Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2018  |  Volume : 14  |  Issue : 9  |  Page : 306--310

Peroxisome proliferators-activated receptor gamma polymorphisms and colorectal cancer risk


Xuemin Liang1, Xiaohua Fan1, Kanglian Tan1, Li Zhang1, Lisi Jian1, Linchong Yu2,  
1 Colorectal Disease of Guangdong Provincial Hospital of Chinese Medicine; The 2nd Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, China
2 The 2nd Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, China

Correspondence Address:
Xuemin Liang
Guangzhou Dade Road No. 111, Guangzhou 510120
China

Abstract

Aims: Several studies evaluated the association between peroxisome proliferators-activated receptor gamma (PPARγ) Pro12Ala (rs1801282), and His477His (rs3856806) polymorphisms and the risk of colorectal cancer (CRC). However, the results were not stable. Materials and Methods: We searched databases containing PubMed and EMBASE. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. Results: A significantly decreased CRC risk was found for PPARγ Pro12Ala polymorphism (OR = 0.88, 95% CI 0.83–0.94, P < 0.0001). In the subgroup analysis by race, a significantly decreased risk was found in the Caucasian population (OR = 0.89, 95% CI 0.83–0.95, P = 0.0003) but not in Asian population (OR = 0.76, 95% CI 0.57–1.02, P = 0.07). In the subgroup analysis by CRC location, significantly decreased risks were found in rectal cancer (OR = 0.88, 95% CI 0.77–1.00, P = 0.05) and colon cancer (OR = 0.82, 95% CI 0.73–0.92, P = 0.0008). In addition, a significantly decreased CRC risk was also detected for PPARγ His477His polymorphism (OR = 0.66, 95% CI 0.44–1.00, P = 0.05). In the subgroup analysis by race, a significantly decreased risk was found in the Caucasian population (OR = 0.43, 95% CI 0.26–0.69, P = 0.0006) but not in Asian population (OR = 0.95, 95% CI 0.73–1.25, P = 0.72). Conclusions: PPARγ Pro12Ala and His477His polymorphisms might be associated with susceptibility of CRC.



How to cite this article:
Liang X, Fan X, Tan K, Zhang L, Jian L, Yu L. Peroxisome proliferators-activated receptor gamma polymorphisms and colorectal cancer risk.J Can Res Ther 2018;14:306-310


How to cite this URL:
Liang X, Fan X, Tan K, Zhang L, Jian L, Yu L. Peroxisome proliferators-activated receptor gamma polymorphisms and colorectal cancer risk. J Can Res Ther [serial online] 2018 [cited 2019 Aug 26 ];14:306-310
Available from: http://www.cancerjournal.net/text.asp?2018/14/9/306/235346


Full Text

 Introduction



Colorectal cancer (CRC) is the second most common cause of cancer-associated mortality worldwide. More than 1 million new cases of CRC are reported annually.[1] The complexity of CRC is primarily attributed to environmental factors. The known risk factors for CRC are food-borne mutagens, pollution, certain commensal bacteria, and chronic intestinal inflammation.[2] Genetic factors also play a role in the development of CRC.[3]

Peroxisome proliferators-activated receptor gamma (PPARγ) is a ligand-activated nuclear transcription factor, which plays a central role in orchestrating gene expression in response to exogenous ligands. PPARγ is expressed at high levels in about 60% of sporadic human CRCs, and specific loss-of-function gene mutations have been reported in 8% of primary CRCs.[4] Recently, Lin et al. found that a correlation of PPARγ expression with a clinical stage in the CRC specimens.[5] Several studies have reported that treatment of cancer cells with PPARγ ligands induces cell differentiation and apoptosis, suggesting their potential application as chemopreventive agents against carcinogenesis.[6]

Previous studies have found two single nucleotide polymorphisms of PPARγ, which were PPARγ Pro12Ala polymorphism (rs1801282) and PPARγ His477His polymorphism (rs3856806). A series of studies have investigated the association between the PPARγ Pro12Ala polymorphism and PPARγ His477His polymorphism and CRC susceptibility, but provided controversial or inconclusive results.[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24] Three meta-analyses investigated the association between PPARγ Pro12Ala polymorphism and CRC risk.[25],[26],[27] However, that the meta-analysis did not assess the association between PPARγ His477His polymorphism and CRC risk. In addition, some new studies have been reported since then. Thus, we decided to perform this meta-analysis to determine the precise association between these two polymorphisms and CRC risk.

 Materials and Methods



Materials

We searched databases containing PubMed and EMBASE up to October 20, 2014, using the following MeSH terms: (“Colorectal neoplasms'' [MeSH terms] or “CRC”) and (“PPARγ”). We limited the languages to English and Chinese. Besides, the references from retrieved articles were also searched.

Inclusion/exclusion criteria

Studies included in this meta-analysis have to meet the following criteria: (1) Case-control study or cohort study studying on associations betweenPPARγ Pro12Ala polymorphism and PPARγ His477His polymorphism and the risk of CRC, (2) all studies should provide adjusted odds ratios (ORs), and their 95% confidence intervals (CIs), (3) published in English or Chinese language, and (4) the distribution of the genotypes in control groups was in the Hardy–Weinberg equilibrium (HWE). Studies were excluded when they were: (1) Duplicate of previous publication, (2) based on incomplete data, and (3) meta-analyses, letters, reviews, or editorial articles.

Data extraction

Data were independently extracted by two reviewers using a standardized data extraction form. Discrepancies were resolved by discussion and if consensus was not achieved the decision was made by all the reviewers. The title and abstract of all potentially relevant articles were screened to determine their relevance. Full articles were also scrutinized if the title and abstract were ambiguous. The following information was collected from each study: Author, year of publication, race, sample size, age, and gender, location of CRC, polymorphisms, and covariates.

