Members of the UKCAP Consortium. Polymorphisms in PTGS1, PTGS2 and IL-10 do not influence colorectal adenoma recurrence in the context of a randomized aspirin intervention trial

Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, United Kingdom.
International Journal of Cancer (Impact Factor: 5.09). 11/2007; 121(9):2001-4. DOI: 10.1002/ijc.22942
Source: PubMed


Regular use of aspirin and other nonsteroidal antiinflammatory drugs reduces both the development of colorectal neoplasia and recurrence of colorectal adenoma (CRA). Modulation of the effects of aspirin by genetic factors has been reported, potentially allowing targeting of treatment to individuals most likely to gain benefit. Prostaglandin H synthase 1 (PTGS1) and PTGS2 are key enzymes in prostaglandin synthesis and are inhibited by aspirin, whilst interleukin-10 (IL-10) is an important antiinflammatory cytokine. We investigated whether functional genetic polymorphisms in the PTGS1, PTGS2 and IL-10 genes influence CRA recurrence in individuals participating in a randomized aspirin intervention trial. DNA was available for genotyping from 546 patients who received aspirin (300 mg daily) or placebo for a mean 41-months' duration. Homozygote carriers of variant alleles for the PTGS1 50C>T, PTGS2 -765G>C and IL-10 -592C>A polymorphisms did not have a significantly altered risk of CRA recurrence (relative risk [RR]=0.91; 95% confidence interval [CI]: 0.14-6.07, RR=1.32; 95% CI: 0.66-2.62 and RR=1.24; 95% CI: 0.74-2.07, respectively). There were also no significant interactions between aspirin intervention and genotype in determining recurrence risk. These data indicate that these polymorphisms are unlikely to influence CRA recurrence and cannot be used to identify individuals who derive benefit from aspirin intervention.

