Association between dietary vitamin B complex intake and risk of thyroid cancer in Korea : A Case Control Study = 한국인에서의 비타민 B군 섭취와 갑상선암 간의 연관성: 환자-대조군 연구

다국어 초록 (Multilingual Abstract)

Introduction: Thyroid cancer is the most common cancer in Korea, especially in women. Vitamin B plays essential roles in DNA synthesis and methylation because they are considered coenzymes in one-carbon metabolism. An increased incidence of vitamin B deficiency has been observed in patients with autoimmune thyroid diseases (ATD) in previous studies. However, there is inconclusive evidence about the relationship between vitamin B and the risk of thyroid cancer. We aimed to examine the association between dietary vitamin B and thyroid cancer incidence through a case-control study based on the Korean population.
Materials and Methods: The study population was selected from the Thyroid Cancer Longitudinal Study (T-CALOS). After applying exclusion criteria and matching, a total of 4,698 participants remained. Dietary intake was assessed using a validated semi-quantitative Food Frequency Questionnaire (SQ-FFQ). Dietary vitamin B intake was categorized based on the Korean Dietary Reference Intakes (KDRIs). Multivariate conditional logistic regression models, stratified by age and sex, were used to estimate the risk of thyroid cancer related to dietary vitamin B intake.
Results: Multivariable logistic regression revealed a distinct biological dichotomy. Folate (Vitamin B9) intake was associated with a significant protective effect (OR=0.73, 95% CI: 0.58-0.91), supporting the ‘genomic stability’ hypothesis. Conversely, vitamins involved in energy metabolism riboflavin (B2), niacin (B3), and cobalamin (B12) were associated with increased risk. Crucially, source-specific analysis indicated that the risk associated with vitamin B12 was significantly modified by meat consumption (P for interaction =0.006) but not by fish consumption, suggesting that dietary B12 primarily serves as a surrogate marker for red meat intake rather than acting as an intrinsic carcinogen. Furthermore, a high vitamin B12/folate ratio emerged as a potent risk factor (OR=2.69), reflecting a state of one-carbon imbalance caused by a disproportionate intake of animal protein relative to plant-based sources. Sex-specific analysis indicated that bioenergetic risks were significantly amplified in males.
Conclusion: The risk of developing thyroid cancer is regulated not by the absolute amount of individual vitamins but by the balance of intake between plant-based (folate) nutrients and animal-based (B12) nutrients. This study suggests that the imbalance in the short-chain carbon cycle caused by an unbalanced, meat-dominated diet is a potential risk factor for thyroid cancer. It further indicates that a balanced diet centered on plant-based foods, designed to correct this imbalance, may contribute to the prevention of thyroid cancer.

국문 초록 (Abstract)

[연구 배경] 2021년 국가암등록통계에 따르면 갑상선암은 한국인에서 발생율이 가장 높은 암이다. 갑상선 질환은 흔히 다양한 식이 요인과 관련된다. 앞선 연구에 따르면 비타민B군의 결핍은 갑상선 호르몬의 생산 및 변환에 영향을 미칠 수 있다. 그러나 비타민 B군과 갑상선암 사이의 관계는 현재까지 명확히 규명되지 않았으며, 이들 간의 인과관계에 대한 근거도 부족하다. 이 연구의 목적은 한국인에서의 비타민B군의 섭취와 갑상선암 간 연관성을 평가하는 것이다.
[연구 방법] 갑상선암 환자군은 서울대병원, 분당서울대병원, 국립암센터에서 모집한 다기관 갑상선암 환자 코호트(N=4,814)명을 사용하였고 갑상선암 및 암 이력이 없는 지역사회 집단(N=13,756)명을 대조군으로 선정하였다. 비타민B군의 섭취, 연령, 성별, 체질량지수 기록이 없는 대상자와 총 칼로리 섭취량이 500-4,000kcal 범위를 초과한 대상자를 제외하고 성별, 연령(±5세)의 기준으로 1:1 매칭하여 최종 4,828명을 연구 대상자로 포함하였다. 식이 섭취량은 타당도가 검증된 반정량 식품 섭취 빈도 조사지(SQ-FFQ)를 사용하여 평가했다. 비타민B군은 피리독신, 엽산, 티아민, 리보플라빈, 판토텐산, 비오틴를 포함하였고 2020년 한국인 영양소 섭취기준(KDRIs)과 미국 영양 섭취기준(DRIs)에 따라 섭취량을 2~3개 그룹으로 분류했다. 그 외 포함한 변수는 총 칼로리 섭취, 체질량지수, 교육수준, 신체활동 수준, 흡연 여부, 음주 여부, 종합 비타민 복용 여부, 갑상선 질환 및 암 가족력을 포함했다. 통계분석방법은 조건부 로지스틱 회귀분석 모델을 사용했다.
[연구결과] 다변량 분석 결과, 엽산(Vitamin B9) 섭취는 갑상선암 위험 감소와 유의한 연관성(OR=0.73)을 보여 유전체 안정성 가설을 지지하였다. 반면, 리보플라빈(B2), 나이아신(B3), 코발라민(B12)은 위험 증가와 양의 상관관계를 보였다. 핵심적으로, 비타민 B12와 관련된 위험 증가는 육류 섭취가 많은 그룹에서만 유의하게 나타났으며(P_{interaction}=0.006), 생선 섭취와는 상호작용이 관찰되지 않았다. 이는 높은 식이 비타민 B12가 그 자체로 직접적인 발암 요인이기보다는 육류섭취의 '대리 지표'로 작용함을 시사한다. 또한, 높은 B12/엽산 섭취 비율이 가장 강력한 위험 요인(OR=2.69)으로 규명되었는데, 이는 식물성 조절 요인 대비 동물성 단백질 섭취가 과도한 단탄소 순환 불균형상태를 반영한다.
[토의] 결론적으로, 갑상선암의 발생 위험은 개별 비타민의 절대적인 양보다는 식물성(엽산) 영양소와 동물성(B12) 영양소 간의 섭취 균형에 의해 조절된다. 본 연구는 육류 위주의 불균형한 식습관이 초래하는 단탄소 순환 불균형이 갑상선암의 잠재적 위험 요인임을 제시하며, 이를 교정하기 위한 식물성 식품 위주의 균형 잡힌 식단이 갑상선암 예방을 기여할 가능성을 시사한다.

