Phospholipase C Epsilon 1 Rs2274223 Research Articles

The Correlation between Phospholipase C Epsilon (PLCE1) Gene Polymorphisms and Risk of Gastric Adenocarcinoma in Iranian Population

Background: Phospholipase C epsilon 1 (PLCE1) gene harbors different single nucleotide polymorphisms (SNPs), which can be correlated with the risk of different types of cancers. In this case-control study, the relationship between rs2274223 (A>G), a single nucleotide polymorphism in phospholipase C epsilon gene, (PLCE1) and gastric cancer was evaluated among Iranian patients. Materials and Methods: The PLCE1 rs2274223 polymorphism was genotyped in 60 patients with gastric cancer and 69 control subjects using polymerase chain reaction and restriction fragment length polymorphisms (PCR-RFLP) methods. Clinical and pathologic parameters such as tumor characteristics and disease stage were also recorded. Results: There were 48 (80%) male patients and 45 (65.5%) healthy male individuals (p=0.077). About 34 (56.6%) patients were smokers. A family history of gastric cancer was found in 21 (35%) cases. GG genotype was observed among 15% of patients and 8.7% of normals, respectively. There was no significant difference between the AA and AG genotypes. Also, there were no significant correlations between AA, AG or GG genotypes and the risk of gastric cancer, gender, tumor size, tumor stage, grade, as well as tumor location and metastasis. Conclusion: The PLCE1 rs2274223 polymorphism was not correlated with gastric cancer in Iranian population. However, a further comprehensive study with larger sample sizes is needed.

Risk prediction for early-onset gastric carcinoma: a case-control study of polygenic gastric cancer in Han Chinese with hereditary background.

Recent genomewide studies have identified several germline variations associated with gastric cancer. The aim of the present study was to identify, in a Chinese Han population, the individual and combined effects of those single nucleotide polymorphisms (SNPs) that increase the risk of early-onset gastric cancer. We conducted a case-control study comprising 116 patients with gastric cancer as well as 102 sex- and age-matched controls and confirmed that the SNPs MUC1 (mucin 1) rs9841504 and ZBTB20 (zinc finger and BTB domain containing 20) rs4072037 were associated with an increased gastric cancer risk. Of the 116 patients diagnosed with cancer, 65 had at least 1 direct lineal relative with carcinoma of the digestive system or breast/ovarian cancer. These 65 had another 4 SNPs associated with gastric cancer susceptibility: PSCA (prostate stem cell antigen) rs2294008, PLCE1 (phospholipase C epsilon 1) rs2274223, PTGER4/PRKAA1 (prostaglandin E receptor 4/protein kinase AMP-activated catalytic subunit alpha 1) rs13361707, and TYMS (thymidylate synthetase) rs2790. However, each of these low-penetrance susceptibility polymorphisms alone is not considered influential enough to predict the absolute risk of early-onset gastric cancer. Thus we decided to study different combinations of polygenes as they affected for our population. Those subjects with both the risk alleles MUC1 rs9841504 and ZBTB20 rs4072037 had a greater than 3-fold increased risk of gastric cancer. Also those with a hereditary background including the risk alleles PLCE1 rs2274223 and PTGER4/PRKAA1 rs13361707 were 3 times more susceptible to cardia cancer than those without. These findings show that the study of combined polymorphisms, instead of single low-penetrance variations in susceptibility, may lead to a high-risk classification for a specific population.

Novel Functional Variants Locus in PLCE1 and Susceptibility to Digestive Tract Cancer in the Chinese Population: A Meta-Analysis

