However, only a handful of MR studies have assessed the causality between glycaemic characteristics and colorectal cancer risk 18, 19, and none of these were from Asian populations. MR uses genetic variants as instrumental variables to determine the unconfounded influence of exposure (glucose intolerance) on outcome (colorectal cancer). Mendelian randomisation (MR) could overcome such biases 17. Therefore, the causality between dysregulated glucose metabolism and colorectal cancer remains largely elusive. These inconclusive results suggest that findings from observational studies may be distorted by confounding factors or reverse causation. Conflicting results also exist on the effect of thiazolidinediones (another type of glucose-lowering medication) on colorectal cancer 15, 16. Although some observational studies suggest that metformin (a widely used hypoglycaemic agent) is associated with reduced colorectal cancer risk and cancer-specific mortality 13, large-scale randomised controlled trials have not reported such a relationship 14. However, there are only a few epidemiological studies assessing the association between hyperglycaemia, hyperinsulinemia, or insulin-related traits and colorectal cancer, and the results remain inconclusive in Asians 8, 9, 10, 11, 12. It is likely that proliferative and anti-apoptotic effects of insulin also promote colorectal tumour growth 4. Hyperglycaemia promotes glucose oxidation in intracellular mitochondria, and subsequent oxidative stress leads to DNA damage 6. The pivotal role of impaired glucose tolerance and insulin resistance has been increasingly recognised in colorectal carcinogenesis 4, 5, 6, 7. Therefore, identifying modifiable risk factors is essential for reducing the incidence of the disease and the associated socioeconomic losses. In fact, nearly a half of the newly diagnosed and prevalent colorectal cancer cases in the last five years have occurred in Asia 3. The drastic alteration in diets and lifestyle due to industrialisation and economic growth has led to an increased colorectal cancer incidence in the Asian population 2. The potential association between insulin resistance and colorectal cancer should be validated in further studies.Ĭolorectal cancer comprises a heterogeneous group of neoplasms influenced by a variety of environmental factors and genes 1. In this study, genetically predicted glycaemic characteristics were not significantly related to colorectal cancer risk. Sensitivity analyses, including Mendelian randomisation-Egger and weighted-median approaches, revealed no significant association between glycaemic characteristics and colorectal cancer ( P > 0.20). In the single nucleotide polymorphism (SNP)-exposure analysis, we meta-analysed study-level genome-wide associations of fasting glucose (~ 17,289 individuals), HbA1c (~ 52,802 individuals), and fasting C-peptide (1,666 individuals) levels from the Japanese Consortium of Genetic Epidemiology studies. A two-sample Mendelian randomisation analysis was performed to determine the causal association between genetic variants associated with elevated fasting glucose, haemoglobin A1c (HbA1c), and fasting C-peptide and colorectal cancer risk. Observational studies suggest that abnormal glucose metabolism and insulin resistance contribute to colorectal cancer however, the causal association remains unknown, particularly in Asian populations.
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