목차 (Table of Contents)

• Table of Contents
• Abstract i
• Chapter 1. Introduction 1
• Chapter 2. Materials and methods 7
• 2.1. Study population 7
• 2.2. Data collection and covariate assessment １０
• 2.3. Dietary assessment and nutrient calculation １１
• 2.4. Exposure variable construction and classification １３
• 2.4.1 Descriptive statistics １３
• 2.4.2 Composite pathway scores (Z-scores) １７
• 2.5. Assessment of covariates １７
• 2.5.1 Sociodemographic and lifestyle determinants １８
• 2.5.2 Anthropometric and clinical history １８
• 2.5.3 Dietary confounders １９
• 2.6. Statistical analysis １９
• 2.6.1 Descriptive statistics and baseline comparisons ２０
• 2.6.2 Analysis of the association between vitamin B Intake and thyroid cancer ２０
• 2.6.3 Dose-response and non-linearity assessment ２１
• 2.6.4 Sensitivity analysis and stratification ２２
• 2.6.5 Heterogeneous treatment effects using Causal Forest ２２
• 2.6.6 Mixture and pathway analysis ２３
• Chapter 3. Results ２５
• 3.1. Baseline characteristics of the study population ２５
• 3.2. Association between dietary vitamin B intake and thyroid cancer risk ３０
• 3.3. Dose-response relationship analysis ３６
• 3.4. Sensitivity analysis: control of confounding via IPTW ４０
• 3.5. Stratification analyses ４３
• 3.5.1. Effect modification by biological sex ４３
• 3.5.2. Stratified analysis by vitamin supplement use ４６
• 3.5.3. Stratified analysis by iodine intake ４７
• 3.5.4. Stratified analysis by BMI ５０
• 3.5.5. Key interactions and subgroup disparities ５２
• 3.6. Individualized treatment effects and heterogeneity ５５
• 3.7. Investigation of the ‘B12 paradox’: food source correlations and nutrient interactions ５８
• 3.8. Integrated pathway analysis: metabolic competition and nutrient imbalance ６４
• Chapter 4. Discussion ６８
• 4.1. Summary of major findings ６８
• 4.2. The protective role of one-carbon metabolism: genomic stability and epigenetic maintenance ６９
• 4.3. The bioenergetic risk: The ‘energy metabolism’ hypothesis ７２
• 4.4. Effect modification: biological heterogeneity and source specificity ７３
• 4.4.1. Sexual dimorphism: the hormonal regulation of one-carbon metabolism ７４
• 4.4.2. The ‘Supplement paradox’: food matrix vs. synthetic isolates ７５
• 4.5. Role of iodine and obesity as modifiers: the environmental and metabolic context ７７
• 4.5.1. Iodine Status: The ‘two-hit’ mechanism for vitamin B12 ７７
• 4.5.2. Adiposity and B5: mitigating lip toxicity ７８
• 4.5.3. Metabolic inflexibility in lean phenotypes ７９
• 4.6. Strengths and limitations ８０
• 4.6.1. Strengths of the study ８０
• 4.6.2. Limitations ８２
• Chapter 5. Conclusion ８５
• References 97
• 국문초록 101