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Genetic variants of peroxisome proliferator-activated receptor ? are associated with gastric cancer.

ABSTRACT: Peroxisome proliferator-activated receptors (PPAR) are implicated in pathogenesis of insulin resistance and cancers of the digestive system.We investigated the associations of single nucleotide polymorphisms (SNPs) of PPAR ? and ? with gastric cancer and explored interactions with risk factors of gastric cancer.We conducted our analysis in a case-control study of 196 gastric cancer patients and 397 controls residing in the Taixing region of Jiangsu, China. Six SNPs in the PPAR? (rs2076167, rs3734254) and PPAR? genes (rs10865710, rs1801282, rs3856806, rs13306747) were genotyped. We employed logistic regression to evaluate the association between each genotype and gastric cancer and tested for gene-environment interaction with Helicobacter pylori (H. pylori) infection, smoking status, and meat and salt intake.We found that the G/G variant rs2076167, in tight linkage disequilibrium with rs3734254 (R (2) = 0.97), was associated with increased risk of gastric cancer in a recessive model (OR 2.20, 95 % CI 1.12, 4.32). The association between G/G variant of rs2016167 and gastric cancer was particularly strong among those with higher salt intake (OR 5.11, 95 % CI 1.11, 23.5), but did not vary by H. pylori infection or smoking status.We found that genetic variants of PPAR? were associated with gastric cancer. If the association is confirmed in larger studies, it may implicate a role for PPAR? activators, such as insulin-sensitizing agents, in prevention of gastric cancer.

SUBMITTER: Jeon C

PROVIDER: S-EPMC3783538 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Genetic variants of peroxisome proliferator-activated receptor δ are associated with gastric cancer.

Jeon Christie C Chang Shen-Chih SC Mu Lina L Zhao Jinkou J Rao Jian-Yu JY Lu Qing-Yi QY Zhang Zuo-Feng ZF

Digestive diseases and sciences 20130802 10

<h4>Background</h4>Peroxisome proliferator-activated receptors (PPAR) are implicated in pathogenesis of insulin resistance and cancers of the digestive system.<h4>Aim</h4>We investigated the associations of single nucleotide polymorphisms (SNPs) of PPAR δ and γ with gastric cancer and explored interactions with risk factors of gastric cancer.<h4>Methods</h4>We conducted our analysis in a case-control study of 196 gastric cancer patients and 397 controls residing in the Taixing region of Jiangsu, ...[more]

PMID: 23907334

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Project description:Peroxisome proliferator activated receptor-gamma (PPAR-gamma) is abundantly expressed in atherosclerotic lesions and is implicated in atherogenesis. The existence of three splice variants, PPAR-gamma 1, PPAR-gamma 2, and PPAR-gamma 3 has been established. Using monocyte-derived macrophages from cynomolgus monkeys, we demonstrate here the identification of two new PPAR-gamma exons, exon C and exon D, which splice together with already established exons A1, A2, and B in the 5(') terminal region to generate four novel PPAR-gamma subtypes, PPAR-gamma 4, -gamma 5, -gamma 6, and -gamma 7. PPAR-gamma 4 and gamma 5 were detected only in macrophages whereas gamma 6 and gamma 7 were expressed both in macrophages and adipose tissues. None of these novel isoforms were detected in muscle, kidney, and spleen from monkeys. We found sequences identical to exons C and D in the human genome database. These and all PPAR-gamma exons known to date are encoded by a single gene, located from region 10498 K to 10384 K on human chromosome 3. We cloned and expressed PPAR-gamma 1, PPAR-gamma 4, and PPAR-gamma 5 proteins in yeast using the expression vector pPICZB. As expected, all recombinant proteins showed a molecular weight of approximately 50 kDa. We also investigated the effect of a high-fat diet on the level of macrophage PPAR-gamma expression in monkeys. RT-PCR showed a significant increase in total PPAR-gamma and ABCA1 mRNA levels in macrophages of fat-fed monkeys (n=7) compared to those maintained on a normal diet (n=2). However, none of the novel isoforms seemed to be induced by fat-feeding. We used tetracycline-responsive expression vectors to obtain moderate expression of PPAR-gamma 4 and -gamma 5 in CHO cells. In these cells, expression of PPAR-gamma 5 but not -gamma 4 repressed the expression of ABCA1. Neither isoform modulated the expression of lipoprotein lipase. Our results suggest that individual PPAR-gamma isoforms may be responsible for unique tissue-specific biological effects and that PPAR-gamma 4 and -gamma 5 may modulate macrophage function and atherogenesis.

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Genetic variants of peroxisome proliferator-activated receptor ? are associated with gastric cancer.

Publications

Genetic variants of peroxisome proliferator-activated receptor δ are associated with gastric cancer.

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