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One-carbon metabolism-related micronutrients intake and risk for hepatocellular carcinoma: A prospective cohort study.

ABSTRACT: Deficient intake of micronutrients involved in one-carbon metabolism (eg, choline, methionine, vitamin B₁₂ and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under-investigated in humans. We investigated the association between one-carbon metabolism-related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow-up in the NIH-AARP study. Dietary intakes and supplement use were ascertained at baseline using a food-frequency questionnaire. Total intake (diet plus supplements) of the following one-carbon metabolism-related micronutrients were calculated: folate, methionine and vitamins B₂ (riboflavin), B₃ (niacin), B₆ and B₁₂ . These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16-year follow-up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B₃ intake was associated with a lower HCC risk (HR_{Q5 vs Q1} = 0.60; 95% CI = 0.42-0.85; P_trend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HR_{Q5 vs Q1} = 0.32; 95% CI = 0.18-0.55; P_trend < .0001). Among participants with >3 years of follow-up, higher total vitamin B₃ intake was again associated with lower risk (HR_{Q5 vs Q1} = 0.37; 95% CI = 0.20-0.68; P_trend = .001), whereas higher total vitamin B₆ intake was associated with higher risk (HR_{Q5 vs Q1} = 2.04; 95% CI = 1.02-4.07; P_trend = .04). Restricted cubic spline analyses showed a dose-response inverse association between total vitamin B₃ intake and HCC risk, and dose-response positive association between total vitamin B₆ intake and HCC risk. The study suggests that higher vitamin B₃ intake is associated with lower HCC risk, whereas higher vitamin B₆ intake is associated with increased risk.

SUBMITTER: Antwi SO

PROVIDER: S-EPMC7875463 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND & AIMS: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is limited, due to inadequate risk stratification and suboptimal performance of current screening modalities.METHODS: We developed a multicenter prospective cohort of patients with cirrhosis undergoing surveillance with MRI and applied global untargeted metabolomics to 612 longitudinal serum samples from 203 patients. Among them, 37 developed HCC during follow-up.RESULTS: We identified 150 metabolites with significant abundance changes in samples collected prior to HCC (Cases) compared to samples from patients who did not develop HCC (Controls). Tauro-conjugated bile acids and gamma-glutamyl amino acids were increased, while acyl-cholines and deoxycholate derivatives were decreased. Seven amino acids including serine and alanine had strong associations with HCC risk, while strong protective effects were observed for N-acetylglycine and glycerophosphorylcholine. Machine learning using the 150 metabolites, age, gender, and PNPLA3 and TMS6SF2 single nucleotide polymorphisms, identified 15 variables giving optimal performance. Among them, N-acetylglycine had the highest AUC in discriminating Cases and Controls. When restricting Cases to samples collected within 1 year prior to HCC (Cases-12M), additional metabolites including microbiota-derived metabolites were identified. The combination of the top six variables identified by machine learning (alpha-fetoprotein, 6-bromotryptophan, N-acetylglycine, salicyluric glucuronide, testosterone sulfate and age) had good performance in discriminating Cases-12M from Controls (AUC 0.88, 95% CI 0.83-0.93). Finally, 23 metabolites distinguished Cases with LI-RADS-3 lesions from Controls with LI-RADS-3 lesions, with reduced abundance of acyl-cholines and glycerophosphorylcholine-related lysophospholipids in Cases.CONCLUSIONS: This study identified N-acetylglycine, amino acids, bile acids and choline-derived metabolites as biomarkers of HCC risk, and microbiota-derived metabolites as contributors to HCC development.

Project description:BACKGROUND:Exposure to inorganic arsenic (iAs) via drinking water is a serious global health threat. Various factors influence susceptibility to iAs-associated health outcomes, including differences in iAs metabolism. Previous studies have shown that obesity is associated with iAs metabolism. It has been hypothesized that this association can be explained by confounding from nutritional factors involved in one-carbon metabolism, such as folate or other B vitamins, whose intake may differ across BMI categories and is known be associated with iAs metabolism. However, no studies have explored whether this association is confounded by nutritional factors. METHODS:We investigated the relationship between body mass index (BMI) and the distribution of urinary arsenic species in a cross-sectional cohort of 1166 adults living in Chihuahua, Mexico from 2008 to 2013. Nutrient intake related to one-carbon metabolism, including folate, vitamin B2, and vitamin B12, was assessed using a food frequency questionnaire developed for Mexican populations. Multivariable linear regression was used to estimate the association between BMI and the distribution of urinary arsenic metabolites. Effect modification by drinking water iAs level and sex was also examined. RESULTS:After adjusting for potential confounders, including age, educational attainment, smoking, alcohol consumption, seafood consumption, water iAs, and sex, BMI was negatively associated with the proportion of urinary inorganic arsenic (%U-iAs) and urinary monomethylated arsenic (%U-MMAs) and positively associated with urinary dimethylated arsenic (%U-DMAs). This relationship was not influenced by additional adjustment for folate, vitamin B2, or vitamin B12 intake. Additionally, there was significant effect modification by both drinking water iAs level and sex. CONCLUSIONS:This study provides further evidence for an association between BMI and arsenic metabolism. However, contrary to previous hypotheses, these results suggest that this association is not confounded by the intake of micronutrients involved in one-carbon metabolism.

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One-carbon metabolism-related micronutrients intake and risk for hepatocellular carcinoma: A prospective cohort study.

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