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Mendelian Randomization Study: The Association Between Metabolic Pathways and Colorectal Cancer Risk.

ABSTRACT: Background: The roles of obesity-related biomarkers and their molecular pathways in the development of postmenopausal colorectal cancer (CRC) have been inconclusive. We examined insulin resistance (IR) as a major hormonal pathway mediating the association between obesity and CRC risk in a Mendelian randomization (MR) framework. Methods: We performed MR analysis using individual-level data of 11,078 non-Hispanic white postmenopausal women from our earlier genome-wide association study. We identified four independent single-nucleotide polymorphisms associated with fasting glucose (FG), three with fasting insulin (FI), and six with homeostatic model assessment-IR (HOMA-IR), which were not associated with obesity. We estimated hazard ratios (HRs) for CRC by adjusting for potential confounding factors plus genetic principal components. Results: Overall, we observed no direct association between combined 13 IR genetic instruments and CRC risk (HR = 0.96, 95% confidence interval [CI]: 0.78-1.17). In phenotypic analysis, genetically raised HOMA-IR exhibited its effects on the increased risk and FG and FI on the reduced risk for CRC, but with a lack of statistical power. Subgroup analyses by physical activity level and dietary fat intake with combined phenotypes showed that genetically determined IR was associated with reduced CRC risk in both physical activity-stratified (single contributor: MTRR rs722025; HR = 0.12, 95% CI: 0.02-0.62) and high-fat diet subgroups (main contributor: G6PC2 rs560887; HR = 0.59, 95% CI: 0.37-0.94). Conclusions: Complex evidence was observed for a potential causal association between IR and CRC risk. Our findings may provide an additional value of intervention trials to lower IR and reduce CRC risk.

SUBMITTER: Jung SY

PROVIDER: S-EPMC7396568 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mendelian Randomization Study: The Association Between Metabolic Pathways and Colorectal Cancer Risk.

Jung Su Yon SY Papp Jeanette C JC Sobel Eric M EM Zhang Zuo-Feng ZF

Frontiers in oncology 20200723

<b>Background:</b> The roles of obesity-related biomarkers and their molecular pathways in the development of postmenopausal colorectal cancer (CRC) have been inconclusive. We examined insulin resistance (IR) as a major hormonal pathway mediating the association between obesity and CRC risk in a Mendelian randomization (MR) framework. <b>Methods:</b> We performed MR analysis using individual-level data of 11,078 non-Hispanic white postmenopausal women from our earlier genome-wide association stu ...[more]

PMID: 32850306

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Project description:BackgroundDiverticular disease has been inconsistently associated with colorectal cancer risk. We conducted a bidirectional Mendelian randomization study to assess this association.MethodsForty-three and seventy single-nucleotide polymorphisms associated with diverticular disease and colorectal cancer at the genome-wide significance level (p < 5 × 10- 8) were selected as instrumental variables from large-scale genome-wide association studies of European descent, respectively. Summary-level data for colon cancer, rectum cancer, and colorectal cancer were obtained from genome-wide association analyses of the FinnGen consortium and the UK Biobank study. Summary-level data for diverticular disease was derived from a genome-wide association study conducted in the UK Biobank population. The random effect inverse-variance weighted Mendelian randomization approach was used as the primary method and MR-Egger, weighted-median, and MR-PRESSO approaches were conducted as sensitivity analyses.ResultsGenetically determined diverticular disease was associated with a higher risk of colorectal cancer (beta = 0.441, 95%CI: 0.081-0.801, P = 0.016) in the FinnGen population, but the association was not found in the UK Biobank (beta = 0.208, 95%CI: -0.291,0.532, P = 0.207). The positive association remained consistent direction in the three sensitivity analyses. In the stratified analysis in the FinnGen consortium, an association was found to exist between genetically predicted diverticular disease and colon cancer (beta = 0.489, 95%CI: 0.020-0.959, P = 0.041), rather than rectum cancer (beta = 0.328, 95%CI: -0.119-0.775, P = 0.151). Besides, we found a slight association between colorectal cancer and diverticular disease (beta = 0.007, 95%CI: 0.004-0.010, P < 0.001) when using colorectal cancer as exposome and diverticular disease as outcome. However, there is a large sample overlap in this step of analysis.ConclusionThis Mendelian randomization study suggests that diverticular disease may be a possible risk factor for colorectal cancer and colon cancer rather than rectum cancer in the FinnGen population.

