Brief Report
Single Nucleotide Polymorphisms of the Peroxisome
Proliferator–Activated Receptor- Gene (PPARA)
Influence the Conversion From Impaired Glucose
Tolerance to Type 2 Diabetes
The STOP-NIDDM Trial
Laura Andrulionyte
,
1
Teemu Kuulasmaa,
1
Jean-Louis Chiasson,
2
and Markku Laakso,
1
for the STOP-NIDDM Study Group*
Peroxisome proliferator–activated receptor (PPAR) ,a
transcription factor of the nuclear receptor superfamily,
regulates fatty acid oxidation. We evaluated the associa-
tion of single nucleotide polymorphisms (SNPs) of the
PPAR- gene (PPARA) with the conversion from impaired
glucose tolerance to type 2 diabetes in 767 subjects of the
STOP-NIDDM trial in order to investigate the effect of
acarbose in comparison with placebo on the prevention of
diabetes. In the placebo group, the G (162V) allele of
rs1800206 increased the risk for diabetes by 1.9-fold (95%
CI 1.05–3.58) and was associated with elevated levels of
plasma glucose and insulin. The effect of this allele on the
risk of diabetes in the placebo group was enhanced by the
simultaneous presence of the risk alleles of the PPAR-2,
PPAR- coactivator 1, and hepatic nuclear factor 4 genes
(odds ratios 2.2, 2.5, and 3.4, respectively). In the acarbose
group, subjects carrying the minor G allele of rs4253776
and the CC genotype of rs4253778 of PPARA had a 1.7- and
2.7-fold increased risk for diabetes. Our data indicate that
SNPs of PPARA increase the risk of type 2 diabetes alone
and in combination with the SNPs of other genes acting
closely with PPAR-. Diabetes 56:1181–1186, 2007
K
ey proteins involved in lipid metabolism are
under the transcriptional control of peroxisome
proliferator–activated receptor (PPAR) (1).
Among the three PPAR subtypes, PPAR- is
found predominantly in the liver, kidney, and heart, where
it upregulates the expression of genes involved in fatty
acid metabolism (1), particularly when activated by
PPAR- coactivator 1 (PGC-1) (2).
PPAR- agonists lower plasma lipid levels, decrease
intrahepatic and skeletal muscle lipid accumulation and
adiposity, and normalize glucose and insulin concentra-
tions, therefore markedly reducing insulin resistance and
the risk of type 2 diabetes (3–5) in various rodent models
of type 2 diabetes and insulin resistance, whereas gemfi-
brozil and fenofibrate can improve insulin sensitivity in
humans (6,7).
Along with regulation of lipid and glucose metabolism,
PPAR- is as an attractive candidate gene for type 2
diabetes. Among previous studies (8,9), only one cross-
sectional study has reported an association of haplotype of
PPARA with the age of diabetes diagnosis (10). Therefore,
we evaluated the association of single nucleotide polymor-
phisms (SNPs) of PPARA with the conversion from im-
paired glucose tolerance (IGT) to type 2 diabetes in
subjects of the STOP-NIDDM trial. Furthermore, the ef-
fects of SNPs of PPARA, along with the SNPs of PPAR-
coactivator 1 (PGC-1A), PPAR-2, (PPARG2), and he-
patic nuclear factor 4 (HNF4A) on the conversion to
diabetes were investigated.
RESEARCH DESIGN AND METHODS
The STOP-NIDDM trial was a double-blind, placebo-controlled study that
randomized 1,429 subjects with IGT to either acarbose or placebo groups (11).
Annual oral glucose tolerance tests were performed to evaluate the conver-
sion to diabetes. The entire population was followed up on an average of 3.3
1.2 years. DNA was available from 767 subjects from seven countries (385 men
and 382 women; 354 treated with acarbose and 413 with placebo). Their mean
BMI was 30.8 4.1 kg/m
2
and age 54.7 7.9 years. All participants signed an
informed consent form, and the study was approved by appropriate institu-
tional review boards.
DNA analyses. We screened three SNPs (rs135559, rs1800206, and rs4253778)
from the study of Flavell et al. (10). In addition, eight SNPs were selected
using the Tagger software (12) (http://www.broad.mit.edu/mpg/tagger/faq.
From the
1
Department of Medicine, University of Kuopio and Kuopio Univer-
sity Hospital, Kuopio, Finland; and the
2
Research Centre, Centre Hospitalier
de l’Universite ´ de Montre ´ al, Ho ˆ tel-Dieu, and Department of Medicine, Univer-
sity of Montreal, Quebec, Canada.
Address correspondence and reprint requests to Markku Laakso, MD,
Academy Professor, Department of Medicine, University of Kuopio and
Kuopio University Hospital, 70210 Kuopio, Finland. E-mail: markku.laakso@
kuh.fi.
Received for publication 10 August 2006 and accepted in revised form 9
January 2007.
Published ahead of print at http://diabetes.diabetesjournals.org on 27 Feb-
ruary 2007. DOI: 10.2337/db06-1110.
IGT, impaired glucose tolerance; LD, linkage disequilibrium; PGC-1,
PPAR- coactivator 1; PPAR, peroxisome proliferator–activated receptor;
SNP, single nucleotide polymorphism.
*A complete list of STOP-NIDDM trial members can be found in ref. 11.
© 2007 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked “advertisement” in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
DIABETES, VOL. 56, APRIL 2007 1181