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Int J Cancer. Author manuscript; available in PMC 2017 July 18. Published in final edited form as: Int J Cancer. 2016 September 01; 139(5): 996–1008. doi:10.1002/ijc.30141.

Vitamin B2 intake and colorectal cancer risk; results from the Nurses’ Health Study and the Health Professionals Follow-up Study cohort Yeong Sook Yoon1,2,*, Seungyoun Jung3,*, Xuehong Zhang4, Shuji Ogino1,4,5, Edward L. Giovannucci1,4, and Eunyoung Cho4,6,7,**

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1Departments

of Nutrition (YSY, ELG) and Departments of Epidemiology (SO, ELG), Harvard T.H. Chan School of Public Health, Boston, MA, USA 2Department

of Family Medicine, Inje University Ilsan Paik Hospital, Goyang-Si, Gyeonggi-Do,

Korea 3Department

of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 4Channing

Division of Network Medicine, Department of Medicine (XZ, ELG, EC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA

5Department

of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

6Department

of Dermatology, Warren Alpert Medical School, Brown University, Providence, RI,

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USA 7Department

of Epidemiology, Brown University School of Public Health, Providence, RI, USA

Abstract

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Vitamin B2 serves as a cofactor to enhance one-carbon metabolism, maintain mucous membranes, and has been implicated in lowering colorectal cancer (CRC) risk. However, few prospective studies have examined the association between vitamin B2 intake and CRC. In this study, we estimated the associations between vitamin B2 intake and CRC risk using the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) cohorts. Vitamin B2 intake was measured by a validated food frequency questionnaire every 4 years. Among 100,033 women in the NHS and 44,007 men in the HPFS we documented a total of 3,037 incident CRC cases (2,093 women and 944 men) during 24–26 years of follow-up until 2010. Intakes of total (from food and supplements), dietary (from food only), and supplemental vitamin B2 were inversely related to CRC risk in age-adjusted analysis in NHS. However, the association was attenuated and no longer statistically significant in multivariate analysis (P-trend ≥0.08). The pooled multivariate relative risks (95% confidence interval) comparing individuals in the extreme quintiles of intakes were 0.93 (0.81–1.06) for total vitamin B2, 0.89 (0.61–1.28) for dietary vitamin B2 and 0.94

**

Correspondence to: Eunyoung Cho, ScD., Address: Department of Dermatology, Warren Alpert Medical School, Brown University, 222 Richmond St, Providence, RI 02903, USA, Phone: +1- 401-863-5895, Fax: +1- 401- 863-5799, [email protected]. *These authors contributed equally to this work Disclosure The authors declare no conflicts of interest.

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(0.81–1.08) for supplemental vitamin B2. These associations of total vitamin B2 intake were similar for risk of CRC with varying lag-time periods (0–4, 4–8, 8–12, or 12–16 years), for risk of CRC subtypes by tumor location, and across strata of intake of folate or alcohol. Our prospective data do not support a beneficial role of vitamin B2 intake in lowering incidence of CRC.

Keywords vitamin B2; colorectal neoplasms; cohort studies; alcohol; folate; diet; supplements; latency

Introduction

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Impairments in the one-carbon metabolism may affect methylation and synthesis of DNA, thereby influencing colorectal carcinogenesis. Within the one-carbon metabolism, vitamin B2 serves as a cofactor for methylenetetrahydrofolate reductase (MTHFR), a crucial enzyme enhancing DNA integrity mediating purine, pyrimidine production, and is involved in epigenetic alteration by promoting the production of methyl donors required for DNA methylation1. Furthermore, vitamin B2 helps to maintain the mucosal membranes in the digestive system and upregulates the immune response by facilitating the conversion of tryptophan into niacin within the kynurenine metabolism1.

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Despite these mechanisms suggesting a potential role of B2 in colorectal carcinogenesis, epidemiological studies have been inconsistent. In contrast to null findings from most individual cohort studies2–8 and case-control studies9–17, a recent meta-analyses found significant inverse association between vitamin B2 intake and risk of colorectal cancer (CRC) from four case-control studies (pooled odds ratio (OR) =0.78, 95% confidence interval (95% CI): 0.66–0.91 for highest versus lowest categories of intake of vitamins B2) and from five prospective cohort studies (pooled OR=0.86, 95% CI: 0.76–0.97)18, 19. These suggest that limited statistical power might have been a reason for the null associations in individual studies. On the other hand, some of the studies included in the meta-analysis had a limited adjustment of risk factors of CRC and thus might have suffered residual confounding. Also, potential publication bias was noted among observational studies included in the meta-analyses 18.

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Most previous studies have assessed vitamin B2 intake only from food sources and did not take into account intake from supplemental sources2–7, 11, 13, 14, 16, 17. Only a few studies evaluated the associations between total vitamin B2 intake including supplements9, 10, 12, 15, 20 or supplemental vitamin B2 intake itself20 and CRC risk. In the Women’s Health Initiative Observational study(WHI-OS) dietary vitamin B2 intake and supplemental vitamin B2 intake were not associated with risk of CRC, but total vitamin B2 intake was significantly associated with a lower risk of CRC (multivariate relative risk [RR] = 0.81; 95% CI = 0.66–0.99, for >3.97 mg/d versus < 1.80 mg/d)20. In addition, the effects of diet or nutrient intake as well as timing of exposure to these dietary factors (i.e., intake in the remote past or in the recent before diagnosis) might have different influences on CRC risk. For example, folate intake in the remote past was found to be most strongly inversely associated with risk of CRC21, which suggests the importance of Int J Cancer. Author manuscript; available in PMC 2017 July 18.

