Peroxisome proliferator-activated receptor (PPAR) g gene polymorphisms
and colorectal cancer risk among Chinese in Singapore
Sue A.Ingles2and Mimi C.Yu1
Department of Community, Occupational and Family Medicine, Yong Loo
Lin School of Medicine, National University of Singapore, Singapore,1The
Cancer Center, University of Minnesota, MN, USA and2USC/Norris
Comprehensive Cancer Center, Keck School of Medicine, University of
Southern California, Los Angeles, CA, USA
?To whom correspondence should be addressedat: Departmentof Community,
Occupational and Family Medicine, Yong Loo Lin School of Medicine,
National University of Singapore, MD3, 16 Medical Drive, Singapore 117597.
Tel: +65 6874 4975; Fax: +65 6779 1489;
Peroxisome proliferator-activated receptor (PPAR) g is a
ligand-activated nuclear receptor that plays a key role in
adipogenesis and adipocyte gene expression, and has
recently been linked with possible antineoplastic effects
in colonic carcinogenesis. PPARg2 and g3 are two tran-
scripts arising from the PPARg gene through differential
promoter usage and alternative splicing. We investigated
the associations between PPARg2 Pro12Ala and PPARg3
C-681G gene polymorphisms and colorectal cancer (CRC)
risk in a case–control study nested within the Singapore
Chinese Health Study. Genotypes for the PPARg2 and
PPARg3 polymorphisms were determined on 362 incident
CRC cases and 1164 cohort controls by direct sequencing
and by fluorogenic 50-nuclease assay. Unconditional logistic
regression models were used for statistical analyses. With
adjustment for CRC risk factors, subjects with one or two
copies of the G allele of the PPARg2 Pro12Ala polymorph-
ism showed a statistically significant reduction in risk com-
pared to those with the CC genotype [odds ratio (OR) ¼
0.53, 95% confidence interval (CI) ¼ 0.30–0.92]. For the
PPARg3 C-681G polymorphism, subjects with one or two
copies of the C allele showed a reduction in risk compared
to those with the GG genotype (OR ¼ 0.72, 95% CI ¼
0.51–1.04). When PPARg2 and PPARg3 genotypes were
considered simultaneously, thenumber of putative low-risk
genotypes was significantly associated with reduced risk of
CRC in a gene-dose-dependent manner; the OR (95% CI)
was 0.72 (0.49–1.07) among subjects possessing one
low-risk genotype (either PPARg2 or PPARg3), and the
comparable figure among subjects possessing both low-risk
genotypes was 0.19 (0.07–0.51).
Colorectal cancer (CRC) has one of the highest incidence rates
among cancers in developed countries. The geographical pat-
tern of high rates in the West and lower rates in Asia suggests
that in addition to genetic determinants, lifestyle and dietary
factors may be important contributors to colonic carcinogen-
esis (1,2). Among them, obesity, which is more prevalent
among Western populations, has been consistently associated
with higher risk of CRC among men and women in both case–
control and cohort studies (reviewed in ref. 3). Epidemiolo-
gical data also suggest that both Type 2 diabetes and impaired
glucose tolerance are risk factors for colon cancer in
Western populations. Together with a growing body of experi-
mental evidence, these epidemiological data suggest that
obesity-induced hyperinsulinemia, hyperlipidemia and insulin
resistance may play a role in colon carcinogenesis (reviewed
in ref. 4).
As a nuclear receptor which plays a pivotal role in regu-
lating adipocyte differentiation, glucose and lipid homeo-
stasis, and intracellular insulin-signaling events, peroxisome
proliferators-activated receptor (PPAR) g has received grow-
ing interest for its possible role in CRC. PPARg forms func-
tional heterodimers with members of the retinoid X-receptor
family of nuclear receptors and activates the transcription of
target genes by the release of corepressors and recruitment of
coactivators (5). Putative endogenous ligands for PPARg
include both polyunsaturated fatty acids (PUFAs) and arachi-
donic acid derivatives (6). Experimental evidence has sugges-
ted that activation of PPARg in the colon results in growth
inhibition and differentiation, and reduces the malignant
potential of CRC cells (7). In addition, administration of the
PPARg ligand troglitazone significantly inhibits chemically
induced colitis and formation of aberrant crypt foci in rats (8).
The PPARg gene produces four different PPARg mRNAs
by differential promoter usage and alternative splicing, giving
rise to two different protein isoforms. The PPARg1, PPARg3
and PPARg4 transcripts, although possessing different
upstream regulatory sequences, give rise to identical proteins
encoded by exons 1–6. A functional C-to-G polymorphism in
the promoter region for the PPARg3 transcript at position
?681 from the beginning of exon A2 has been associated
with increased body weight and circulating levels of choles-
terol (9,10). The PPARg2 transcript gives rise to a protein with
an additional 28 amino acids encoded by the PPARg2-specific
exon B (11,12). A polymorphism (proline-to-alanine substitu-
tion at codon 12) in exon B has been associated with reduced
risk of diabetes mellitus (13–15) and CRC (16). We investig-
ated the associations of these two polymorphisms in the
PPARg2 coding region and the PPARg3 regulatory region
with CRC risk in a nested case–control study within the Sin-
gapore Chinese Health Study, a prospective investigation of
diet and cancer in 63000 Chinese men and women.