Download full-text


Available from: Richard F Logan, Oct 06, 2014
11 Reads
  • Source
    • "The characteristics of the selected studies are summarized in Table 1 and Table S1. The 13 studies analyzed the following polymorphism: PTGS1 rs3842787 (n = 3) [4]–[6], PTGS2 rs5275 (n = 8) [5], [7]–[13], PTGS2 rs20417 (n = 7) [4], [8]–[10], [12], [14], [15], PTGS2 rs689466 (n = 3) [8], [11], [12], and rs2745557 (n = 3) [5], [9], [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Several studies have investigated whether the polymorphisms in the prostaglandin endoperoxide synthase 1 (PTGS1) and PTGS2 genes and nonsteroidal anti-inflammatory drug (NSAID) use are associated with cancer risk; however, those studies have produced mixed results. Therefore, we performed a meta-analysis to evaluate the association between the PTGS1 and PTGS2 polymorphisms and the effect of NSAID use on the risk of developing cancer. We conducted a comprehensive search in PubMed through March 2012. The odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were calculated using the fixed-effect model or the random-effect model. The database search generated 13 studies that met the inclusion criteria. For PTGS1 rs3842787, NSAID users homozygous for the major allele (CC) had a significantly decreased cancer risk compared with non-NSAID users (OR = 0.73, 95% CI = 0.59-0.89). For PTGS2 rs5275 and rs20417, there were no significant differences between the gene polymorphism and NSAID use on cancer risk among the 8 and 7 studies, respectively. However, in the stratified analysis by the type of cancer or ethnicity population, NSAID users homozygous for the major allele (TT) in rs5275 demonstrated significantly decreased cancer risk compared with non-NSAID users in cancer type not involving colorectal adenoma (OR = 0.70, 95% CI = 0.59-0.83) and among the USA population (OR = 0.67, 95% CI = 0.56-0.82). NSAID users homozygous for the major allele (GG) in rs20417 displayed a significantly decreased cancer risk than non-NSAID users among the US population (OR = 0.72, 95% CI = 0.58-0.88). For the PTGS2 rs689466 and rs2745557 SNPs, there were no significant differences. This meta-analysis suggests that the associations between PTGS polymorphisms and NSAID use on cancer risk may differ with regard to the type of cancer and nationality.
    PLoS ONE 08/2013; 8(8):e71126. DOI:10.1371/journal.pone.0071126 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cyclooxygenases (COX) are important enzymes not only in the maintenance of mucosal integrity but also in pathological processes, namely in inflammation and tumor development in the gastrointestinal tract. Our goal was to understand whether there is a clear role for COX polymorphisms in gastric and colorectal carcinogenesis. A systematic review was conducted on observational studies assessing the involvement of COX polymorphisms at the onset of gastric or colorectal lesions, retrieved through a MEDLINE database search by May 2008. The dominant genetic model was assumed for each polymorphism and a random-effect model was used for pooling results. Twenty-two studies were retrieved reporting a total of 26 COX polymorphisms (nine in COX1 and 17 in COX2 genes). Carriers of -1329A, -899C alleles, and *429TT genotype revealed increased risk for gastric cancer [odds ratio (OR)=1.83; 95% confidence interval (CI): 1.07-3.10, OR=2.02; 95% CI: 1.00-4.10 and OR=1.34; 95% CI: 1.06-1.71, respectively). For colorectal lesions, the -899G>C and -1329G>A polymorphisms also showed an increased risk for cancer (OR=1.35; 95% CI: 1.01-1.81 and OR=1.36; 95% CI: 1.11-1.66, respectively). Furthermore, C allele carriers of V102V single nucleotide polymorphisms presented a decreased risk for colorectal adenoma onset (OR=0.77; 95% CI: 0.58-1.03). Although further studies, namely cohorts and/or adequately matched case-control studies, are required to unravel the impact of most COX polymorphisms, clearly there are evidences that support the involvement of -899G>C and -1329G>A COX2 polymorphisms in either gastric or colorectal carcinogenesis. These markers could be used to optimize management strategies (follow-up and/or chemoprevention).
    European journal of gastroenterology & hepatology 02/2009; 21(1):76-91. DOI:10.1097/MEG.0b013e32830ce7ba · 2.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Polymorphisms in drug-related enzymes and receptors are often strongly related to altered drug response and to the risk of developing drug intolerance. Aspirin, usually available as an over-the-counter drug, is one of the most used drugs worldwide and is a common cause of drug intolerance events. Aspirin undergoes polymorphic metabolism. Among the enzymes involved in aspirin biodisposition a major role is played by the enzymes UDP-glucuronosyltransferase UGT1A6, cytochrome P450 CYP2C9 and the xenobiotic/medium chain fatty acid:CoA ligase ACSM2, although other UGTs and ACSMs enzymes may significantly contribute to aspirin metabolism. UGT1A6, CYP2C9 and ACSM2 are polymorphic, as well as PTGS1 and PTGS2, the genes coding for the enzymes cyclo-oxygenases COX1 and COX2, respectively. The present review analyzes the importance of genetic variations in enzymes involved in the metabolism and in the effects of aspirin and common polymorphisms related to aspirin intolerance, and it raises hypotheses on genetic factors related to altered response to aspirin that require further investigation. Major polymorphisms related to aspirin biodisposition are rs2070959, rs1105879 and rs6759892 for the UGT1A6 gene, rs1133607 for the ACSM2 gene, and rs1799853, rs1057910, rs28371686, rs9332131 and rs28371685 for the CYP2C9 gene. Regarding aspirin effects, major PGTS1 targets are rs3842787 and rs5789 for European subjects, and rs3842789 and rs3842792 for African subjects. For the PTGS2 gene nonsynonymous SNPs are likely to be of low relevance because of the influence of transcriptional and posttranscriptional factors. Combined studies for the above mentioned polymorphisms and those corresponding to other genes related to aspirin intolerance will provide excellent tools to identify individuals with a high risk to develop intolerance to aspirin.
    Current Drug Metabolism 11/2009; 10(9):998-1008. DOI:10.2174/138920009790711814 · 2.98 Impact Factor
Show more