Three large-scale genome-wide association studies (GWAS) have identified a shared susceptibility variation phospholipase C epsilon 1 (PLCE1) rs2274223 for esophageal squamous cell carcinoma (ESCC) and/or gastric cardia adenocarcinomas (GCA) in the Chinese population. However, the association between PLCE1 rs2274223 A>G and the risk of digestive tract cancer (DTC) has been inconsistent. We therefore carried out a meta-analysis of published case-control studies to derive a more precise estimation of the association between PLCE1 rs2274223 A>G and DTC risk. A comprehensive search was conducted to identify all eligible studies of PLCE1 rs2274223 polymorphism and DTC risk. Crude odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to estimate the strength of associations in fixed or random effect models. Heterogeneity and publication bias were also assessed. A total of 15 case-control studies were identified, including 29,805 cases and 32,225 controls. Overall, we found a statistically significant association between the PLCE1 rs2274223 polymorphism and DTC risk (G vs A: OR=1.29, 95% CI: 1.17-1.43; GA vs AA: OR=1.33, 95% CI: 1.18-1.51; GG vs AA: OR=1.71, 95% CI: 1.26-2.32; GG/GA vs AA: OR=1.33, 95% CI: 1.17-1.51), but the recessive model did not reach statistical significance (GG vs GA/AA: OR=0.94, 95% CI: 0.63-1.42). In the subgroup analysis by cancer types, we observed a significant risk for DTC in the ESCC and GCA subgroups. When stratified for source of controls, the results of the population-based subgroup analysis showed that the variant G allele might generally induce a significantly increased risk of DTC, except in hospital-based subgroups. In conclusion, PLCE1 rs2274223 polymorphism may be used as a potential biomarker for DTC susceptibility particularly for ESCC and GCA in the Chinese population.

Role of novel and GWAS originated PLCE1 genetic variants in susceptibility and prognosis of esophageal cancer patients in northern Indian population.

Recent genome-wide association studies (GWAS) have identified variants in phospholipase C epsilon1 (PLCE1) as novel susceptibility markers for esophageal squamous cell carcinoma (ESCC) in Chinese population. Although few studies have replicated this findings in other populations, but results are contradictory. So, we aimed to replicate association of two previously reported non-synonymous polymorphisms (rs2274223A>G and rs3765524C>T) from haplotype block 10 and evaluated a novel variant (rs7922612C>T) from haplotype block 2 of PLCE1 with susceptibility and prognosis of ESCC in northern Indian population. The genotyping of PLCE1 variants were performed in 293 histopathologically confirmed incident ESCC cases (including 177 follow-up cases) and 314 age-, gender-, and ethnicity-matched controls using PCR RFLP. All statistical analyses were performed through SPSS version 15.0. Modeling and functional prediction of two non-synonymous variants were carried out using bioinformatics tools. PLCE1 polymorphisms were not associated with susceptibility to ESCC or its clinical phenotypes (tumor location/lymph node metastasis). No interaction with environmental risk factors was found. In silico analysis suggested negligible effect on structure of PLCE1 protein due to PLCE1 rs2274223 (H1927R) and rs3765524 (T1777I) polymorphisms. Survival analysis showed PLCE1 rs7922612CT + TT genotype conferred adverse outcome to ESCC patients. Our study for the first time suggests that GWAS originated PLCE1 variants do not have independent role in susceptibility of ESCC in northern Indian population; however, a novel haplo-tagging SNP rs7922612 may modify survival outcome of ESCC patients.

Genetic polymorphism of the phospholipase C epsilon 1 gene and risk of gastric cancer.

The pathogenesis of gastric cancer (GC) involves environmental and genetic factors. Recently, two genome-wide association studies found that phospholipase C epsilon 1 (PLCE1) polymorphisms might be related to GC risk, and several studies further validated this finding. However, these studies yielded inconsistent results. A comprehensive database search was performed to identify eligible studies. Odds ratios with 95% confidence intervals were calculated to assess the strength of the association between PLCE1 rs2274223, rs753724, and rs11187842 and risk of GC. Subgroup analyses, publication bias, and sensitivity analyses were also conducted. Eleven studies (12 cohorts) were included in the meta-analysis. Based on 13 676 cases and 23 569 controls, a significant association between PLCE1 rs2274223 and GC risk was detected under various genotypic models. In the subgroup analyses, the association was significant for cardia GC, but weak for non-cardia GC. The association under the heterozygote model was detected for PLCE1 rs753724 and rs11187842 based on three studies involving 2768 cases and 3890 controls. Our findings demonstrate that the presence of the G allele at rs2274223 of the PLCE1 gene may contribute to susceptibility to GC, especially cardia GC. PLCE1 rs753724 and rs11187842 are associated with GC risk under the heterozygote model. Further well-designed large studies are warranted to validate these findings.

