Peroxisome proliferator-activated receptor (
PPAR) gamma 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.
PPARgamma2 and gamma3 are two transcripts arising from the
PPARgamma gene through differential promoter usage and alternative splicing. We investigated the associations between
PPARgamma2 Pro12Ala and
PPARgamma3 C-681G gene polymorphisms and
colorectal cancer (CRC) risk in a case-control study nested within the Singapore Chinese Health Study. Genotypes for the
PPARgamma2 and
PPARgamma3 polymorphisms were determined on 362 incident CRC cases and 1164 cohort controls by direct sequencing and by fluorogenic 5'-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
PPARgamma2 Pro12Ala polymorphism showed a statistically significant reduction in risk compared to those with the CC genotype [odds ratio (OR)=0.53, 95% confidence interval (CI)=0.30-0.92]. For the
PPARgamma3 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=0.72, 95% CI=0.51-1.04). When
PPARgamma2 and
PPARgamma3 genotypes were considered simultaneously, the number 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
PPARgamma2 or
PPARgamma3), and the comparable figure among subjects possessing both low-risk genotypes was 0.19 (0.07-0.51).