Project description:BackgroundHigher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.MethodsWe examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.ResultsIn sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.ConclusionsOur results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

Project description:Background: Previous observational studies have provided inconsistent evidence for the association between alcohol consumption and the risk of colorectal cancer (CRC). To assess this potential causal effect, we performed bidirectional Mendelian randomization (MR) analysis. Methods: We selected six single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) associated with alcohol consumption (ever versus never drinker) and two SNPs representing the number of drinks per week from a genome-wide association study (GWAS) of the Japanese population. Summary data for CRC were obtained from a GWAS meta-analysis in the Japanese population of 6,692 CRC cases and 27,178 controls. MR analysis was performed by the inverse-variance weighted (IVW) method primarily, supplemented with several sensitivity methods including the weighted median method, maximum likelihood method, MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger regression, Causal Analysis Using Summary Effect estimates (CAUSE) method, as well as constrained maximum likelihood and model averaging and Bayesian information criterion (cML-MA-BIC) method. Multivariable Mendelian randomization (MMR) analyses were used to adjust for potential confounders. Reverse MR analyses were also performed to assess the potential causal effect of CRC on alcohol consumption. Results: Genetically predicted alcohol consumption (ever versus never drinker) was positively associated with the risk of CRC (odds ratio (OR) = 1.08, 95% confidence interval (CI): 1.05-1.12, p = 1.51 × 10-5 by IVW). The number of alcoholic drinks per week was also associated with an increased risk of CRC (OR = 1.39, 95%CI: 1.27-1.52, p = 5.29 × 10-13 by IVW). Sensitivity analysis yielded similar results. Reverse MR analyses found no evidence that CRC contributes to either ever drinkers (OR = 1.00, 95%CI: 0.99-1.00, p = 0.339 by IVW) or added number of drinks per week (OR = 1.01, 95%CI: 0.98-1.05, p = 0.545 by IVW). Conclusion: Our study suggested a potential causal association between alcohol consumption and the risk of CRC among Asians. Reducing drinking may be beneficial to the prevention and management of CRC.

Project description:Background: Colorectal cancer and Alzheimer's disease are both common life-threatening diseases in the elderly population. Some studies suggest a possible inverse relationship between colorectal cancer and Alzheimer's disease, but real-world research is subject to many biases. We hope to clarify the causal relationship between the two through a bidirectional two-sample Mendelian randomization study. Methods: In our study, we used genetic summary data from large-scale genome-wide association studies to investigate the relationship between colorectal cancer and Alzheimer's disease. Our primary analysis employed the inverse-variance weighted method and we also used complementary techniques, including MR-Egger, weighted median estimator, and Maximum likelihood. We applied simex adjustment to the MR-Egger results. We also utilized the MRlap package to detect potential sample overlap and its impact on the bias of the results. In addition, we performed several sensitivity and heterogeneity analyses, to ensure the reliability of our results. Results: The combined effect size results of the inverse-variance weighted method indicate that colorectal cancer may decrease the incidence of Alzheimer's disease, with an odds ratio (OR) of 0.846 (95% CI: 0.762-0.929). Similar results were observed using other methods such as MR-Egger, weighted median estimator, and Maximum likelihood. On the other hand, Alzheimer's disease may slightly increase the incidence of colorectal cancer, with an OR of 1.014 (95% CI: 1.001-1.027). However, the results of one subgroup were not significant, and the results from MRlap indicated that sample overlap introduced bias into the results. Therefore, the results of the reverse validation are not reliable. The F-statistic for all SNPs was greater than 20. Four SNPs related to the outcome were excluded using Phenoscanner website but the adjustment did not affect the overall direction of the results. The results of these statistics were further validated by MR-PRESSO, funnel plots, leave-one-out analyses, Cochran's Q, demonstrating the reliability of the findings. Conclusion: According to the findings of this Mendelian randomization study, there appears to be a causal association between colorectal cancer and Alzheimer's disease. These results could have important implications for clinical practice in terms of how colorectal cancer and Alzheimer's disease are treated. To better understand the relationship between these two diseases, more research and screening are needed in clinical settings.

Dataset Information

Mendelian Randomization Study: The Association Between Metabolic Pathways and Colorectal Cancer Risk.

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Mendelian Randomization Study: The Association Between Metabolic Pathways and Colorectal Cancer Risk.

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