Abstract
Purpose:
We prospectively examined associations of lung cancer risk with food intakes of B vitamins involved in one-carbon metabolism and the use of folic acid-containing supplements among a low-income population of black and white adults in the southeastern US.
Methods:
Within the Southern Community Cohort Study, we included 1,064 incident lung cancer cases among 68,236 participants aged 40–79 years at study enrollment. Food intakes and use of folic acid-containing supplements were assessed using a validated food frequency questionnaire at study enrollment. Multivariate Cox regression was used to estimate hazards ratios (HRs) and the 95% confidence intervals (CIs).
Results:
Folate and/or folic acid intakes from food were not associated with lung cancer risk; HRs (95% CI) for highest compared with lowest quartile were 1.04 (0.87–1.24) for total dietary folate, 0.95 (0.80–1.13) for food folate, and 1.07 (0.90–1.27) for food folic acid, respectively. Similarly, no associations were observed after stratifying by sex, race and smoking status, except for a positive association with total dietary folate intake among black women (HR=1.46, 95% CI=1.04–2.05 for the highest quartile compared with the lowest quartile, P-trend=0.02). Neither the use of folic acid-containing supplements nor food intakes of vitamin B6, vitamin B12 and riboflavin were associated with lung cancer risk.
Conclusions:
Our findings do not support a protective effect of folate or folic acid for lung cancer prevention in a low-income population of black and white adults in the southeastern US. Our finding of a positive association with total dietary folate intake among black women needs to be interpreted with caution and replicated in other studies.
Keywords: Folate, folic acid, lung cancer, African Americans
INTRODUCTION
Folate is found in food in multiple chemical forms, including folic acid, which is often used in fortified foods and vitamin supplements. In the human body, the metabolic function of folate coenzymes is to mediate the transfer of one-carbon units. Folate, as a methyl group donor and acceptor, along with vitamin B6, vitamin B12 and riboflavin, participates in DNA synthesis, methylation, and repair and affects DNA integrity. In addition to neural tube defects [1], it has been well documented that folate plays a role in carcinogenesis [2]. It has been reported that the levels of carcinogen DNA adducts (mainly derived by cigarette smoking) in adjacent normal tissue samples of lung cancer patients were non-significantly inversely associated with dietary folate intakes, which became statistically significant among patients who carried the AC/CC genotype of the MTHFR A1298C polymorphism [3], suggesting that dietary folate intake and folate metabolism may play important roles in lung carcinogenesis. In addition, folate deficiency is associated with diminished DNA stability, which consequently affects cancer risk [4]. Fortification of the US food supply with folic acid within the last couple of decades has resulted in an increase in both folate intake and circulating blood folate levels [5] and decreased occurrence of neural tube defects [6–9], although sub-population groups, such as low-income households and non-Hispanic black women, continue to be more at risk for folate inadequacy than other groups [5]. The effect of the recent increase in folate and folic acid intake on cancer incidence has been investigated, but results are conflicting. Some reports suggest that the increased folate intake might be responsible for an increase in the risk of colorectal cancer [6–8]. In contrast, other recent studies have reported that fortification of the US food supply with folic acid, and an increased use of vitamin supplements containing folic acid, may have resulted in decreasing colorectal cancer incidence among whites, but not among blacks, suggesting race-specific effects [10,11].
A meta-analysis combining 13 clinical trials of folic acid, vitamin B6 and/or vitamin B12 supplementation, designed for cardiovascular disease or colorectal adenoma recurrence prevention, found no effect on lung cancer incidence [11]. Another meta-analysis of nine prospective cohort studies reported a marginally statistically significant inverse association between folate intake and lung cancer risk among all participants, which became statistically significant only among men [12]. In brief, a few case-control studies found an inverse association between folate intake or circulating folate level and lung cancer risk in adults and former smokers [13–16]. Most cohort studies reported no association of lung cancer risk with dietary or supplemental folate intake [17–25], and one study reported a positive association for dietary folate intake [26]. The majority of studies included in these two meta-analyses were conducted in populations predominately of European descent and high socioeconomic status. Limited evidence exists for underserved populations such as blacks and low-income populations. For example, black men experience a disproportionately higher risk of lung cancer than whites [27], and potential sex differences in lung cancer etiology have also been reported [28,29]. Moreover, black women and low-income households have a higher prevalence of inadequate folate intake compared with whites or Hispanics and high-income households [30], which we also observed in our study population [31]. However, potential differential associations between folate and lung cancer risk by sex and race have not been well investigated. In this report, we conducted a study within the Southern Community Cohort Study (SCCS) [32], a low-income population (in which two-thirds are blacks) living in the southeastern US, to test the hypothesis that intake of folate and folic acid from foods is associated with risk of incident lung cancer, and whether the association differs by race or sex.
MATERIALS AND METHODS
Study population
The SCCS is a population-based, prospective cohort study of nearly 86,000 adults designed to assess disparities in the risk of chronic diseases among adults in urban and rural areas [32]. Study participants were recruited from 12 states in the southeastern US (Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, Virginia, and West Virginia). Participating adults were 40–79 years at the time of recruitment, which occurred between March 2002 and September 2009. The majority of study participants (about 85%) were enrolled from 71 community health centers (CHC), where study questionnaires were administered using computer-assisted personal interviewing by trained interviewers. An additional 15% of the cohort enrolled from 2004 to 2006 by responding to a mailed questionnaire sent to randomly selected residents of the same 12 states. Approximately two-thirds of participants self-reported being black, and about 60% had a household income of less than $15,000 annually. The study protocol was approved by the institutional review boards of Vanderbilt University and Meharry Medical College, and all participants provided written informed consent.
In the current analysis, among 84,521 participants who were actively enrolled in the study in August 2016, we excluded: 1) those who had been diagnosed with any cancer at baseline (n=5,815); 2) those who did not have valid dietary intake information due to missing responses for more than 10 food items or reporting extreme total energy intake (<600 or >8,000 Kcal per day) (n=6,688); 3) those who had missing information for at least one of the following covariates [smoking status, pack-years of smoking, body mass index (BMI), chronic obstructive pulmonary disease (COPD), race, education and income] (n=3,756); and 4) those who had less than a month between enrollment and last follow-up age (n=26), leaving a total of 1,064 cases among 68,236 participants for the current analysis.
Baseline data collection and dietary assessment
As part of the study protocol, participants completed a food frequency questionnaire (FFQ) that assessed typical intake frequency of 104 food items and food groups during the past year. The FFQ was developed for the SCCS and embraces the unique ethnic and cultural diversity of the study population [33]. The amounts of individual food items consumed per day were estimated in two steps. First, the FFQ asked participants for the frequency of consumption of food items (responses ranged from “never” to “two or more times per day,” with nine potential responses). Second, the portion size of each food item for each participant was estimated by applying the average race, sex, and census-region-specific portion size of each food item reported in national dietary surveys [i.e., National Health and Nutrition Examination Survey (NHANES) and Continuing Survey of Food Intakes by Individuals (CSFII)] by participants residing in the southeastern US [34]. Then, nutrient intakes per day were estimated by applying the nutrient compositions of the food items used in the NHANES and CFSII, which were based on food composition table databases from the United States Department of Agriculture and the University of Minnesota Nutrition Coordinating Center [34]. The FFQ was validated in a subset of 209 SCCS participants [35]. Total dietary folate intake was calculated as a sum of food folate (natural form) and folic acid (synthetic form used in fortification) from food sources only (no supplemental intake information was added, as the dosage of supplements taken was not assessed in our study), and estimated as dietary folate equivalents [36]. Previously, we validated total dietary folate intake against serum folate concentration (r=0.26) in another subset of SCCS participants [31]. In addition, the FFQ included questions on supplement use and asked for the type of supplements (e.g., multivitamins) and frequency of use, but not the dosage. In this analysis, the use of folic acid-containing supplements (any vs. none) was based on responses to two types of supplements, multivitamins and individual folic acid.