Statistical analysis

Statistical analysis was conducted by using STATA statistical package (version 11, STATA, College Station, TX, USA). The distributions of genotypes in controls were tested by HWE using the Chi-square test. The association of PPARγ Pro12Ala polymorphism and PPARγ His477His polymorphism, and CRC risk was estimated by ORs with 95% CIs in the recessive model. The heterogeneity was tested by the Q-statistics with P < 0.1, and its possible sources of heterogeneity were assessed by subgroup analysis. Subgroup analysis was conducted by race and location of CRC. The random effect model or fixed effect model was selected to summarize the combined OR and their 95% CI. The significance of the pooled OR was determined by the Z-test. Publication bias was investigated by the method of Egger's linear regression test.[28] All the P values were two-sided. P < 0.05 was considered statistically significant.

 Results



Eligible studies

According to the inclusion criteria, 17 case-control studies were included. The publication year of involved studies ranged from 2003 to 2012. In total, 14,451 CRC cases and 18,013 healthy controls were involved in this meta-analysis, which evaluated the relationship between PPARγ Pro12Ala polymorphism and PPARγ His477His polymorphism and CRC risk. The characteristics of the included studies are summarized in [Table 1].{Table 1}

Quantitative synthesis

The main results of this meta-analysis and the heterogeneity test were shown in [Table 2]. A significantly decreased CRC risk was found for PPARγ Pro12Ala polymorphism [OR = 0.88, 95% CI 0.83–0.94, P < 0.0001, [Figure 1]. In the subgroup analysis by race, a significantly decreased risk was found in the Caucasian population (OR = 0.89, 95% CI 0.83–0.95, P = 0.0003) but not in Asian population (OR = 0.76, 95% CI 0.57–1.02, P = 0.07). In the subgroup analysis by CRC location, significantly decreased risks were found in rectal cancer (OR = 0.88, 95% CI 0.77–1.00, P = 0.05) and colon cancer (OR = 0.82, 95% CI 0.73–0.92, P = 0.0008). In addition, a significantly decreased CRC risk was also detected for PPARγ His477His polymorphism [OR = 0.66, 95% CI 0.44–1.00, P = 0.05, [Figure 2]. In the subgroup analysis by race, a significantly decreased risk was found in the Caucasian population (OR = 0.43, 95% CI 0.26–0.69, P = 0.0006) but not in Asian population (OR = 0.95, 95% CI 0.73–1.25, P = 0.72). Furthermore, the heterogeneity was decreased in this subgroup analysis, suggesting that the main source of heterogeneity was from race.{Table 2}{Figure 1}{Figure 2}

The Egger's test was performed to assess the publication bias of literatures. The Egger's test indicated that there was no obvious publication bias (P = 0.132 and P = 0.103).

 Discussion



Although, many studies reported the results about the PPARγ Pro12Ala polymorphism and PPARγ His477His polymorphism and CRC risk, definite conclusions cannot be drawn. Therefore, we did this meta-analysis to estimate the relationships between PPARγ Pro12Ala polymorphism and PPARγ His477His polymorphism, and susceptibility to CRC. The meta-analysis involved 17 articles. The results from this meta-analysis showed that the PPARγ Pro12Ala polymorphism and PPARγ His477His polymorphism had a significant protective effect against CRC. However, both of these two polymorphisms did not show a protective effect against CRC in Asians. Only three studies with Asians were included in this meta-analysis. Thus, more studies are still needed to assess the relationship between PPARγ Pro12Ala polymorphism and CRC in Asians, because a marginal association was found. In addition, marginal association between PPARγ Pro12Ala polymorphism and CRC risk among Asians might be related to their low frequency in that ethnic group. PPARγ Pro12Ala polymorphism decreased both rectal cancer and colon cancer risks, suggesting that this polymorphism could influence rectal cancer and colon cancer risks.

To our knowledge, there was a published meta-analysis regarding PPARγ Pro12Ala polymorphism and CRC risk.[25] Lu et al. found that PPARγ Pro12Ala polymorphism was associated with colon cancer risk, but not associated with CRC and rectal cancer risk.[25] However, we found that PPARγ Pro12Ala polymorphism showed decreased CRC, colon cancer, and rectal cancer risks. It was possible that there was significant heterogeneity in their meta-analysis, and no significant heterogeneity was found in our meta-analysis. In addition, more studies were included in our meta-analysis. Thus, our results were more reliable.

The PPARγ Ala allele has been shown to have decreased activity relative to the more common Pro allele, which may account for the inverse association with obesity and insulin sensitivity associated with this polymorphism.[29] Although it is not clear how polymorphisms in the PPARγ gene influence the risk of CRC, evidence to date suggests that mechanisms may include both insulin and inflammation-related pathways.[30]

This meta-analysis had several limitations. First, the number of studies with Asians included in our meta-analysis remained small. Second, CRC is a complex process modulated by a series of genetic factors beyond PPARγ. However, this analysis only tried to explore the effect of two polymorphisms on CRC, which failed to link other gene variants that may be involved in pathophysiological pathways. Therefore, in the future, larger clinical studies are required to validate the hypothesis and findings obtained in this study. Once validated, they can be very helpful evidence to develop tailored therapeutics for individual patients. Finally, no prospective studies have addressed the association between PPARγ polymorphisms and CRC risk, and all included studies followed a retrospective case-control design. Thus, owing to the limitations of case-control design, we can't exclude the possibility of undetected bias.

 Conclusion



This meta-analysis suggested that PPARγ Pro12Ala and His477His polymorphisms might be associated with susceptibility of CRC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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