A multigenic approach to evaluate genetic variants of PLCE1, LXRs, MMPs, TIMP, and CYP genes in gallbladder cancer predisposition

Gallbladder cancer (GBC) is a violent neoplasm associated with late diagnosis, unsatisfactory treatment, and poor prognosis. The disease shows complex interplay between multiple genetic variants. We analyzed 15 polymorphisms in nine genes involved in various pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were matrix metalloproteinases (MMP-2, MMP-7, and MMP-9), tissue inhibitor of metalloproteinases (TIMP-2), cytochrome P450 (CYP)1A1, CYP1B1, phospholipase C epsilon 1 (PLCE1), liver X receptor (LXR)-alpha, and LXR-beta. Genotypes were determined by PCR-RFLP and TaqMan probes. Statistical analysis was done by SPSS version 16. Multilocus analysis was performed by Classification and Regression Tree (CART) analysis and multifactor dimensionality reduction (MDR) to gene-gene interactions in modifying GBC risk. In silico analysis was done using various bioinformatics tools (F-SNP, FAST-SNP). Single locus analysis showed association of MMP-2 (-735 C > T, -1306 C > T), MMP-7 - 181 A > G, MMP-9 (P574R, R668Q), TIMP-2 - 418 G > C, CYP1A1-MspI, CYP1A1-Ile462Val, PLCE1 (rs2274223 A > G, rs7922612 T > C) and LXR-beta T > C (rs3546355 G > A, rs2695121 T > C) polymorphisms with GBC risk (p < 0.05) whereas CYP1B1 and LXR-α variants were not associated with GBC risk. Multidimensional reduction analysis revealed LXR-β (rs3546355 G > A, rs2695121 T > C), MMP-2 (-1306 C > T), MMP-9 (R668Q), and PLCE1 rs2274223 A > G to be key players in GBC causation (p < 0.001, CVC = 7/10). The results were further supported by independent CART analysis (p < 0.001). In silico analysis of associated variants suggested change in splicing or transcriptional regulation. Interactome and STRING analysis showed network of associated genes. The study found PLCE1 and LXR-β network interactions as important contributory factors for genetic predisposition in gallbladder cancer.

Association between phospholipase C epsilon gene (PLCE1) polymorphism and colorectal cancer risk in a Chinese population

To investigate the association between a single nucleotide polymorphism rs2274223 (adenine [A] to guanine [G]) in the phospholipase C epsilon 1 (PLCE1) gene and susceptibility to colorectal cancer (CRC). The PLCE1 rs2274223 polymorphism was genotyped in patients with CRC and age- and sex-matched cancer-free control subjects from a Chinese population in a case-control study. PLCE1 mRNA levels in pair-matched tumour and adjacent noncancerous tissue were evaluated by real-time quantitative reverse transcription-polymerase chain reaction. A total of 417 patients with CRC and 416 control subjects were enrolled in the study. The AG and GG genotypes of PLCE1 rs2274223 were associated with a significantly increased risk of CRC (for AG + GG versus AA: adjusted odds ratio 1.52, 95% confidence interval 1.15, 2.00). PLCE1 mRNA levels were significantly lower in tumours than in adjacent noncancerous tissue. Lower levels of PLCE1 mRNA were observed in both AG and GG genotype carriers compared with the AA genotype carriers. These results indicate that the PLCE1 rs2274223 A > G change might reduce gene expression and that the variant G genotype might contribute to the increased risk of CRC.

