{"doi":"10.1002/ijc.33184","title":"Comments on “<scp>One</scp>‐carbon metabolism‐related micronutrients intake and risk for hepatocellular carcinoma: A prospective cohort study”","abstract":"Primary liver cancer (PLC) is characterized by aggressive growth and high rates of metastasis, recurrence and suboptimal treatment. Worldwide, the PLC is the sixth most common cancer and the second leading cause of cancer-related death. In the United States, the incidence of hepatocellular carcinoma (HCC), accounting for >85% of the PLC, has tripled in the past three decades.1 It is projected to surpass breast, prostate and colorectal cancers to become the third leading cause of cancer-related death by 2030.2 The currently known major risk factors for PLC include chronic infections with hepatitis B virus (HBV), hepatitis C virus (HCV), aflatoxin B1 contaminated foods, heavy alcohol intake, obesity and type 2 diabetes mellitus. Although diet has been hypothesized as a promising modifiable risk factor for PLC, epidemiological studies on diet and PLC are limited. Recently, Dr Antwi and his colleges examined one-carbon metabolism-related micronutrients intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow-up in the NIH-AARP study.3 They observed that higher vitamin B3 intake is associated with lower HCC risk, whereas higher vitamin B6 intake is associated with increased HCC risk. In the discussion, they mentioned that one limitation is the lack of the HBV/HCV status, which might be a confounder between diet and HCC risk. This is an important issue to address because most large-scale epidemiological studies do not have complete HBV/HCV data either for the HCC cases or in the entire cohort, which precludes adjustment for this important risk factor when studying exposure-liver cancer associations. Therefore, it is imperative to understand the extent to which the lack of HBV/HCV infection status might have impacted the scientific validity of the research on diet, lifestyle factors and liver cancer risk. We argue that diet-liver cancer associations are unlikely substantially confounded by HBV/HCV status for the following reasons. First, there appears no correlation between diet, lifestyle factors and HBV/HCV status. For example, in the Liver Cancer Pooling Project of >15 U.S. based cohort studies,4 body mass index, smoking, alcohol use and coffee intake were not correlated with HBV/HCV infection. In the Nurses' Health Study and Health Professionals Follow-up Study, we also observed no correlations between HBV/HCV infection status and dietary pattern such the alternate healthy eating index-2010, fiber, nuts, fatty acids, dairy foods and meats. Second, the existing epidemiological studies,5-9 although limited and not entirely consistent, have reported similar findings with or without adjustment for HBV/HCV infection status (Table 1). High vs low Tooth loss ncases = 112, ncontrols = 269; 1.90 (0.90-4.04) ncases = 112, ncontrols = 269; 1.95 (0.91-4.17) ncases = 191; 0.83 (0.74-0.95) 0.80 (0.69-0.97) ncases = 122, ncontrols = 242; 0.86 (0.66-1.11) 0.74 (0.50-1.00) Tertile 3 vs tertile 1 BMI WHR ncases = 177; 2.28 (1.50-3.45) 1.93 (1.25-2.97) ncases = 115, ncontrols = 229; 1.44 (0.64-3.23) 2.63 (1.10-6.29) Quintile 5 vs quintile 1 Iron intake Manganese intake ncases = 536; 0.62 (0.39-1.00) 0.51 (0.35-0.73) ncases = 363, ncontrols = 3511; 0.33 (0.15-0.71) 0.38 (0.21-0.69) Highest vs lowest Coffee Tea ncases = 201; 0.28 (0.16-0.50) 0.41 (0.22-0.78) ncases = 125, ncontrols = 250; 0.54 (0.19-1.58) 0.36 (0.13-0.99) Third, we further conducted a sensitivity analysis using E-value to estimate the extent to which HBV/HCV status might have confounded the vitamin B3-liver cancer risk. The E-value is a measure to represent the minimum strength of associations between an unmeasured confounder and the exposure/outcome on the risk ratio scale to fully explain away a specific exposure-outcome association after controlling other covariates.10 We denote the relative risk (RR) for HBV infection comparing the highest vs lowest vitamin B3 intake as RREU and the association between HBV and HCC risk as RRUD. Then, we could ca","journal":"International Journal of Cancer","year":2020,"id":115716,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":269896,"name":"Xuehong Zhang","orcid":"0000-0002-8260-8508","position":1,"is_corresponding":false},{"id":542357,"name":"Longgang Zhao","orcid":"0000-0001-9254-1952","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:13:40.596604Z","pmid":"32621756","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}