<div>Abstract<p>Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E<sub>2</sub>. We investigated whether 35 SNPs in oxylipin metabolism genes such as <i>cyclooxygenase</i> (<i>PTGS</i>) and <i>lipoxygenase</i> (A<i>LOX</i>), as well as 7 SNPs already associated with colorectal cancer risk reduction by aspirin (e.g., <i>TP53</i>; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomized 2 × 2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the <i>P</i> and <i>q</i> value. 542 (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with nonaspirin users was restricted to rs4837960 (<i>PTGS1</i>) common homozygotes [IRR, 0.69; 95% confidence interval (CI), 0.53–0.90); <i>q</i> = 0.06], rs2745557 (<i>PTGS2</i>) compound heterozygote-rare homozygotes [IRR, 0.60 (0.41–0.88); <i>q</i> = 0.06], rs7090328 (<i>ALOX5</i>) rare homozygotes [IRR 0.27 (0.11–0.64); <i>q</i> = 0.05], rs2073438 (<i>ALOX12</i>) common homozygotes [IRR, 0.57 (0.41–0.80); <i>q</i> = 0.05], and rs104522 (<i>TP53</i>) rare homozygotes [IRR, 0.37 (0.17–0.79); <i>q</i> = 0.06]. No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalized, predictive models of colorectal cancer chemoprevention by aspirin.</p>Prevention Relevance:<p>Single-nucleotide polymorphisms in genes controlling lipid mediator signaling may modify the colorectal polyp prevention activity of aspirin. Further investigation is required to determine whether testing for genetic variants can be used to target cancer chemoprevention by aspirin to those who will benefit most.</p></div>
<p>Supplementary Table 2 shows the results of Negative binomial regression analysis of total colorectal polyp number according to aspirin use stratified for each SNP</p>
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Introduction Gestational diabetes mellitus (GDM) is the most common pregnancy complication worldwide and is associated with short- and long-term health implications for both mother and child. Prevalence of GDM varies between ethnicities, with South Asians (SAs) experiencing up to three times the risk compared to white Europeans (WEs). Recent evidence suggests that underlying metabolic difference contribute to this disparity, but an investigation of causality is required. Methods To address this, we paired metabolite and genomic data to evaluate the causal effect of 146 distinct metabolic characteristics on gestational dysglycemia in SAs and WEs. First, we performed 292 GWASs to identify ethnic-specific genetic variants associated with each metabolite (P ≤ 1 x 10-5) in the Born and Bradford cohort (3688 SA and 3354 WE women). Following this, a one-sample Mendelian Randomisation (MR) approach was applied for each metabolite against fasting glucose and 2-hr post glucose at 26-28 weeks gestation. Additional GWAS and MR on 22 composite measures of metabolite classes were also conducted. Results This study identified 15 novel genome-wide significant (GWS) SNPs associated with tyrosine in the FOXN and SLC13A2 genes and 1 novel GWS SNP (currently in no known gene) associated with acetate in SAs. Using MR approach, 14 metabolites were found to be associated with postprandial glucose in WEs, while in SAs a distinct panel of 11 metabolites were identified. Interestingly, in WEs, cholesterols were the dominant metabolite class driving with dysglycemia, while in SAs saturated fatty acids and total fatty acids were most commonly associated with dysglycemia. Discussion In summary, we confirm and demonstrate the presence of ethnic-specific causal relationships between metabolites and dysglycemia in mid-pregnancy in a UK population of SA and WE pregnant women. Future work will aim to investigate their biological mechanisms on dysglycemia and translating this work towards ethnically tailored GDM prevention strategies.
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BackgroundAspirin and eicosapentaenoic acid (EPA) have colorectal polyp prevention activity, alone and in combination. This study measured levels of plasma and rectal mucosal oxylipins in participants of the seAFOod 2 × 2 factorial, randomised, placebo-controlled trial, who received aspirin 300 mg daily and EPA 2000 mg free fatty acid, alone and in combination, for 12 months.MethodsResolvin (Rv) E1, 15-epi-lipoxin (LX) A4 and respective precursors 18-HEPE and 15-HETE (with chiral separation) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry in plasma taken at baseline, 6 months and 12 months, as well as rectal mucosa obtained at trial exit colonoscopy at 12 months, in 401 trial participants.ResultsDespite detection of S- and R- enantiomers of 18-HEPE and 15-HETE in ng/ml concentrations, RvE1 or 15‑epi-LXA4 were not detected above a limit of detection of 20 pg/ml in plasma or rectal mucosa, even in individuals randomised to both aspirin and EPA. We have confirmed in a large clinical trial cohort that prolonged (12 months) treatment with EPA is associated with increased plasma 18-HEPE concentrations (median [inter-quartile range] total 18-HEPE 0.51 [0.21–1.95] ng/ml at baseline versus 0.95 [0.46–4.06] ng/ml at 6 months [P<0.0001] in those randomised to EPA alone), which correlate strongly with respective rectal mucosal 18-HEPE levels (r = 0.82; P<0.001), but which do not predict polyp prevention efficacy by EPA or aspirin.ConclusionAnalysis of seAFOod trial plasma and rectal mucosal samples has not provided evidence of synthesis of the EPA-derived specialised pro-resolving mediator RvE1 or aspirin-trigged lipoxin 15‑epi-LXA4. We cannot rule out degradation of individual oxylipins during sample collection and storage but readily measurable precursor oxylipins argues against widespread degradation.
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