APOA5 genotype modulates 2-y changes in lipid profile in response to
weight-loss diet intervention: the Pounds Lost Trial1–3
Xiaomin Zhang, Qibin Qi, George A Bray, Frank B Hu, Frank M Sacks, and Lu Qi
Background: The apolipoprotein A5 gene (APOA5) is a major gene
that regulates lipid metabolism and is modulated by dietary factors.
A novel variant rs964184 in APOA5 was identified to be associated
with lipids in genome-wide association studies.
Objective: We examined whether this variant modified changes in
lipid concentrations in response to a 2-y weight-loss diet interven-
tion in a randomized trial.
Design: The current analyses were secondary analyses of a data set
from the Pounds Lost Trial. We genotyped APOA5 rs964184 in 734
overweight or obese adults who were randomly assigned to one of 4
diets that differed in percentages of energy derived from fat, protein,
and carbohydrate for 2 y. We evaluated changes in fasting serum
concentrations of total cholesterol (TC), LDL cholesterol, HDL
cholesterol, and triglyceride from baseline to 2 y of follow-up.
Results: After a 2-y dietary intervention, we showed significant
interactions between the APOA5 rs964184 polymorphism and di-
etary fat intake (low compared with high) in the determination of
changes in TC, LDL cholesterol, and HDL cholesterol (P-interaction
= 0.007, 0.017, and 0.006, respectively). In the low-fat intake group
(20% of energy derived from fat), carriers of the risk allele (G
allele) exhibited greater reductions in TC and LDL cholesterol than
did noncarriers (P = 0.036 and 0.039, respectively), whereas in the
high-fat diet group (40% of energy derived from fat), participants
with the G allele had a greater increase in HDL cholesterol than did
participants without this allele (P = 0.038).
Conclusion: Our data showed better improvement in lipid profiles
from long-term low-fat diet intake in the APOA5 rs964184 risk
allele. The Pounds Lost Trial was registered at clinicaltrials.gov
as NCT00072995. Am J Clin Nutr 2012;96:917–22.
Unfavorable blood lipid concentrations, including high tri-
glyceride, total cholesterol (TC), and LDL cholesterol and low
HDL cholesterol, have been associated with increased risk of
cardiovascular disease (1–3). Lipid profiles are determined by
interactions between genetic and environmental factors, such as
diet and lifestyle (4). Genetic variants in the apolipoprotein A5
gene (APOA5), which are located in the APOA1-APOC3-
APOA4-APOA5 gene cluster on human chromosome 11q23, are
widely studied in relation to lipid profiles in candidate gene
studies (5–8). In addition, observational studies and short-
term (,3 mo) intervention trials have shown that several com-
mon variants in the APOA5 gene interact with dietary factors,
especially dietary fat, in the determination of blood lipid
concentrations (5, 9–17). However, gene-diet interactions in
long-term randomized intervention settings have been rarely
In genome-wide association studies, a novel variant rs964184
in the APOA5 locus was identified to be associated with in-
creased triglyceride, TC, and LDL cholesterol and decreased
HDL cholesterol for the risk allele (18–21). Furthermore, this
variant showed the strongest associations with serum tri-
glyceride concentrations in a dyslipidemic population (22).
rs964184 resides 11 kb upstream of APOA5 and in the 5# un-
translated region of a zinc finger protein, which may be involved
in signal transduction and have multiple physiologic functions
(22). However, to our knowledge, no study has examined the
effect of rs964184 on protein function or availability. In the
current study, we aimed to investigate whether the APOA5
rs964184 genotype may interact with weight-loss diets that vary
in macronutrients on 2-y changes in lipid concentrations in the
randomized intervention study the Pounds Lost Trial (www.
1From the Departments of Nutrition (XZ, QQ, FBH, FMS, and LQ) and
Epidemiology (FBH), Harvard School of Public Health, Boston, MA; the
Department of Occupational and Environmental Health and the Ministry of
Education Key Laboratory of Environment and Health, School of Public
Health, Tongji Medical College, Huazhong University of Science and Tech-
nology, Wuhan, China (XZ); the Pennington Biomedical Research Center of
the Louisiana State University System, Baton Rouge, LA (GAB); and the
Channing Laboratory, Department of Medicine, Brigham and Women’s Hos-
pital and Harvard Medical School, Boston, MA (FBH, FMS, and LQ).
2Supported by the National Heart, Lung, and Blood Institute (grant
HL071981), the General Clinical Research Center (grant RR-02635), the
Boston Obesity Nutrition Research Center (grant DK46200), the National
Institute of Diabetes and Digestive and Kidney Diseases (grant DK091718),
an American Heart Association Scientist Development Award (0730094N; to
LQ), the National Natural Science Foundation of China (NNSFC 30972453;
to XZ), and the Program for New Century Excellent Talents in University
3Address correspondence and reprint requests to L Qi, Department of
Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston,
MA 02115. E-mail: email@example.com; or X Zhang, Department
of Occupational and Environmental Health and the Ministry of Education
Key Laboratory of Environment and Health, School of Public Health, Tongji
Medical College, Huazhong University of Science and Technology, Wuhan
430030, China. E-mail: firstname.lastname@example.org.
Received April 9, 2012. Accepted for publication June 28, 2012.
Firstpublished online August 22, 2012; doi: 10.3945/ajcn.112.040907.
Am J Clin Nutr 2012;96:917–22. Printed in USA. ? 2012 American Society for Nutrition
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