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timing of intake of one-carbon metabolism-related nutrients on the development of CRC. However, previous cohort studies2–8, 20 only had a single assessment of vitamin B2 intake. No study has examined the latency of vitamin B2 intake in relation to CRC risk. Furthermore, the association between vitamin B2 intake and CRC risk might be modified by other factors. Alcohol is known to disrupt the metabolism of vitamin B2 and induce DNA instability and abnormal DNA methylation22. Thus, alcohol intake might modify the association between vitamin B2 and CRC, but findings have been inconsistent2, 6, 9, 20. Onecarbon metabolism is a complex network that interconnects multiple nutrients. The association between vitamin B2 intake and CRC risk might be modified by folate2, 4, 9, 20 and other nutrients related to the one-carbon metabolism.

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Hence, we performed this study to evaluate the association of intakes of total (from foods and supplements), dietary (from foods only), and supplemental vitamin B2 with risk of CRC. Further, we evaluated whether the association varies according to the time between vitamin B2 intakes and CRC diagnosis and anatomic subsites and by several CRC risk factors including alcohol consumption, smoking status, multivitamin use, folate intake, calcium intake and family history of CRC.

Methods Study design and participants

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The Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) are ongoing prospective cohort studies21, 23, 24. The NHS was initiated in 1976 including 121,700 registered female nurses of aged 30 to 55 years. The HPFS was a prospective cohort study including 51,529 male health professionals aged 40–75 years initiated it 1986. Participants responded to biennial follow-up questionnaires including demographic information, medical histories, lifestyles, and risk factors for chronic diseases. The followup of both cohorts was generally complete for more than 90%.

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For the current examination of vitamin B2 intake in relation to CRC risk, the baseline year was 1984 in the NHS and 1986 in HPFS, when vitamin B2 was first assessed from a comprehensive dietary food frequency questionnaire (FFQ) with ~130 food items. We excluded participants who reported implausible calorie intake (3500 kcal/d for women and 4200 kcal/d for men) or left more than 70 questions blank in the FFQ. We also excluded participants who were previously diagnosed with cancer (except nonmelanoma skin cancer) and who had ulcerative colitis or Crohn’s disease at baseline. Consequently, 100,033 women in the NHS and 44,007 men in the HPFS were included in this analysis and followed until 2010. These studies were approved by the institutional review board at the Harvard T.H. Chan School of Public Health and Brigham and Women’s Hospital, Boston, Massachusetts. Assessment of dietary intake Dietary information was collected using a validated FFQ with ~130 food items approximately every 2–4 years since 1984 in the NHS and since 1986 in the HPFS25. Nutrient intake was calculated by multiplying the frequency response of each specified food

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item by the nutrient content of the specified portion sizes and by summing these products for all food items. A food composition database from the US Department of Agriculture and other sources was used to estimate nutrient intake26, 27. The use of multivitamins and other dietary supplements was ascertained via biennial questionnaires. Total vitamin B2 intake included intakes from foods and supplements, whereas dietary vitamin B2 intake included intakes from foods only. Intakes of vitamins B2 measured by FFQ have previously been validated25, 28–30. For participants in NHS and HPFS, approximately 60% amount of total vitamin B2 intake was from supplements containing vitamin B2. Nutrient intakes were cumulatively averaged and adjusted for energy intake using residual methods31. The correlation coefficients of total vitamin B2 intake and dairy foods (main food sources of vitamin B2) from FFQ and from two one-week diet records were 0.88 and 0.70 for men and 0.58 and 0.79 for women25, 28–30, respectively.

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Ascertainment of CRC cases Newly diagnosed CRC cases from baseline until 2010 were identified through participants’ self-report on each biennial questionnaire, and confirmed through medical and pathological record review. The National Death Index was used to identify participants whose death was attributable to CRC32. Information on tumor location was extracted from medical records and pathology reports. A total of 2,093 incident CRC cases in the NHS and 944 cases in the HPFS were identified and included in the analysis. Assessment of confounding variables

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Information on potential confounders such as body mass index (BMI), physical activity, smoking status, aspirin use, hormone replacement therapy (only in NHS), multivitamin supplement use, family history of CRC, and history of sigmoidoscopy/colonoscopy were collected from self-reported biennial questionnaires. Statistical analysis We used cumulative average vitamin B2 intakes as our primary exposure33 and also separately estimated baseline vitamin B2 intakes and intakes with a varying lag time before diagnosis of CRC to evaluate the latency between vitamin B2 intake and CRC21, 23. For example, in the HPFS, for latency of 0–4 years before diagnosis, we used vitamin B2 intake in 1986 for cases diagnosed from 1986 through 1990; intake in 1990 for cases diagnosed from 1990 through 1994; and so forth. The lag time of vitamin B2 intake for non-cases was assessed in the same way relative to censor time. We categorized vitamin B2 intake into quintiles based on the intake distribution in our study population.

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A Cox proportional hazards model was used to estimate RR and 95% CI across quintiles of vitamin B2 intake for risk of overall CRC and anatomic subsites of CRC separately in NHS and HPFS. Person-years of follow-up for every analysis was calculated from the date of baseline questionnaire return (1984 for NHS; 1986 for HPFS) to the date of CRC diagnosis, death, loss to follow-up, or end of the follow-up (2010), whichever came first. Age at baseline (in months) and the calendar year of questionnaire return were included as stratification variables. The multivariate model adjusted for factors associated with CRC risk and vitamin B2 intakes as follows: BMI (

Vitamin B2 intake and colorectal cancer risk; results from the Nurses' Health Study and the Health Professionals Follow-Up Study cohort.

Vitamin B2 serves as a cofactor to enhance one-carbon metabolism, maintain mucous membranes, and has been implicated in lowering colorectal cancer (CR...
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