Causality of blood metabolites on hepatocellular carcinoma and cholangiocarcinoma: a metabolome-wide mendelian randomization study

Reportedly, there is an association between body metabolites and the risk of Hepatocellular Carcinoma (HCC) & Cholangiocarcinoma (CCA), possibly due to disrupted metabolic pathways leading to oxidative stress and an imbalance in cell proliferation and apoptosis, thereby increasing the risk of cancer. However, whether metabolites play a role in the onset of HCC or CCA remains inconclusive. The aim of our study is to explore the potential causal relationship between metabolites and the risk of HCC&CCA. Our study investigated the causal relationship between 1400 metabolites and HCC&CCA using publicly available genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with both metabolites and HCC&CCA were chosen as instrumental variables (IVs). The main approaches employed include inverse variance weighted (IVW), MR-Egger regression, and weighted median estimator (WME), with odds ratios (OR) used as the assessment criterion. Heterogeneity testing and sensitivity analyses were conducted to validate the results. We also conducted a reverse MR analysis to further validate the relationship between exposure and disease outcomes. This Mendelian Randomization (MR) study indicates a significant causal relationship between 19 metabolites and the risk of HCC&CCA. Among them, the risk factors include "Bilirubin (E, Z or Z, E) levels," "Bilirubin (Z, Z) to taurocholate ratio," "Dimethylarginine (sdma + adma) levels," "N-methyltaurine levels," "4-vinylguaiacol sulfate levels," "Cholate to adenosine 3',5'-cyclic monophosphate (cAMP) ratio," "Glycohyocholate levels," "Cholesterol levels," and "4-methylguaiacol sulfate levels." The incidence risk of HCC and CCA increases with the elevation of these metabolites. Protective factors include "Ursodeoxycholate levels," "3-hydroxybutyroylglycine levels," "Linoleoylcholine levels," "Nonanoylcarnitine (C9) levels," "Pristanate levels," "Heptenedioate (C7:1-DC) levels," "Mannonate levels," "N-acetyl-L-glutamine levels," "Sphinganine levels," and "N-lactoyl isoleucine levels." The incidence risk of HCC and CCA potentially decreases as the levels of these metabolites increase. Heterogeneity tests show that most instrumental variables do not exhibit inter-gene heterogeneity, and the possibility of pleiotropy in the analysis is very low according to the sensitivity analysis. The reverse MR analysis did not yield positive results. Our study has unveiled the intricate causal relationships between metabolites and the risk of HCC&CCA. Through our analysis, we identified nine metabolites, including "Bilirubin (E, Z or Z, E) levels," "Dimethylarginine (sdma + adma) levels," "Cholesterol levels,"ect, as risk factors for HCC&CCA. The incidence risk of HCC and CCA increases with their elevation. On the other hand, ten metabolites, such as "Ursodeoxycholate levels," "Linoleoylcholine levels," "Pristanate levels," ect, were identified as protective factors for HCC&CCA. The risk of developing HCC and CCA decreases with an increase in these metabolites. In conclusion, these findings further explore the physiological metabolic pathways underlying the pathogenesis of HCC and CCA, emphasizing future research directions. They pave the way for researchers to delve into the biological mechanisms of these diseases, facilitating early intervention and treatment strategies for these conditions.