Lung cancer case ascertainment
Incident lung cancer cases, defined as first, primary lung cancer [ICD-O3 (International Classification of Diseases for Oncology, 3rd edition) codes of C34.0 to C34.9], were ascertained through participants’ data file linkage to state cancer registries [37]. The last data linkage to respective state cancer registry databases was completed up to 2014. Vital status was ascertained through linkage to Social Security Administration and National Death Index data files. A total of 1,064 lung cancer cases were available for the current analysis.
Statistical analysis
All statistical analyses were conducted using SAS 9.4 (SAS Institute, Inc., Cary, NC). Among 68,236 participants, during the follow-up period, 1,064 were censored due to lung cancer diagnosis, 9,098 were censored due to deaths and 25 due to lost-to-follow-up, leaving 58,049 who were censored at the last data linkage date through December 2014. Dietary intakes of B vitamins were adjusted for total energy intake by calculating intakes per 1,000 Kcal. Quartiles for dietary intake variables were created based on their intake distributions among all participants by applying sex- and race-specific (blacks or whites and other races) cut-off points, and entered simultaneously with continuous total energy intake variables (Kcal per day) into a model. Spearman correlation coefficients were calculated between dietary B vitamin intakes per 1,000 Kcal. Multivariate Cox proportional hazards models with underlying time metrics, from study enrollment to the first primary lung cancer diagnosis, were performed to estimate hazards ratios (HRs) and the corresponding 95% confidence intervals (CIs) for lung cancer risk in each intake quartile using the first (lowest) quartile as a reference. To test for a linear trend, variables for each median quartile values were entered into the model continuously. For associations with the use of folic acid-containing supplements, we estimated lung cancer risk associated with “any use” (regardless of the amount, given that no information was available on the dosage) by using “no use” as the reference. We first adjusted for age, sex, race (black, white, or others), recruitment method (CHC vs. mailing), and cigarette smoking history [pack-years of smoking, five categories including none (never smokers), >0–20, 20–40, 40–60, or ≥60 pack-years and current cigarette smoking status (current or past smokers)] in our smoking-adjusted model (Model 1). Then, we further adjusted for education, income, BMI (<25, ≥25-<30, or ≥30 kg/m2) and personal medical history of COPD by a priori selection of confounders that are known risk factors for lung cancer based on our previous publications [37–40] in our fully-adjusted model (Model 2). We tested the proportional hazard assumption by including interaction terms of time and covariates in multivariate models and found no evidence of violation of the assumption.
Associations of lung cancer risk with total dietary folate, food folate, or food folic acid intakes were stratified by sex (men or women), race (black or white; other race groups were excluded due to the small sample size), sex and race groups combined (white men, black men, white women, or black women), smoking status among smokers (current or past cigarette smokers; never smokers were excluded from this analysis due to the small sample size), alcohol consumption (any or none), and supplement use (any or none for the use of folic acid-containing supplements from individual folic acid or multivitamin supplements). The potential effect modification was evaluated by including the cross-product term of the main effect and effect modifier and assessing the P-value of the cross-product term.
RESULTS
Characteristics of the study population
About two-thirds of participants in the SCCS were black, and about 60% were women. The mean age was 51.8 years. Participants in the highest quartile of total dietary folate intake tended to be older and have a higher socioeconomic status based on household income and education (Table 1). In addition, those at higher quartiles of total dietary folate intake tended more likely to be never smokers, have less passive smoking exposure, have used vitamin supplements, and have consumed less alcohol than those at lower quartiles. Total energy intake tended to be lower as quartiles increased. The strongest correlation among B vitamins tested was observed between intakes of total dietary folate and food folic acid (r=0.84), followed by the correlation between vitamin B6 and total dietary folate (r=0.72), and the correlation between riboflavin and total dietary folate (r=0.61) (Table 2). The median total dietary folate intakes were 248 μg/1000 Kcal among white men, 238 μg/1000 Kcal among black men, 271 μg/1000 Kcal among white women, and 251 μg/1000 Kcal among black women. Presented in Table 3 are cut-offs of B vitamin intakes per quartiles by race and sex groups.
TABLE 1.
Characteristics of the study population by quartiles of total dietary folate intake from food in the Southern Community Cohort Study1
| Quartiles of total dietary folate intake from foods | ||||
|---|---|---|---|---|
| 1 (Lowest) | 2 | 3 | 4 (Highest) | |
| Number | 17,061 | 17,058 | 17,060 | 17,060 |
| Women | 59.0% | 59.0% | 59.0% | 59.0% |
| Age at interview | 49.6 ± 7.4 | 51.0 ± 8.2 | 52.4 ± 8.7 | 54.2 ± 6.3 |
| Race | ||||
| White | 28.9% | 28.9% | 28.6% | 28.2% |
| Black | 67.5% | 67.5% | 67.5% | 67.5% |
| Others | 3.6% | 3.6% | 3.9% | 4.3% |
| Recruitment through CHC | 89.5% | 89.3% | 89.4% | 88.5% |
| Having insurance | 53.4% | 57.8% | 60.3% | 65.4% |
| Household income | ||||
| <$15,000 | 57.5% | 55.5% | 55% | 54% |
| $15,000-$25,000 | 21.7% | 22% | 21.5% | 21% |
| >$25,000 | 20.8% | 22.5% | 23.5% | 25% |
| Education | ||||
| <12 years | 29.0% | 28.6% | 28.0% | 28.6% |
| 12 years | 35.9% | 33.6% | 33.1% | 30.8% |
| >12 years | 35.1% | 37.8% | 38.9% | 40.6% |
| Family history of lung cancer | 11.5% | 11.2% | 11.2% | 10.9% |
| Personal history of lung disease | 23.4% | 22.3% | 21.8% | 20.8% |
| COPD | 9.4% | 9.0% | 8.3% | 7.8% |
| Tuberculosis | 3.4% | 3.0% | 3.0% | 2.5% |
| Asthma | 15.1% | 14.6% | 14.5% | 14.3% |
| Smoking status | ||||
| Current smokers | 51.8% | 44.7% | 39.3% | 30.8% |
| Past smokers | 17.4% | 20.4% | 22.8% | 26.5% |
| Never smokers | 30.8% | 35.0% | 37.8% | 42.7% |
| Pack-years of smoking | 24.3 ± 22.8 | 22.8 ± 21.7 | 22.5 ± 22.5 | 21.7 ± 22.5 |
| Age started smoking (years) | 17.0 ± 5.7 | 17.5 ± 5.9 | 17.8 ± 6.1 | 17.9 ± 6.0 |
| Age stopped smoking (years) | 39.0 ± 11.8 | 39.2 ± 12.2 | 39.5 ± 12.4 | 40.1 ± 12.8 |
| Average cigarettes (per day) | 16.3 ± 13.3 | 15.6 ± 12.8 | 15.4 ± 13.3 | 15.0 ± 12.9 |
| Menthol cigarette use | 46.9% | 43.0% | 39.8% | 35.4% |
| Passive smoking exposure | 62.0% | 57.6% | 52.7% | 45.6% |
| BMI (kg/m2) | 30.1 ± 7.7 | 30.4 ± 7.7 | 30.5 ± 7.5 | 30.5 ± 7.3 |
| <25 kg/m2 | 28.0% | 26.3% | 24.2% | 23.2% |
| 25–29.55 kg/m2 | 28.8% | 29.2% | 30.2% | 30.8% |
| >30 kg/m2 | 43.2% | 44.5% | 45.6% | 46.0% |
| Any vitamin supplement use | 38.8% | 43.8% | 47.7% | 52.2% |
| Folic acid supplement use | ||||
| None | 93.8% | 92.1% | 91.3% | 90.1% |
| Less than once a day | 3.3% | 4.2% | 4.8% | 5.0% |
| At least once a day | 2.9% | 3.7% | 3.9% | 4.9% |
| Multivitamin supplement use | ||||
| None | 67.2% | 62.3% | 59.1% | 55.6% |
| Less than once a day | 9.8% | 10.9% | 10.8% | 10.3% |
| At least once a day | 23.0% | 26.8% | 30.1% | 34.1% |
| Alcohol consumption (drinks/day) | 2.9 ± 6.0 | 1.8 ± 3.0 | 0.7 ± 2.0 | 0.4 ± 1.4 |
| None | 36.2% | 43.1% | 48.9% | 56.8% |
| <2 drinks/day | 35.5% | 40.4% | 40.0% | 37.7% |
| ≥2 drinks/day | 28.3% | 16.5% | 11.1% | 5.5% |
| Total energy (kcal/day) | 2842± 1587 | 2679± 1500 | 2534±1409 | 2277 ± 1263 |
Nutrient intakes were adjusted for total caloric intake and presented as mean ± standard error; the rest of the continuous variables were presented as mean ± standard deviations.
