1 Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
2 Slone Epidemiology Center, Boston University, Boston, MA, USA.
3 Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
4 Health Science Center, University of Florida, Jacksonville, FL, USA.
5 Division of Cancer Epidemiology and Genetics, The National Cancer Institute, Bethesda, MD, USA.
6 Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
7 Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA.
Deficient intake of micronutrients involved in one-carbon metabolism (e.g., choline, methionine, vitamin B12 , and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but it 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 (HRQ5vsQ1 =0.60; 95%CI=0.42-0.85; Ptrend =0.008), and the association remained significant when all six micronutrients were examined simultaneously (HRQ5vsQ1 =0.32; 95%CI=0.18-0.55; Ptrend <0.0001). Among participants with >3 years of follow-up, higher total vitamin B3 intake was again associated with lower risk (HRQ5vsQ1=0.37; 95%CI=0.20-0.68; Ptrend =0.001), whereas higher total vitamin B6 intake was associated with higher risk (HRQ5vsQ1 =2.04; 95%CI=1.02-4.07; Ptrend =0.04). 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.