Meta-analysis of phospholipase C epsilon 1 polymorphism and cancer risk

Phospholipase C epsilon 1 (PLCE1) plays crucial roles in carcinogenesis and progression of several cancers. A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus. To evaluate the role of the Phospholipase C epsilon 1 (PLCE1) polymorphism in cancer susceptibility. We performed a meta-analysis of all available studies, including 8,689 cases and 10,794 controls to derive a more precise relationship. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association between PLCE1 rs2274223 polymorphism and cancer risk. A total of 14 case-control studies were included in the present meta-analysis. Overall significant associations were observed (AG vs. AA: OR=1.17, 95%CI=1.04-1.31; GG vs. AA: OR=1.32, 95%CI=1.06-1.66; AG/GG vs. AA: OR=1.19, 95%CI=1.05-1.34; G vs. A: OR=1.16, 95%CI=1.04-1.29) in all cancer types. In the subgroup analysis, PLCE1 rs2274223 polymorphism was significantly increased risk of cancer in Chinese population by ethnicity and upper aerodigestive tract cancer by cancer types. Our meta-analysis suggested the PLCE1 rs2274223 might act as a cancer risk factor among all subjects, especially in the Chinese population and upper aerodigestive tract cancer.

Heterozygote of PLCE1 rs2274223 increases susceptibility to human papillomavirus infection in patients with esophageal carcinoma among the Kazakh populations

The involvement of human papillomavirus (HPV) in the carcinogenesis of esophageal squamous carcinoma remains undetermined. However, three genome-wide association studies of esophageal cancer have identified a shared susceptibility locus at 10q23 (rs2274223: A5780G) in phospholipase C epsilon 1 (PLCE1). The current study aims to present a comprehensive and novel spectrum about the HPV genotype distribution of esophageal carcinoma in Kazakhs and assess its association with PLCE1 polymorphisms. The HPV genotypes in 183 patients with esophageal cancer and 89 controls selected from the Kazakh population were evaluated using the HPV gene chip. The PLCE1 rs2274223 variant was genotyped in esophageal carcinoma patients by MALDI-ToF Mass Spectrometry. The presence of seven HPV genotypes in esophageal carcinoma tissues-including HPV 16, 18, 35, 52, 6, 11, 43-was significantly higher at 31.7% than those in controls at 9.0% (P < 0.001). Such presence was strongly associated with increased risk of esophageal carcinoma (OR 4.70; 95% CI 2.13-10.36). Among all HPV genotypes detected, HPV16 was the most common genotype identified (29.0%, OR 4.13; 95% CI 1.87-9.13), which is significantly associated with well-differentiated esophageal carcinoma (P = 0.037). HPV-positive patients were generally younger than HPV-negative patients (70.1% vs. 29.3%, P = 0.013). PLCE1 rs2274223 genotypes AG and AG/GG were significantly associated with HPV-positive patients with esophageal carcinoma (OR 2.05, 95% CI 1.03-4.08 and OR 1.98, 95% CI 1.02-3.84, respectively). These findings suggest that heterozygote of PLCE1 rs2274223 increases susceptibility to HPV infection in patients with esophageal carcinoma among the Kazakh populations.

Increased Risk of Developing Digestive Tract Cancer in Subjects Carrying the PLCE1 rs2274223 A&gt;G Polymorphism: Evidence from a Meta-Analysis