Materials and methods
The study design and subject recruitment of the Singapore Chinese Health
Abbreviations: BMI, body mass index; CRC, colorectal cancer; EM
algorithm, expectation–maximization algorithm; LD, linkage disequilibrium;
PPAR, peroxisome proliferators-activated receptor.
Carcinogenesis vol.27 no.9 pp.1797–1802, 2006
Advance Access publication March 2, 2006
#The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com
by guest on June 1, 2013
28.Werman,A., Hollenberg,A., Solanes,G., Bjorbaek,C., Vidal-Puig,A.J. and
Flier,J.S. (1997) Ligand-independent activation domain in the N terminus
of peroxisome proliferator-activated receptor gamma (PPARgamma).
Differential activity of PPARgamma1 and -2 isoforms and influence of
insulin. J. Biol. Chem., 272, 20230–20235.
29.Yen,C.J., Beamer,B.A., Negri,C., Silver,K., Brown,K.A., Yarnall,D.P.,
Burns,D.K., Roth,J. and Shuldiner,A.R. (1997) Molecular scanning of
the human peroxisome proliferator activated receptor gamma (hPPAR
gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR
gamma 2 missense mutation. Biochem Biophys Res. Commun., 241,
Tan,C.E. and Ordovas,J.M. (2004) Differential effects of the C1431T
and Pro12Ala PPARgamma gene variants on plasma lipids and diabetes
risk in an Asian population. J. Lipid Res., 45, 674–685.
31.The International HapMap Consortium. (2003) The International HapMap.
Project. Nature, 426, 789–796.
32.Jiang,J., Gajalakshmi,V., Wang,J., Kuriki,K., Suzuki,S., Nakamura,S.,
Akasaka,S., Ishikawa,H. and Tokudome,S. (2005) Influence of the
C161Tbut notPro12Ala polymorphism
proliferator-activated receptor-gamma on colorectal cancer in an Indian
population. Cancer Sci., 96, 507–512.
33.Rangwala,S.M. and Lazar,M.A. (2004) Peroxisome proliferator-activated
receptor gamma in diabetes and metabolism. Trends Pharmacol. Sci., 25,
34.Bustin,S.A.,Dorudi,S., Phillips,S.M., Feakins,R.M. and Jenkins,P.J. (2002)
Local expression of insulin-like growth factor-I affects angiogenesis in
colorectal cancer. Tumour Biol., 23, 130–138.
35.Reinmuth,N., Fan,F., Liu,W., Parikh,A.A., Stoeltzing,O., Jung,Y.D.,
Bucana,C.D., Radinsky,R., Gallick,G.E. and Ellis,L.M. (2002) Impact of
insulin-like growth factor receptor-I function on angiogenesis, growth, and
metastasis of colon cancer. Lab Invest., 82, 1377–1389.
37.Giovannucci,E. (2001) Insulin, insulin-like growth factors and colon
cancer: a review of the evidence. J. Nutr., 131, 3109S–3120S.
38.Bull,A.W., Steffensen,K.R., Leers,J. and Rafter,J.J. (2003) Activation of
PPAR gamma in colon tumor cell lines by oxidized metabolites of
linoleic acid, endogenous ligands for PPAR gamma. Carcinogenesis, 24,
39.Gupta,R.A., Brockman,J.A., Sarraf,P., Willson,T.M. and DuBois,R.N.
(2001) Target genesof
receptor gamma in colorectal cancer cells.
40.Shimada,T., Kojima,K., Yoshiura,K., Hiraishi,H. and Terano,A. (2002)
Characteristics of the peroxisome proliferator activated receptor gamma
(PPARgamma) ligand induced apoptosis in colon cancer cells. Gut, 50,
41.Su,C.G., Wen,X., Bailey,S.T., Jiang,W., Rangwala,S.M., Keilbaugh,S.A.,
Flanigan,A., Murthy,S., Lazar,M.A. and Wu,G.D. (1999) A novel therapy
for colitis utilizing PPAR-gamma ligands to inhibit the epithelial
inflammatory response. J. Clin. Invest., 104, 383–389.
de la Chapelle,A., Spiegelman,B.M. and Eng,C. (1999) Loss-of-function
mutationsin PPAR gamma associatedwith human colon cancer. Mol. Cell,
43.Parkin,D.M., Whelan,S.L., Ferlay,J., Teppo,L. and Thomas,D. (2002)
Cancer Incidence in Five Continents. IARC, Lyon.
J. Biol. Chem., 276,
Received November 23, 2005; revised January 31, 2006;
accepted February 21, 2006
W.-P.Koh et al.
by guest on June 1, 2013