Abbreviations: CHC, community health centers; COPD, chronic obstructive pulmonary disease; BMI, body mass index.
TABLE 2.
Spearman correlation among food B vitamin intakes (n=68, 236)1
| Riboflavin | Vitamin B6 | Total dietary folate | Dietary folate | Dietary folic acid | Vitamin B12 | |
|---|---|---|---|---|---|---|
| Riboflavin | - | |||||
| Vitamin B6 | 0.54 | - | ||||
| Total dietary folate | 0.61 | 0.72 | - | |||
| Food folate | 0.30 | 0.56 | 0.54 | - | ||
| Food folic acid | 0.54 | 0.50 | 0.84 | 0.08 | - | |
| Vitamin B12 | 0.53 | 0.54 | 0.40 | 0.14 | 0.41 | - |
B vitamin intakes are based on per 1000 kcal.
Table 3.
Cut-offs of B vitamin intakes per quartile by sex and race groups
| Quartile | White/other men | Black men | White/other women | Black women | |
|---|---|---|---|---|---|
| Total dietary folate intake | |||||
| (μg/1000 kcal) | 1 | <209 | <201 | <223 | >210 |
| 2 | 209–249 | 201–238 | 223–271 | 210–251 | |
| 3 | 249–307 | 238–289 | 271–344 | 251–306 | |
| 4 | >307 | >289 | >344 | >306 | |
| Food folate | |||||
| (μg/1000 kcal) | 1 | <94 | <90 | <99 | <94 |
| 2 | 94–111 | 90–107 | 99–121 | 94–114 | |
| 3 | 111–133 | 107–127 | 121–148 | 114–141 | |
| 4 | >133 | >127 | >148 | >141 | |
| Food folic acid | |||||
| (μg/1000 kcal) | 1 | <62 | <56 | <59 | <57 |
| 2 | 62–84 | 56–74 | 59–78 | 57–76 | |
| 3 | 84–121 | 74–100 | 78–108 | 76–102 | |
| 4 | >121 | >100 | >108 | >102 | |
| Riboflavin | |||||
| (mg/1000 kcal) | 1 | <0.89 | <0.77 | <0.96 | <0.74 |
| 2 | 0.89–1.05 | 0.77–0.88 | 0.96–1.16 | 0.74–0.85 | |
| 3 | 1.05–1.25 | 0.88–1.02 | 1.16–1.43 | 0.85–1.00 | |
| 4 | >1.25 | >1.02 | >1.43 | >1.00 | |
| Vitamin B6 | |||||
| (mg/1000 kcal) | 1 | <0.77 | <0.75 | <0.77 | <0.73 |
| 2 | 0.77–0.92 | 0.75–0.88 | 0.77–0.95 | 0.73–0.88 | |
| 3 | 0.92–1.11 | 0.88–1.03 | 0.95–1.20 | 0.88–1.07 | |
| 4 | >1.11 | >1.03 | >1.20 | >1.07 | |
| Vitamin B12 | |||||
| (μg/1000 kcal) | 1 | <2.14 | <1.95 | <2.11 | <1.99 |
| 2 | 2.14–2.71 | 1.95–2.53 | 2.11–2.72 | 1.99–2.58 | |
| 3 | 2.71–3.39 | 2.53–3.22 | 2.72–3.44 | 2.58–3.32 | |
| 4 | >3.39 | >3.22 | >3.44 | >3.32 |
Food folate and folic acid intakes and lung cancer risk
Among all participants, total dietary folate intake was not associated with lung cancer risk (HR=1.04, 95% CI=0.87–1.24 for the highest quartile compared with the lowest, P-trend=0.47) (Model 1). In a fully-adjusted model (Model 2), total dietary folate intake was also not associated with lung cancer risk (HR=1.08, 95% CI=0.91–1.29, P-trend=0.28) (Table 4). When we further investigated natural dietary folate (“food folate”) and synthetic folic acid (“food folic acid”) intakes from foods separately (Table 4), neither of them were associated with lung cancer risk (food folate: HR=1.00, 95% CI=0.84–1.19, P-trend=0.79; food folic acid: HR=1.09, 95% CI=0.91–1.30, P-trend=0.44). Similar associations with food folate or folic acid intakes were observed in our smoking-adjusted model.
TABLE 4.
Risk of lung cancer by quartiles of food B vitamin intakes per 1000 kcal1
| Model 1 | Model 2 | |||||||
|---|---|---|---|---|---|---|---|---|
| Nutrient | Quartiles | Cases | HR | 95% CI | P-trend | HR | 95% CI | P-trend |
| Total dietary folate | 1 (lowest) | 274 | Reference | Reference | ||||
| (μg/1000 kcal) | 2 | 258 | 0.96 | 0.81, 1.14 | 0.97 | 0.82, 1.15 | ||
| 3 | 271 | 1.02 | 0.86, 1.21 | 1.05 | 0.89, 1.25 | |||
| 4 (highest) | 261 | 1.04 | 0.87, 1.24 | 0.47 | 1.08 | 0.91, 1.29 | 0.28 | |
| Food folate | 1 | 280 | Reference | Reference | ||||
| (μg/1000 kcal) | 2 | 277 | 0.98 | 0.83, 1.16 | 0.99 | 0.84, 1.17 | ||
| 3 | 251 | 0.89 | 0.75, 1.05 | 0.92 | 0.77, 1.09 | |||
| 4 | 256 | 0.95 | 0.80, 1.13 | 0.41 | 1.00 | 0.84, 1.19 | 0.79 | |
| Food folic acid | 1 | 260 | Reference | Reference | ||||
| (μg/1000 kcal) | 2 | 275 | 1.08 | 0.91, 1.28 | 1.09 | 0.92, 1.30 | ||
| 3 | 273 | 1.10 | 0.92, 1.30 | 1.11 | 0.94, 1.32 | |||
| 4 | 256 | 1.07 | 0.90, 1.27 | 0.54 | 1.09 | 0.91, 1.30 | 0.44 | |
| Riboflavin | 1 | 249 | Reference | Reference | ||||
| (mg/1000 kcal) | 2 | 247 | 1.00 | 0.84, 1.20 | 1.03 | 0.86, 1.22 | ||
| 3 | 271 | 1.04 | 0.87, 1.23 | 1.06 | 0.89, 1.27 | |||
| 4 | 297 | 1.09 | 0.91, 1.29 | 0.14 | 1.14 | 0.96, 1.36 | 0.08 | |
| Vitamin B6 | 1 | 326 | Reference | Reference | ||||
| (mg/1000 kcal) | 2 | 267 | 0.90 | 0.76, 1.05 | 0.91 | 0.78, 1.08 | ||
| 3 | 247 | 0.86 | 0.73, 1.02 | 0.89 | 0.76, 1.06 | |||
| 4 | 224 | 0.84 | 0.70, 1.00 | 0.07 | 0.89 | 0.75, 1.06 | 0.24 | |
| Vitamin B12 | 1 | 300 | Reference | Reference | ||||
| (μg/1000 kcal) | 2 | 232 | 0.82 | 0.69, 0.97 | 0.84 | 0.71, 1.00 | ||
| 3 | 267 | 0.94 | 0.80, 1.11 | 0.98 | 0.83, 1.16 | |||
| 4 | 265 | 0.95 | 0.80, 1.12 | 0.87 | 0.99 | 0.84, 1.17 | 0.73 | |
Model 1 adjusted for age, sex, race, recruitment method, pack-years of smoking, current cigarette smoking status (current vs past), and total energy intake; Model 2 adjusted for age, sex, race, recruitment method, pack-years of smoking, current cigarette smoking status, total energy intake, education, income, BMI category, and history of COPD.
