical Activity
Nanci S Guest, Andrea R Josse, Ahmed El-Sohemy
NUTRITIONAL SCIENCES, UNIVERSITY OF TORONTO, TORONTO, ON, CANADA
ABSTRACT
The peroxisome proliferator-activated receptor-gamma co-activator-1alpha
(PGC1alpha) gene has been shown to play an important role in skeletal muscle
and energy metabolism. This has implications for exercise performance and
physiology, and may also influence disease risk pathways. Genetic variation in
PCG1alpha may affect habitual physical activity (PA) levels. We aimed to
determine whether the Gly482Ser (rs8192678) polymorphism in the PCG1alpha
gene affects habitual PA levels and if this in turn affects biomarkers of
cardiometabolic risk (e.g. glucose, Insulin, triglycerides, cholesterol) body
mass index (BMI) and waist circumference (WC). Fasting blood samples were
collected and DNA was analyzed from Caucasian subjects (n=722) aged 20-29
years from the Toronto Nutrigenomics and Health Study (TNH). Subjects
completed questionnaires on PA and general health. PA was quantified as
metabolic task equivalent (MET) hrs/wk. Subjects were divided into 2 groups
according to the median PA level of 8 MET-hrs/wk. We examined the Gly482Ser
polymorphism against the 2 levels of PA using logistic regression adjusted for
age, sex, and BMI. We then assessed whether cardiometabolic risk factors,
BMI, WC and mean levels of PA differed between genotypes using ANCOVA.
Individuals who were Ser/Ser homozygous were significantly more physically
active than Gly/Gly homozygotes, but Gly/Ser heterozygotes were not.
Compared to those with the Gly/Gly genotype, the OR (95% CIs) for the Gly/Ser
and Ser/Ser genotypes were 1.15 (0.84-1.58) and 2.21 (1.34-3.63), respectively.
Mean levels of PA were greater for Ser/Ser ([MeanSE] 9.00.3 MET-hrs/wk)
than Gly/Gly (8.00.2 MET-hrs/wk) (P=0.014), but not with Gly/Ser (8.30.2 METhrs/wk). There were no significant differences between genotypes for any
cardiometabolic risk or anthropometric biomarkers. In summary, the Gly482Ser
polymorphism in the PCG1alpha gene is associated with habitual PA levels
such that subjects with the Ser/Ser genotype have higher PA levels than those
with the Gly/Gly genotype. Further study is needed to elucidate the mechanism
by which this variant in PGC1alpha affects PA levels.

INTRODUCTION

PGC-1alpha is a member of a family of transcription co-activators that plays a

central role in the regulation of cellular energy metabolism

Increases in energy production driven by PGC-1alpha and activated gene

regulatory programs helps to equip cells to meet the energy demands of a
changing environment, including augmentation of mitochondrial biogenesis,
cellular respiration rates and energy substrate uptake and utilization [1, 2]

PGC-1alpha largely mediates the adaptive response of skeletal muscle to

endurance exercise, which includes a reduction in lactate generation along with
the remodeling of muscle tissue to a fiber-type composition (slow-twitch fibers)
that is metabolically more oxidative and less glycolytic in nature [3, 4]
Genetic variation within the Gly482Ser polymorphism of the PGC1apha gene
has been associated with endurance performance in athletes, where the
Gly482 allele (wildtype) has been shown to be the most beneficial or common
genotype in elite endurance athletes [5-7].

In contrast, the 482Ser allele has been associated with cardiometabolic risk
factor biomarkers such as high blood pressure [8] as well as type 2 diabetes [9,
10] and obesity [11, 12] possibly through PCG1-alphas regulatory function in
lipid and carbohydrate metabolism [1]

This has implications for exercise performance and physiology, and may also
influence disease risk pathways. Associations between the Gly482Ser
polymorphism of the PCG1alpha gene with habitual physical activity levels and
cardiometabolic risk factors have not been studied in a young adult population.

OBJECTIVES

To determine whether the Gly482Ser (rs) polymorphism in the PCG1alpha

gene affects habitual PA levels
To determine if this association, if present, affects biomarkers of
cardiometabolic risk (e.g. glucose, Insulin, triglycerides, cholesterol) body
mass index [BMI] and waist circumference [WC])

METHODS

RESULTS

Study Design and Participants: Subjects were part of the Toronto Nutrigenomics and Health (TNH) study, a cross-sectional
examination of Caucasian (n=722) men and women aged 20-29 years. Participants gave a fasting blood sample and completed a
general health and lifestyle questionnaire (GHLQ), including a physical activity questionnaire, and a food frequency questionnaire.
Anthropometric measurements, including height, weight, BMI, WC and resting blood pressure were taken when participants were
dressed in light clothing and no shoes, as described previously [13]
Physical Activity (PA) Assessment: Habitual PA was measured by questionnaire and was expressed as metabolic equivalent task
(MET)-hours per week. Habitual (over the previous month) weekday and weekend activity was recorded separately and then combined to
total 7 days. PA MET intensity levels were assigned based on previously published work [14]
Genotyping: The Gly482Ser (rs8192678) SNP was genotyped using the iPLEX Gold assay on the Sequenom MassARRAY platform at
the Clinical Genomics Centre (Mount Sinai Hospital, Toronto, ON)[13]
Statistical Analyses: Statistical analyses were carried out using SAS (version 9.2; SAS Institute Inc, Cary, NC, USA). Subjects were
divided into 2 groups according to the median PA level of 8 MET-hrs/wk to carry out the logistic regression analysis (median PA level by
genotype)

