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.

Coffee Consumption and Prostate Cancer Risk: Results from National Health and Nutrition Examination Survey 1999–2010 and Mendelian Randomization Analyses

“…Mendelian randomization (MR) is an epidemiological method, which uses genetic variants to evaluate the effect of exposure (e.g., coffee consumption) on an outcome (e.g., prostate cancer risk) [ 11 ]. Since the genetic variants are assorted randomly during gamete formation and mostly independent from environmental or lifestyle factors, MR is less vulnerable to the biases from reverse causation and confounding.…”

Associations between potential causal factors and colorectal cancer risk: A systematic review and meta‐analysis of Mendelian randomization studies

“…The sample size of exposure and outcome ranged between 1475 and 898 130 and between 1475 and 706 031, respectively (Table S3). The causal factors can be classified into eight categories: anthropometric characteristics and obesity‐related biomarkers ( n = 31), 7–16 lifestyle habits ( n = 15), 9,10,17–21 blood micronutrients ( n = 36), 10,22–31 blood fatty acids (FAs) and lipids ( n = 43), 10,24,32–37 inflammatory biomarkers ( n = 14), 10,38–42 pathological conditions and related biomarkers ( n = 30), 10,43–50 reproductive factors ( n = 12), 10,51,52 and other biomarkers ( n = 9) 10,53–57 (Table 1, Figure 2).…”

“…three studies 46,47 but not in another, 10 and the largest one reported an OR (95% CI) of 1.11 (1.01-1.22). 47 Furthermore, no associations were found for a homeostatic model assessment for beta-cell function (HOMA-B), 45 homeostatic model assessment for insulin resistance (HOMA-IR), 48 glycosylated hemoglobin A1c (HbA1c), 45 HbA, 10 fasting glucose, 10,43,45,48 fasting insulin, 43,48 fasting proinsulin, 10 gallstone disease, 49 and bilirubin 49,50 (Table 1, Figures 2 and 3, Figure S6).…”

“…A total of 57 studies 7,10,13,17,18,24,26,41,45,48,50,[51][52][53] (men: 24, women: 33) were included in subgroup analyses according to sex. Most results were consistent with the main results, except for AMPA, lifetime smoking amount, some FAs (LA, ALA, EPA, and DPA), and total testosterone.…”

Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

“…Furthermore, a meta-analysis has revealed that the homeostasis model of risk assessment-insulin resistance (HOMA-IR) was significantly associated with CRC risk [25]. In addition, a recent Mendelian randomization study pointed towards a potential causal relationship between genetically driven IR and CRC risk in postmenopausal women [26]. However, it should be noted that a retrospective study that used the National Health and Nutrition Examination Survey (NHANES) data [27] failed to demonstrate a significant difference in HOMA-IR between patients with and without CRC within a time frame of 5 years.…”