Overall, there were no statistically significant associations of total dietary folate or separately by food folate or folic acid intakes with risk of lung cancer in groups stratified by sex, race, smoking status, alcohol consumption or the use of folic acid-containing supplements (Table 5 and Supplemental Table), similar to associations observed among all participants. We further stratified our analyses on associations between folate and/or folic acid from foods and lung cancer risk by sex and race (Table 6). A statistically significant positive association was observed between total dietary folate intake and lung cancer risk among black women (HR=1.46, 95% CI=1.04–2.05 for the highest quartile compared with the lowest quartile, P-trend=0.02). This positive association of total dietary folate intake among black women was observed only for food folic acid intake (HR=1.30, 95% CI=0.94–1.81 for the highest quartile compared with the lowest quartile, P-trend=0.06), although the association was not statistically significant. The association with total dietary folate intake was not statistically significant in white men or women and black men (Table 6). Similarly, the associations with food folate and folic acid intakes were not statistically significant in all subgroups stratified by sex and race (Table 6).
TABLE 5.
Risk of lung cancer by food folate or folic acid intakes stratified by sex, race, or smoking status1
| Quartiles | Cases | HR | 95% CI | P-trend | P-interaction | |
|---|---|---|---|---|---|---|
| Total dietary folate (μg/1000 kcal) | ||||||
| By sex | ||||||
| Men | 1 | 156 | Reference | |||
| 2 | 129 | 0.85 | 0.67, 1.07 | |||
| 3 | 153 | 1.02 | 0.81, 1.28 | |||
| 4 | 132 | 0.94 | 0.74, 1.19 | 0.94 | ||
| Women | 1 | 118 | Reference | |||
| 2 | 129 | 1.12 | 0.87, 1.44 | |||
| 3 | 118 | 1.08 | 0.84, 1.41 | |||
| 4 | 129 | 1.25 | 0.97, 1.62 | 0.16 | 0.39 | |
| By race | ||||||
| Whites | 1 | 86 | Reference | |||
| 2 | 88 | 1.01 | 0.78, 1.32 | |||
| 3 | 79 | 1.11 | 0.86, 1.45 | |||
| 4 | 79 | 1.00 | 0.76, 1.32 | 0.95 | ||
| Blacks | 1 | 179 | Reference | |||
| 2 | 163 | 0.90 | 0.74, 1.11 | |||
| 3 | 182 | 1.07 | 0.87, 1.30 | |||
| 4 | 174 | 1.08 | 0.88, 1.33 | 0.24 | 0.83 | |
| By smoking status | ||||||
| Past smokers | 1 | 38 | Reference | |||
| 2 | 41 | 0.83 | 0.53, 1.29 | |||
| 3 | 57 | 0.97 | 0.64, 1.47 | |||
| 4 | 76 | 1.01 | 0.68, 1.51 | 0.51 | ||
| Current smokers | 1 | 229 | Reference | |||
| 2 | 198 | 0.94 | 0.78, 1.14 | |||
| 3 | 199 | 1.04 | 0.86, 1.26 | |||
| 4 | 168 | 1.07 | 0.87, 1.31 | 0.42 | 0.94 | |
| Food folate (μg/1000 kcal) | ||||||
| By sex | ||||||
| Men | 1 | 150 | Reference | |||
| 2 | 143 | 0.92 | 0.73, 1.16 | |||
| 3 | 135 | 0.89 | 0.70, 1.13 | |||
| 4 | 142 | 1.00 | 0.79, 1.26 | 0.98 | ||
| Women | 1 | 130 | Reference | |||
| 2 | 134 | 1.09 | 0.85, 1.39 | |||
| 3 | 116 | 0.95 | 0.74, 1.22 | |||
| 4 | 114 | 0.98 | 0.76, 1.28 | 0.68 | 0.67 | |
| By race | ||||||
| Whites | 1 | 83 | Reference | |||
| 2 | 93 | 1.03 | 0.80, 1.34 | |||
| 3 | 79 | 0.94 | 0.72, 1.23 | |||
| 4 | 77 | 1.00 | 0.76, 1.32 | 0.92 | ||
| Blacks | 1 | 187 | Reference | |||
| 2 | 177 | 0.95 | 0.78, 1.16 | |||
| 3 | 165 | 0.91 | 0.74, 1.12 | |||
| 4 | 169 | 0.99 | 0.81, 1.22 | 0.85 | 0.77 | |
| By smoking status | ||||||
| Past smokers | 1 | 46 | Reference | |||
| 2 | 41 | 0.72 | 0.47, 1.10 | |||
| 3 | 48 | 0.68 | 0.45, 1.02 | |||
| 4 | 77 | 0.85 | 0.58, 1.24 | 0.89 | ||
| Current smokers | 1 | 216 | Reference | |||
| 2 | 217 | 1.06 | 0.88, 1.28 | |||
| 3 | 190 | 1.01 | 0.83, 1.23 | |||
| 4 | 171 | 1.10 | 0.89, 1.35 | 0.52 | 0.19 | |
| Food folic acid (μg/1000 kcal) | ||||||
| By sex | ||||||
| Men | 1 | 140 | Reference | |||
| 2 | 160 | 1.19 | 0.95, 1.50 | |||
| 3 | 141 | 1.05 | 0.83, 1.33 | |||
| 4 | 129 | 1.01 | 0.79, 1.29 | 0.67 | ||
| Women | 1 | 120 | Reference | |||
| 2 | 115 | 0.97 | 0.75, 1.26 | |||
| 3 | 132 | 1.19 | 0.92, 1.52 | |||
| 4 | 127 | 1.17 | 0.91, 1.51 | 0.18 | 0.26 | |
| By race | ||||||
| Whites | 1 | 91 | Reference | |||
| 2 | 80 | 0.98 | 0.76, 1.28 | |||
| 3 | 89 | 1.05 | 0.81, 1.36 | |||
| 4 | 72 | 0.93 | 0.71, 1.22 | 0.68 | ||
| Blacks | 1 | 163 | Reference | |||
| 2 | 187 | 1.16 | 0.95, 1.42 | |||
| 3 | 172 | 1.10 | 0.90, 1.35 | |||
| 4 | 176 | 1.17 | 0.95, 1.44 | 0.23 | 0.24 | |
| By smoking status | ||||||
| Past smokers | 1 | 38 | Reference | |||
| 2 | 44 | 1.09 | 0.71, 1.69 | |||
| 3 | 63 | 1.41 | 0.94, 2.12 | |||
| 4 | 67 | 1.19 | 0.80, 1.79 | 0.36 | ||
| Current smokers | 1 | 216 | Reference | |||
| 2 | 215 | 1.04 | 0.86, 1.26 | |||
| 3 | 194 | 1.01 | 0.83, 1.23 | |||
| 4 | 169 | 1.02 | 0.83, 1.25 | 0.99 | 0.53 | |
Cox proportional hazards adjusted for age, sex, race, recruitment method, pack-years of smoking, current cigarette smoking status, education, income, BMI category, history of COPD, and total energy intake. Estimates for smoking status, folic acid-containing supplement use, alcohol consumption, and household income come from models containing the interaction terms between the variable and the nutrient intake.
TABLE 6.
Risk of lung cancer by folate or folic acid intakes stratified by sex and race1
| Quartiles | Cases | HR | 95% CI | P-trend | P-interaction | ||
|---|---|---|---|---|---|---|---|
| Total dietary folate (μg/1000 kcal) | sex | race | |||||
| White men | 1 | 42 | Reference | ||||
| 2 | 34 | 0.81 | 0.51, 1.28 | ||||
| 3 | 37 | 0.90 | 0.57, 1.41 | ||||
| 4 | 34 | 0.89 | 0.56, 1.44 | 0.80 | |||
| White women | 1 | 44 | Reference | ||||
| 2 | 54 | 1.20 | 0.80, 1.79 | ||||
| 3 | 42 | 1.07 | 0.70, 1.64 | ||||
| 4 | 45 | 1.11 | 0.72, 1.70 | 0.84 | |||
| Black men | 1 | 112 | Reference | ||||
| 2 | 93 | 0.86 | 0.65, 1.14 | ||||
| 3 | 112 | 1.05 | 0.80, 1.37 | ||||
| 4 | 93 | 0.93 | 0.70, 1.23 | 0.88 | |||
| Black women | 1 | 67 | Reference | ||||
| 2 | 70 | 1.09 | 0.77, 1.52 | ||||
| 3 | 70 | 1.13 | 0.80, 1.59 | ||||
| 4 | 81 | 1.46 | 1.04, 2.05 | 0.02 | 0.30 | 0.82 | |
| Dietary folate (μg/1000 kcal) | |||||||
| White men | 1 | 36 | Reference | ||||
| 2 | 39 | 1.04 | 0.66, 1.65 | ||||
| 3 | 38 | 1.03 | 0.65, 1.64 | ||||
| 4 | 34 | 0.97 | 0.60, 1.58 | 0.88 | |||
| White women | 1 | 47 | Reference | ||||
| 2 | 54 | 1.25 | 0.84, 1.85 | ||||
| 3 | 41 | 0.93 | 0.61, 1.42 | ||||
| 4 | 43 | 1.03 | 0.67, 1.59 | 0.82 | |||
| Black men | 1 | 111 | Reference | ||||
| 2 | 102 | 0.89 | 0.68, 1.16 | ||||
| 3 | 93 | 0.83 | 0.63, 1.09 | ||||
| 4 | 104 | 1.01 | 0.76, 1.32 | 0.96 | |||
| Black women | 1 | 76 | Reference | ||||
| 2 | 75 | 1.02 | 0.74, 1.40 | ||||
| 3 | 72 | 1.01 | 0.73, 1.40 | ||||
| 4 | 65 | 0.96 | 0.68, 1.36 | 0.80 | 0.62 | 0.82 | |
| Dietary folic acid (μg/1000 kcal) | |||||||
| White men | 1 | 45 | Reference | ||||
| 2 | 35 | 0.83 | 0.53, 1.30 | ||||
| 3 | 40 | 0.94 | 0.61, 1.44 | ||||
| 4 | 27 | 0.65 | 0.40, 1.06 | 0.11 | |||
| White women | 1 | 46 | Reference | ||||
| 2 | 45 | 0.96 | 0.64, 1.46 | ||||
| 3 | 49 | 1.12 | 0.75, 1.69 | ||||
| 4 | 45 | 1.05 | 0.69, 1.60 | 0.71 | |||
| Black men | 1 | 94 | Reference | ||||
| 2 | 122 | 1.36 | 1.04, 1.79 | ||||
| 3 | 98 | 1.09 | 0.82, 1.45 | ||||
| 4 | 96 | 1.14 | 0.85, 1.52 | 0.83 | |||
| Black women | 1 | 69 | Reference | ||||
| 2 | 65 | 0.95 | 0.68, 1.33 | ||||
| 3 | 74 | 1.18 | 0.85, 1.64 | ||||
| 4 | 80 | 1.30 | 0.94, 1.81 | 0.06 | 0.19 | 0.25 | |
Cox proportional hazards adjusted for recruitment method, pack-years of smoking, current cigarette smoking status, education, income, BMI category, history of COPD, and total energy intake with age in months as the time scale.
Vitamin B6, vitamin B12 and riboflavin intakes and lung cancer risk
Intakes of vitamin B6, vitamin B12 and riboflavin were not associated with lung cancer risk among all participants (Table 4).
Folic acid-containing supplement use and lung cancer risk
The use of folic acid-containing supplements was not associated with lung cancer risk among all participants (HR=1.06, 95% CI=0.93–1.21 for any use compared with no use) (data not shown). When stratified by sex and race, the use of folic acid-containing supplements was not associated with lung cancer risk among men (HR=0.95, 95% CI=0.79–1.14), women (HR=1.17, 95% CI=0.97–1.42), whites (HR=1.02, 95% CI=0.81–1.29) or blacks (HR=1.06, 95% CI=0.90–1.25) (data not shown).
DISCUSSION
In this large prospective study with a high proportion of blacks and low-income households, we observed no association of lung cancer risk with folate and/or folic acid intake from foods among all participants or subgroups by sex and/or race, except for a positive association between total dietary folate intake and lung cancer risk observed among black women. Furthermore, the use of folic acid-containing supplements was not associated with the risk of lung cancer either among all participants or by sex and race subgroups. Food intakes of vitamin B6, vitamin B12 and riboflavin were also not associated with lung cancer risk.
Our finding of no statistically significant association with total dietary folate intake among all participants or smokers is consistent with some previous studies [17,18,22,23,41–44], but not all [26,13]. Among the previous studies that assessed food folate intake specifically, or food folate intake before folic acid fortification was implemented, our finding of no association between food folate intake and lung cancer risk is consistent with most of the previous studies [41,42,18,21–23,44], but conflicts with a few other studies that reported an inverse association [45,13,46,16]. We also found no association with folic acid intake from foods among all participants or smokers. Notably, we observed that the average folic acid intake from foods was much lower, and with a narrower range, than food folate intake. Moreover, we were unable to include folic acid intake from supplements in our intake estimation, a limitation which needs to be addressed in future studies of lung cancer along with folate and folic acid intake from foods.
In our stratified analysis by sex, we also did not observe clear differences in associations between folate and/or folic acid intake and lung cancer risk. Our finding based on sex-specific analysis is consistent with the pooled analysis that did not find an association or sex difference [17], but not with a recent meta-analysis of cohort studies in which the inverse association was limited to men [12]. Among four previous studies that measured circulating folate concentration [47,14,15,19], two studies evaluated sex-specific associations and reported significant [15] or non-significant [47] inverse associations among both men and women. Taken together, potential sex differences in lung cancer etiologies have been implicated [28], and sex differences in associations of lung cancer risk with two genetic variants in the MTHFR gene, known to affect folate metabolism, were reported from a previous US case-control study of non-Hispanic whites [48]. However, in previous studies or our current study, folate intake, per se, was not differentially associated with lung cancer risk when stratified by sex. Hence, currently, there is no strong evidence to suggest that the association between folate intake and lung cancer risk differs by sex. Although our study largely lacks MTHFR genotype information, future studies of folate and lung cancer need to consider polymorphisms in MTHFR and other genes related to folate metabolism.
As to racial differences, among men, a disproportionately high lung cancer risk among black men has been reported [27]; however, in terms of folate intake, both white and black men are considered to have adequate folate status [8]. In our study population, black women had a lower serum folate concentration than white women or black and white men, as we reported previously [31]. This is consistent with a higher prevalence of inadequate folate intake among black women compared with white women in the US population [6]. To our knowledge, our study is the first to investigate and report no associations of lung cancer risk with food folate and/or folic acid intake specifically among black men. In contrast, our study is also the first to report a positive association between total dietary folate intake and lung cancer risk among black women, although the effects of interactions for sex or race were not significant. Hence, the observed positive association among black women may be a chance finding and needs to be interpreted with caution. One previous study in Denmark reported a positive association between dietary folate intake and lung cancer risk [26]. They noted that their relatively high folate intake (330 μg/day) might have led to a positive association, which may also be the case in our study, as our intake (mean total dietary folate intake: 695 μg/day) was higher than intakes reported in most previous studies [13,18,17,21,26,43,41,42]. In addition, given a non-significant positive association with food folic acid intake, but not with food folate, the positive association for total dietary folate intake may be more due to food folic acid than food folate. Major food sources of natural folate are vegetables, whereas synthetic folic acid is from fortified cereal grain products. Hence, it is possible that this finding may be driven by other compounds found in these cereal grain products, but not folic acid per se. Among white men or women and black men, we found no association between food folic acid intake and lung cancer risk, which suggests that there may be no benefit of folic acid fortification on lung cancer risk in these subgroups. Considering the long latency period for lung cancer, our findings may need to be re-evaluated one or two decades after the initiation of folic acid fortification to fully assess its effect on lung cancer risk, as has been previously suggested for colorectal cancer [10]. Nonetheless, our study is one of the first to investigate and report a positive association of total dietary folate intake from food with lung cancer risk among black women, which underscores the need for replication in other studies.
Consistent with findings from the US [20,25] and Danish [26] cohort studies, our results do not support the protective effect of folic acid-containing supplement use on lung cancer risk. In contrast to the US cohorts that comprised a predominately white population from mostly high-income households [20,25], our cohort included a high proportion of blacks and low-income households, who might have been more vulnerable to folate inadequacy than other population subgroups [5,8,30,6], and thus, be expected to benefit more from folate supplementation. Hence, it is noteworthy that we were able to replicate the null finding reported by previous US cohort studies [20,25].
A strength of our study is the inclusion of one of the largest numbers of lung cancer cases among blacks (n=698) and adults from low-income households (n=719) within a single cohort study in the US, to our knowledge. A comprehensive set of prospectively collected exposures associated with lung cancer risk enabled us to adjust for several confounders. Dietary assessment was initiated in 2002, which was after the mandatory folic acid fortification of the food supply was implemented in the US. Thus, the assessment of total dietary folate intake was less likely to be affected by changes in food content of folic acid over time than the intakes reported in other cohort studies [17]. In addition, the correlation between total dietary folate intake and circulating folate level in the subset of the SCCS cohort (r=0.26) [31] was comparable to other studies [49]. This relatively high intake level might have limited our ability to observe any association between folate intake and lung cancer risk.
Our study also has limitations. Due to a lack of data, we were not able to estimate the amount of folic acid intake from supplements. It is important to collect this information in future studies because it is possible that associations of lung cancer risk may be different for folate from food and supplemental folate sources, as previously suggested [26]. An increased risk of lung cancer was reported among male current smokers who took individual vitamin B6 or B12 supplements in high doses in the Vitamins and Lifestyle (VITAL) cohort study [25]. A very recent study from the Lung Cancer Cohort Consortium reported that circulating vitamin B12 level was positively associated with lung cancer risk, and the positive association was further confirmed by a Mendelian randomization approach [50]. Given that vitamins B6 and B12 contribute to one-carbon metabolism along with folate, we investigated the associations of lung cancer risk with vitamins B6 or B12 from food, but observed no associations. It may also be important to investigate the association of lung cancer risk with the use of vitamins B6 and B12 supplements. However, our SCCS only assessed folic acid among B vitamins as an individual vitamin supplement, but not vitamin B6 or B12. Hence, we were not able to investigate the association with the use of vitamin B6 or B12 from individual supplements in our study, which needs to be explored in other study populations. Although we have adjusted for both smoking status and pack-years of smoking, residual confounding by smoking cannot be completely ruled out [51].
In conclusion, in a cohort study with a large proportion of blacks and low-income households in the southeastern United States, our findings do not offer additional evidence supporting a protective effect of folate intake on lung cancer prevention. Our finding of a positive association between total dietary folate intake and lung cancer risk among black women needs to be viewed with caution and replicated in other study populations.
Supplementary Material
Acknowledgements
This study was funded by the National Cancer Institute (grant numbers: R01 CA092447 and U01CA202979 to W.J. Blot). Data collection was performed by the Survey and Biospecimen Shared Resource, which is supported in part by the Vanderbilt-Ingram Cancer Center (P30CA68485). The authors thank the study participants and research staff of the Southern Community Cohort Study (SCCS) for their contribution to this study. We thank Ms. Nan Kennedy and Dr. Mary Shannon Byers for assistance with editing and manuscript preparation. Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; and Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR. The Arkansas Central Cancer Registry was fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry, which participates in the National Program of Cancer Registries of the Centers for Disease Control and Prevention. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry.
Footnotes
Conflict of Interest: None to declare.
References
- 1.Blom HJ, Shaw GM, den Heijer M, Finnell RH (2006) Neural tube defects and folate: case far from closed. Nat Rev Neurosci 7 (9):724–731. doi: 10.1038/nrn1986 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Ames BN (2001) DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res 475 (1–2):7–20 [DOI] [PubMed] [Google Scholar]
- 3.Lee MS, Asomaning K, Su L, Wain JC, Mark EJ, Christiani DC (2012) MTHFR polymorphisms, folate intake and carcinogen DNA adducts in the lung. Int J Cancer 131 (5):1203–1209. doi: 10.1002/ijc.27338 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Choi SW, Mason JB (2000) Folate and carcinogenesis: an integrated scheme. J Nutr 130 (2):129–132. doi: 10.1093/jn/130.2.129 [DOI] [PubMed] [Google Scholar]
- 5.Tinker SC, Hamner HC, Qi YP, Crider KS (2015) U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012. Birth Defects Res A Clin Mol Teratol 103 (6):517–526. doi: 10.1002/bdra.23378 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Crider KS, Bailey LB, Berry RJ (2011) Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients 3 (3):370–384. doi: 10.3390/nu3030370 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr., Garcia FA, Kemper AR, Krist AH, Kurth AE, Landefeld CS, Mangione CM, Phillips WR, Phipps MG, Pignone MP, Silverstein M, Tseng CW (2017) Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement. JAMA 317 (2):183–189. doi: 10.1001/jama.2016.19438 [DOI] [PubMed] [Google Scholar]
- 8.Bailey RL, Dodd KW, Gahche JJ, Dwyer JT, McDowell MA, Yetley EA, Sempos CA, Burt VL, Radimer KL, Picciano MF (2010) Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006. Am J Clin Nutr 91 (1):231–237. doi: 10.3945/ajcn.2009.28427 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Williams J, Mai CT, Mulinare J, Isenburg J, Flood TJ, Ethen M, Frohnert B, Kirby RS, Centers for Disease C, Prevention (2015) Updated estimates of neural tube defects prevented by mandatory folic Acid fortification - United States, 1995–2011. MMWR Morb Mortal Wkly Rep 64 (1):1–5 [PMC free article] [PubMed] [Google Scholar]
- 10.Keum N, Giovannucci EL (2014) Folic acid fortification and colorectal cancer risk. Am J Prev Med 46 (3 Suppl 1):S65–72. doi: 10.1016/j.amepre.2013.10.025 [DOI] [PubMed] [Google Scholar]
- 11.Vollset SE, Clarke R, Lewington S, Ebbing M, Halsey J, Lonn E, Armitage J, Manson JE, Hankey GJ, Spence JD, Galan P, Bonaa KH, Jamison R, Gaziano JM, Guarino P, Baron JA, Logan RF, Giovannucci EL, den Heijer M, Ueland PM, Bennett D, Collins R, Peto R, Collaboration BVTT (2013) Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals. Lancet 381 (9871):1029–1036. doi: 10.1016/S0140-6736(12)62001-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Zhang YF, Zhou L, Zhang HW, Hou AJ, Gao HF, Zhou YH (2014) Association between folate intake and the risk of lung cancer: a dose-response meta-analysis of prospective studies. PLoS One 9 (4):e93465. doi: 10.1371/journal.pone.0093465 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Shen H, Wei Q, Pillow PC, Amos CI, Hong WK, Spitz MR (2003) Dietary folate intake and lung cancer risk in former smokers: a case-control analysis. Cancer Epidemiol Biomarkers Prev 12 (10):980–986 [PubMed] [Google Scholar]
- 14.Hartman TJ, Woodson K, Stolzenberg-Solomon R, Virtamo J, Selhub J, Barrett MJ, Albanes D (2001) Association of the B-vitamins pyridoxal 5’-phosphate (B(6)), B(12), and folate with lung cancer risk in older men. Am J Epidemiol 153 (7):688–694 [DOI] [PubMed] [Google Scholar]
- 15.Johansson M, Relton C, Ueland PM, Vollset SE, Midttun O, Nygard O, Slimani N, Boffetta P, Jenab M, Clavel-Chapelon F, Boutron-Ruault MC, Fagherazzi G, Kaaks R, Rohrmann S, Boeing H, Weikert C, Bueno-de-Mesquita HB, Ros MM, van Gils CH, Peeters PH, Agudo A, Barricarte A, Navarro C, Rodriguez L, Sanchez MJ, Larranaga N, Khaw KT, Wareham N, Allen NE, Crowe F, Gallo V, Norat T, Krogh V, Masala G, Panico S, Sacerdote C, Tumino R, Trichopoulou A, Lagiou P, Trichopoulos D, Rasmuson T, Hallmans G, Riboli E, Vineis P, Brennan P (2010) Serum B vitamin levels and risk of lung cancer. JAMA 303 (23):2377–2385. doi: 10.1001/jama.2010.808 [DOI] [PubMed] [Google Scholar]
- 16.Durda K, Kaklewski K, Gupta S, Szydlowski M, Baszuk P, Jaworska-Bieniek K, Sukiennicki G, Kaczmarek K, Waloszczyk P, Narod S, Lubinski J, Jakubowska A (2017) Serum folate concentration and the incidence of lung cancer. PLoS One 12 (5):e0177441. doi: 10.1371/journal.pone.0177441 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Cho E, Hunter DJ, Spiegelman D, Albanes D, Beeson WL, van den Brandt PA, Colditz GA, Feskanich D, Folsom AR, Fraser GE, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Miller AB, Rohan TE, Sellers TA, Virtamo J, Willett WC, Smith-Warner SA (2006) Intakes of vitamins A, C and E and folate and multivitamins and lung cancer: a pooled analysis of 8 prospective studies. Int J Cancer 118 (4):970–978. doi: 10.1002/ijc.21441 [DOI] [PubMed] [Google Scholar]
- 18.Kabat GC, Miller AB, Jain M, Rohan TE (2008) Dietary intake of selected B vitamins in relation to risk of major cancers in women. Br J Cancer 99 (5):816–821. doi: 10.1038/sj.bjc.6604540 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Rossi E, Hung J, Beilby JP, Knuiman MW, Divitini ML, Bartholomew H (2006) Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia. Ann Epidemiol 16 (3):206–212. doi: 10.1016/j.annepidem.2005.03.010 [DOI] [PubMed] [Google Scholar]
- 20.Slatore CG, Littman AJ, Au DH, Satia JA, White E (2008) Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer. Am J Respir Crit Care Med 177 (5):524–530. doi: 10.1164/rccm.200709-1398OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Yuan JM, Stram DO, Arakawa K, Lee HP, Yu MC (2003) Dietary cryptoxanthin and reduced risk of lung cancer: the Singapore Chinese Health Study. Cancer Epidemiol Biomarkers Prev 12 (9):890–898 [PubMed] [Google Scholar]
- 22.Takata Y, Cai Q, Beeghly-Fadiel A, Li H, Shrubsole MJ, Ji BT, Yang G, Chow WH, Gao YT, Zheng W, Shu XO (2012) Dietary B vitamin and methionine intakes and lung cancer risk among female never smokers in China. Cancer Causes Control 23 (12):1965–1975. doi: 10.1007/s10552-012-0074-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Takata Y, Xiang YB, Yang G, Li H, Gao J, Cai H, Gao YT, Zheng W, Shu XO (2013) Intakes of fruits, vegetables, and related vitamins and lung cancer risk: results from the Shanghai Men’s Health Study (2002–2009). Nutr Cancer 65 (1):51–61. doi: 10.1080/01635581.2013.741757 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Alpha-Tocopherol BCCPSG (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330 (15):1029–1035. doi: 10.1056/NEJM199404143301501 [DOI] [PubMed] [Google Scholar]
- 25.Brasky TM, White E, Chen CL (2017) Long-Term, Supplemental, One-Carbon Metabolism-Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort. J Clin Oncol:JCO2017727735. doi: 10.1200/JCO.2017.72.7735 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Roswall N, Olsen A, Christensen J, Dragsted LO, Overvad K, Tjonneland A (2010) Source-specific effects of micronutrients in lung cancer prevention. Lung Cancer 67 (3):275–281. doi: 10.1016/j.lungcan.2009.11.010 [DOI] [PubMed] [Google Scholar]
- 27.Centers for Disease C, Prevention (2010) Racial/Ethnic disparities and geographic differences in lung cancer incidence --- 38 States and the District of Columbia, 1998–2006. MMWR Morb Mortal Wkly Rep 59 (44):1434–1438 [PubMed] [Google Scholar]
- 28.Patel JD (2005) Lung cancer in women. J Clin Oncol 23 (14):3212–3218. doi: 10.1200/JCO.2005.11.486 [DOI] [PubMed] [Google Scholar]
- 29.Payne PW, Sebo TJ, Doudkine A, Garner D, MacAulay C, Lam S, LeRichie JC, Palcic B (1997) Sputum screening by quantitative microscopy: a reexamination of a portion of the National Cancer Institute Cooperative Early Lung Cancer Study. Mayo Clin Proc 72 (8):697–704 [DOI] [PubMed] [Google Scholar]
- 30.Bailey RL, Akabas SR, Paxson EE, Thuppal SV, Saklani S, Tucker KL (2017) Total Usual Intake of Shortfall Nutrients Varies With Poverty Among US Adults. J Nutr Educ Behav. doi: 10.1016/j.jneb.2016.11.008 [DOI] [PubMed] [Google Scholar]
- 31.Signorello LB, Buchowski MS, Cai Q, Munro HM, Hargreaves MK, Blot WJ (2010) Biochemical validation of food frequency questionnaire-estimated carotenoid, alpha-tocopherol, and folate intakes among African Americans and non-Hispanic Whites in the Southern Community Cohort Study. Am J Epidemiol 171 (4):488–497. doi: 10.1093/aje/kwp402 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Signorello LB, Hargreaves MK, Steinwandel MD, Zheng W, Cai Q, Schlundt DG, Buchowski MS, Arnold CW, McLaughlin JK, Blot WJ (2005) Southern community cohort study: establishing a cohort to investigate health disparities. J Natl Med Assoc 97 (7):972–979 [PMC free article] [PubMed] [Google Scholar]
- 33.Buchowski MS, Schlundt DG, Hargreaves MK, Hankin JH, Signorello LB, Blot WJ (2003) Development of a culturally sensitive food frequency questionnaire for use in the Southern Community Cohort Study. Cell Mol Biol (Noisy-le-grand) 49 (8):1295–1304 [PubMed] [Google Scholar]
- 34.Signorello LB, Munro HM, Buchowski MS, Schlundt DG, Cohen SS, Hargreaves MK, Blot WJ (2009) Estimating nutrient intake from a food frequency questionnaire: incorporating the elements of race and geographic region. Am J Epidemiol 170 (1):104–111. doi: 10.1093/aje/kwp098 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Schlundt DG, Buchowski MS, Hargreaves MK, Hankin JH, Signorello LB, Blot WJ (2007) Separate estimates of portion size were not essential for energy and nutrient estimation: results from the Southern Community Cohort food-frequency questionnaire pilot study. Public Health Nutr 10 (3):245–251. doi: 10.1017/S1368980007258574 [DOI] [PubMed] [Google Scholar]
- 36.Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate OBV, and Choline. (1998) Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academics Press (US), Washington, DC: [PubMed] [Google Scholar]
- 37.Blot WJ, Cohen SS, Aldrich M, McLaughlin JK, Hargreaves MK, Signorello LB (2011) Lung cancer risk among smokers of menthol cigarettes. J Natl Cancer Inst 103 (10):810–816. doi: 10.1093/jnci/djr102 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Epplein M, Burk RF, Cai Q, Hargreaves MK, Blot WJ (2014) A prospective study of plasma Selenoprotein P and lung cancer risk among low-income adults. Cancer Epidemiol Biomarkers Prev 23 (7):1238–1244. doi: 10.1158/1055-9965.EPI-13-1308 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Haznadar M, Cai Q, Krausz KW, Bowman ED, Margono E, Noro R, Thompson MD, Mathe EA, Munro HM, Steinwandel MD, Gonzalez FJ, Blot WJ, Harris CC (2016) Urinary Metabolite Risk Biomarkers of Lung Cancer: A Prospective Cohort Study. Cancer Epidemiol Biomarkers Prev 25 (6):978–986. doi: 10.1158/1055-9965.EPI-15-1191 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Sanderson M, Aldrich MC, Levine RS, Kilbourne B, Cai Q, Blot WJ (2018) Neighbourhood deprivation and lung cancer risk: a nested case-control study in the USA. BMJ Open 8 (9):e021059. doi: 10.1136/bmjopen-2017-021059 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Aune D, Deneo-Pellegrini H, Ronco AL, Boffetta P, Acosta G, Mendilaharsu M, De Stefani E (2011) Dietary folate intake and the risk of 11 types of cancer: a case-control study in Uruguay. Ann Oncol 22 (2):444–451. doi: 10.1093/annonc/mdq356 [DOI] [PubMed] [Google Scholar]
- 42.Bassett JK, Hodge AM, English DR, Baglietto L, Hopper JL, Giles GG, Severi G (2012) Dietary intake of B vitamins and methionine and risk of lung cancer. Eur J Clin Nutr 66 (2):182–187. doi: 10.1038/ejcn.2011.157 [DOI] [PubMed] [Google Scholar]
- 43.Neuhouser ML, Patterson RE, Thornquist MD, Omenn GS, King IB, Goodman GE (2003) Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the beta-carotene and retinol efficacy trial (CARET). Cancer Epidemiol Biomarkers Prev 12 (4):350–358 [PubMed] [Google Scholar]
- 44.Jatoi A, Daly BD, Kramer G, Mason JB (2001) Folate status among patients with non-small cell lung cancer: a case-control study. J Surg Oncol 77 (4):247–252 [DOI] [PubMed] [Google Scholar]
- 45.Bandera EV, Freudenheim JL, Marshall JR, Zielezny M, Priore RL, Brasure J, Baptiste M, Graham S (1997) Diet and alcohol consumption and lung cancer risk in the New York State Cohort (United States). Cancer Causes Control 8 (6):828–840 [DOI] [PubMed] [Google Scholar]
- 46.Voorrips LE, Goldbohm RA, Brants HA, van Poppel GA, Sturmans F, Hermus RJ, van den Brandt PA (2000) A prospective cohort study on antioxidant and folate intake and male lung cancer risk. Cancer Epidemiol Biomarkers Prev 9 (4):357–365 [PubMed] [Google Scholar]
- 47.Ito Y, Wakai K, Suzuki K, Ozasa K, Watanabe Y, Seki N, Ando M, Nishino Y, Kondo T, Ohno Y, Tamakoshi A, Group JS (2005) Lung cancer mortality and serum levels of carotenoids, retinol, tocopherols, and folic acid in men and women: a case-control study nested in the JACC Study. J Epidemiol 15 Suppl 2:S140–149 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Shi Q, Zhang Z, Li G, Pillow PC, Hernandez LM, Spitz MR, Wei Q (2005) Sex differences in risk of lung cancer associated with methylene-tetrahydrofolate reductase polymorphisms. Cancer Epidemiol Biomarkers Prev 14 (6):1477–1484. doi: 10.1158/1055-9965.EPI-04-0905 [DOI] [PubMed] [Google Scholar]
- 49.Park JY, Vollset SE, Melse-Boonstra A, Chajes V, Ueland PM, Slimani N (2013) Dietary intake and biological measurement of folate: a qualitative review of validation studies. Mol Nutr Food Res 57 (4):562–581. doi: 10.1002/mnfr.201200105 [DOI] [PubMed] [Google Scholar]
- 50.Fanidi A, Carreras-Torres R, Larose TL, Yuan JM, Stevens VL, Weinstein SJ, Albanes D, Prentice R, Pettinger M, Cai Q, Blot WJ, Arslan AA, Zeleniuch-Jacquotte A, McCullough ML, Le Marchand L, Wilkens LR, Haiman CA, Zhang X, Stampfer MJ, Smith-Warner SA, Giovannucci E, Giles GG, Hodge AM, Severi G, Johansson M, Grankvist K, Langhammer A, Brumpton BM, Wang R, Gao YT, Ericson U, Bojesen SE, Arnold SM, Koh WP, Shu XO, Xiang YB, Li H, Zheng W, Lan Q, Visvanathan K, Hoffman-Bolton J, Ueland PM, Midttun O, Caporaso NE, Purdue M, Freedman ND, Buring JE, Lee IM, Sesso HD, Michael Gaziano J, Manjer J, Relton CL, Hung RJ, Amos CI, Johansson M, Brennan P, consortium LC, the Tc (2018) Is high vitamin B12 status a cause of lung cancer? Int J Cancer. doi: 10.1002/ijc.32033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Dallongeville J, Marecaux N, Fruchart JC, Amouyel P (1998) Cigarette smoking is associated with unhealthy patterns of nutrient intake: a meta-analysis. J Nutr 128 (9):1450–1457 [DOI] [PubMed] [Google Scholar]
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