BackgroundTo date, the association between phospholipase C epsilon 1 (PLCE1) rs2274223 A>G and risk of digestive tract cancer (DTC) remains inconclusive. To derive a more precise estimation of the association, we conducted a meta-analysis on all eligible case–control studies involving 8281 cases and 10,532 controls.MethodsA comprehensive search was conducted to identify all eligible studies of PLCE1 rs2274223 polymorphism and digestive tract cancer risk. The pooled odds ratio (OR) and the 95% confidence interval (95% CI) were calculated using a fixed or random effect model. Heterogeneity, publication bias, and sensitivity analysis were also explored.ResultsOverall, the PLCE1 rs2274223 A>G polymorphism was associated with risk of DTC in all genetic models (GA vs. AA: OR = 1.21, 95% CI = 1.14–1.29, P<0.001; GG vs. AA: OR = 1.30, 95% CI = 1.06–1.60, P = 0.012; GG/GA vs. AA: OR = 1.20, 95% CI = 1.10–1.32, P<0.001; GG vs. GA/AA: OR = 1.21, 95% CI = 1.01–1.46, P = 0.040). The recessive model did not reach statistically significance when the P values were Bonferroni corrected to 0.0125. In the stratified analysis by cancer type, ethnicity, and source of controls, significantly increased risk was observed for esophagus cancer, Asians in three genetic models (heterozygote comparison, homozygote comparison and dominant model), population-based studies in all genetic models, and for gastric cancer in the heterozygote comparison and dominant model after Bonferroni correction. However, in the subsite of gastric cancer, no significant association was found either in cardia or non-cardia gastric cancer.ConclusionOur study indicated that PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of DTC, especially among Asian populations. Due to some minor limitations, our findings should be confirmed in further studies.

Multiple polymorphisms within the PLCE1 are associated with esophageal cancer via promoting the gene expression in a Chinese Kazakh population

Although recent genome-wide association studies of esophageal squamous cell carcinoma (ESCC) identified a susceptibility locus in phospholipase C epsilon 1 (PLCE1) in Chinese Han populations, few studies further confirmed these findings in pure Kazakh population in which there are higher incidence and mortality of ESCC. Here, we investigated the potential associations between 19 SNPs of PLCE1 and susceptibility to ESCC in 222 cases and 326 controls from a pure ethnic population of Kazakh. Real-time PCR and immunohistochemistry were performed to detect the PLCE1 expression levels and evaluate their association with PLCE1 polymorphism. We found that only 4 SNPs (rs753724, rs11187842, rs2274223, and rs12263737) with moderate linkage disequilibrium (LD) confer significantly increased risk of ESCC, with the ORs ranging from 1.43 to 2.04, and there was a risk allele dose-dependent increase in ESCC risk (P-trend=0.043). Especially, the risk effects of rs2274223 were more evident in poor differentiation and advanced clinical stages of Kazakh ESCC. Additionally, the significantly lowest PLCE1 mRNA expression was found in the KYSE-150 cell line having no risk alleles compared with other three cell lines having risk alleles, and the normal tissues of both homozygous mutant type of PLCE1 rs12263737 and rs2274223 had a higher PLCE1 staining score than that of homozygous wild type. Our findings suggested that genetic variants in PLCE1 might serve as candidate markers for Kazakh ESCC susceptibility, and these LD variants might influence ESCC risk individually and jointly by promoting the messenger RNA and protein expression of the gene.

Association of Potentially Functional Genetic Variants of PLCE1 with Gallbladder Cancer Susceptibility in North Indian Population

Phospholipase C epsilon 1 (PLCE1) plays crucial roles in carcinogenesis and progression of esophageal and gastric cancers. In the present study, we investigated association of GWAS identified rs2274223 A>G and. rs7922612 T>C polymorphism of PLCE1 with susceptibility to gallbladder cancer (GBC). The study involved genotyping of selected PLCE1 variants in 416 GBC cases and 225 controls. Haplotype analysis was done by SNPStats. In silico analyses were performed using bioinformatic tools. PLCE1 rs2274223 [AG] and rs7922612 [CC] genotypes were found to be significantly associated with an increased risk of GBC [OR = 1.9, p = 0.002; OR = 2.0, p = 0.04, respectively]. PLCE1 haplotype [Grs2274223-Crs7922612] also showed significant association with GBC [OR = 1.8, p = 0.04]. The association was significant in females and GBC patients with stones and female GBC patients with gallstones [OR = 2.6, p = 0.01; OR = 3.3, p = 0.007], respectively. However, no significant associations with other risk factors such as tobacco usage and age of onset were found. Functional prediction of rs2274223 A>G suggested change in protein coding and splicing regulation. The present study found a significant association of PLCE1 rs2274223 and rs7922612 polymorphisms with susceptibility to GBC probably through gallstone-mediated inflammatory pathway.