RESULTS

Characteristic
Age (y)
Female sex (%)
BMI (kg/m2)
Waist Circumference (cm)
Energy intake (kcal/d)
Energy from carbohydrates (%
per day)
Energy from protein (% per day)
Energy from fat (% per day)
Sucrose (g/d)
Alcohol intake (g/d)

23.12
70
23.36
76.05
2013.07

> 8 MET
hrs/wk

2.56

p-value

23.39 2.58
67
3.52
23.34 3.5
8.86
75.59 8.71
606.94 2097.06 686.55

52.07 7.94
16.7 2.82
30.92 6.46
45.96 23.11
7.57 9.37

52.04 8.31
16.88 3.38
30.51 6.53
49.07 25.68
9.36 12.48

0.15
0.20
0.93
0.47
0.08

8 MET hrs/wk
GG
23.52 3.4

GA (n=308)

AA (n=88)

8.3 3.1

9.0 2.7*

48

33

52
0.008
1.14 (0.83 1.55)
1.15 (0.84 1.58)

67

0.97
0.43
0.4
0.18
0.03

> 8 MET hrs/wk

GA
AA
GG
23.28 3.6 23.32 3.76 22.88 3.17

GA
23.8 3.66

2.16 (1.32 3.55)

2.21 (1.34 3.63)

In the Gly482Ser polymorphism in the PCG1alpha gene

subjects with the Ser/Ser genotype have higher PA levels
than those with the Gly/Gly genotype
Increased PA seen in the Ser/Ser genotype is in contrast to
athletic populations showing Gly/Gly to be more commonly
associated with endurance and higher values of aerobic
performance [7,8]. However, our self-reported measurements
of PA in a non-athletic population would not detect such
differences in endurance capacities

Table 2. Relationship between genotype of the Gly482Ser (rs8192678) SNP and cardiometabolic risk factors stratified by median MET level. There were no significant
differences between any of the groups.

Risk Factor

Gly482Ser
(rs8192678)
GG (n=326)
mean METhrs/wk
SD
8.0 3.0
8 MET hrs/wk
(%)
52
> 8 MET hrs/wk
(%)
48
2 p-value
Model 1 - OR
(95% CI)
1.00
Model 2 - OR
(95% CI)
1.00

CONCLUSIONS

Table 1. Subject characteristics stratified by median PA level.

8 MET
hrs/wk

Table 3. Results of the square and logistic regression analyses of the Gly482Ser (rs8192678)
SNP. Model 1 is unadjusted, model 2 is adjusted for age, sex, BMI. *P=0.014 vs. GG.

AA
23.49 3.87

BMI (kg/m2)
Waist
Circumference (cm) 76.79 8.92 75.42 8.92 75.74 8.45 74.8 8.12
76.66 9.32 75.41 8.54
116.12
112.83
116.92
114.83
Systolic BP (mmHg)
11.68
114.7 11.09
10.15
11.11
116.54 11.82
10.88
Diastolic BP
(mmHg)
69.99 7.72 69.19 7.9 68.17 5.81 69.42 7.58 70.03 8.93 69.37 8.84
50.93
37.89
38.24
insulin (pmol/l)
57.47
43.4 25.59
22.91
41.4 32.9 45.08 25.69
20.62
glucose (mmol/l)
4.75 0.35
4.72 0.3
4.83 0.41 4.75 0.35
4.76 0.34
4.79 0.3
total Cholesterol
(mmol/l)
4.24 0.78 4.19 0.76 4.06 0.65 4.24 0.78
4.26 0.85
4.35 0.76
LDL (mmol/l)
2.28 0.66
2.2 0.53
2.11 0.52 2.24 0.68
2.28 0.65
2.3 0.66
HDL (mmol/l)
1.5 0.37
1.56 0.42
1.57 0.3
1.58 0.41
1.53 0.42
1.6 0.34
Triglycerides
(mmol/l)
1.03 0.46 0.94 0.39 0.83 0.25 0.93 0.41
1.03 0.73
1 0.44

There were no significant differences between genotypes for

any cardiometabolic risk or anthropometric biomarkers, which
is expected in a healthy young adult population, but is also in
contrast to other studies where Ser/Ser genotype is
associated with obesity, BP and T2DM [9-12]
Further study is needed to elucidate the mechanism by which
this variant in PGC1alpha affects PA levels, and if this
translates into the exercise-mediated change in PGC1alpha
expression that regulates mechanisms that may provide
protection against cardiometabolic disease

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Acknowledgements: