The bioactive form of vitamin D (1,25(OH)2D) has been hypothesised to lower non-Hodgkin's lymphoma (NHL) risk through its anti-proliferative and immunomodulatory effects(Reference Armstrong and Kricker1, Reference Cantorna, Zhu and Froicu2). Most previous studies evaluated the effect of direct or indirect measures of sun exposure and a recent pooled analysis has found an inverse association with recreational sun exposure and NHL risk (OR = 0·76; 95 % CI: 0·63, 0·91)(Reference Kricker, Armstrong and Hughes3). However, evidence on the effect of dietary vitamin D is limited in general(Reference Chang, Balter and Torrang4) and scarce in non-white ethnic groups with darker skin pigmentation and less efficient synthesis from solar UV radiation(Reference Giovannucci5). Therefore, we analysed the association between vitamin D from food sources plus multivitamins and NHL risk prospectively in a large US cohort of Caucasians, African Americans, Native Hawaiians, Japanese Americans and Latinos.
Methods
Subjects from five main ethnic groups (Caucasian, African American, Native Hawaiian, Japanese American and Latino), who were 45–75 years old and resided in Hawaii or Los Angeles, were recruited in the multiethnic cohort study of diet and cancer between 1993 and 1996. Participants filled out a mailed baseline questionnaire, including a quantitative FFQ(Reference Kolonel, Henderson and Hankin6). The quantitative FFQ included food items that were identified from 3-d food records so as to capture 85 % or more of the ethnic-specific intake of main nutrients. A calibration substudy indicated good agreement between the quantitative FFQ and three 24 h recalls(Reference Stram, Hankin and Wilkens7). Levels of vitamin D intake from food sources were determined using a customised and ethnic-specific food composition database based on the US Department of Agriculture Nutrient Database and additional laboratory analyses of local foods(Reference Kolonel, Henderson and Hankin6). In addition to the quantitative FFQ, the baseline questionnaire queried subjects about the duration, frequency and amount of multivitamin use. Information on supplements was considered complete (only 2 % missing) and 50 % of the population indicated multivitamin use. For this analysis, only regular supplement use, defined as use for >1 year, was considered, and each tablet was estimated to contain 10 μg vitamin D. We did not inquire about vitamin D as a single supplement, but at the time, single vitamin D supplement use was not common. Dietary vitamin D was computed as vitamin D from foods plus multivitamins.
After exclusions (13 992 not in main ethnic groups, 8264 invalid dietary information and 514 prior NHL cases), 87 078 men and 105 972 women were part of the analysis. The present study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures involving human subjects were approved by the Institutional Review Boards at the University of Hawaii and at the University of Southern California. Written informed consent was obtained from all subjects.
Incident NHL cases were ascertained through annual linkages of the multiethnic cohort with the tumour registries of Hawaii and Los Angeles. Deaths from cancer and other causes were identified from the state death certificate files and the National Death Index. A low outmigration rate was reported previously(Reference Kolonel, Henderson and Hankin6). Follow-up ended at the earliest of the following events: diagnosis of NHL, death or 31 December 2003. NHL was classified into the most common subtypes according to the adaptation of the WHO classification for epidemiologic studies(Reference Morton, Turner and Cerhan8, Reference Jaffe, Harris and Stein9).
All statistical analyses were performed using the SAS statistical software, version 9.1 (SAS Institute, Inc., Cary, NC, USA). Dietary vitamin D was energy adjusted, and the association with NHL was estimated as hazard ratios (HR) and 95 % CI using proportional hazards regression that compared vitamin D tertiles with age as the underlying time metric and with stratification by follow-up time ( ≤ 2 years, 2–5 years and >5 years)(Reference Thiebaut and Benichou10). Due to previously reported associations with NHL, the models were adjusted for age at cohort entry, ethnicity, education, BMI, alcohol use and total energy. We tested for linear trend using an ordinal variable with median values for each tertile. Stratified analyses by ethnicity and NHL subgroups were performed.
Results
After a median follow-up of 10 years, 939 (514 men and 425 women) incident NHL cases were identified. NHL cases were more likely to be older and Caucasian compared with non-cases at baseline (Table 1). Diffuse large B-cell lymphoma was the most common NHL subgroup among Native Hawaiians (34 %), Japanese Americans (37 %) and Latinos (45 %), while 32 % of Caucasians and 28 % of African Americans were affected by small lymphocytic lymphoma/chronic lymphocytic leukaemia. The proportion of follicular lymphoma was low across all ethnicities. Mean intake of vitamin D in IU/4184 kJ/d (1000 kcal/d) was highest among Caucasians (215), followed by Japanese Americans (180), African Americans (179), Latinos (152) and Native Hawaiians (146).
Baseline characteristics (in percentage) of non-Hodgkin's lymphoma (NHL) cases and subjects without NHL, the multiethnic cohort study, 1993–2003
DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; SLL/CLL, small lymphocytic lymphoma/chronic lymphocytic leukaemia.
* Might not add up to 100 % due to missing values.
Dietary vitamin D was not associated with NHL risk among men (P trend = 0·72) and women (P trend = 0·83) overall (Table 2). The interaction between ethnicity and dietary vitamin D was not significant (P = 0·70). However, after stratification by ethnic group, a significant inverse association was observed among African American women with HR = 0·50 (95 % CI: 0·28, 0·90; P trend = 0·03) comparing the highest tertile to the lowest. A lowered NHL risk, although non-significant, was also observed among African American men (HR = 0·68; 95 % CI: 0·39, 1·19; P trend = 0·31). Native Hawaiian women and men experienced a non-significant 38 and 14 % lowered risk, respectively. On the other hand, non-statistically significant increased risks were seen in Latino men and women and Caucasian women. Stratification by NHL subtypes revealed a non-significant inverse association between dietary vitamin D and diffuse large B-cell lymphoma, follicular lymphoma and small lymphocytic lymphoma/chronic lymphocytic leukaemia in women, but not in men (Table 2).
(Hazard ratios (HR) and 95 % CI)
DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; SLL/CLL, small lymphocytic lymphoma/chronic lymphocytic leukaemia.
* Number of NHL cases. May not add up to total (n 939) due to missing values.
† Hazards ratios and 95 % CI were adjusted for education ( ≥ 12 v. < 12 years), BMI (overweight (25·0–29·9), obese ( ≥ 30·0) v. normal ( < 25·0)), alcohol intake ( < 1·0, 1·0–1·9, 2·0–2·9, and ≥ 3 v. 0 servings/d), and total energy (log transformed). For the overall category, they were also adjusted for ethnicity (African American, Native Hawaiian, Japanese American, and Latino v. Caucasian).
Discussion
In agreement with the present hypothesis that vitamin D intake may be more protective against NHL in non-Caucasians, we found an association between vitamin D from foods plus multivitamins and lower NHL risk in African Americans, and to a lesser degree among Native Hawaiians. The few previous studies on dietary vitamin D among primarily Caucasians did not find an association(Reference Chang, Balter and Torrang4, Reference Zheng, Holford and Leaderer11–Reference Hartge, Lim and Freedman13), except for one case–control study that reported an inverse association with an OR = 0·6 (95 % CI: 0·4, 0·9)(Reference Polesel, Talamini and Montella14). The major source of vitamin D in human subjects is UV-B light, which accounts for more than 90 % of vitamin D requirement, rather than food items(Reference Giovannucci5, Reference Holick15). This might explain the lack of an overall association in the present study. However, increased pigmentation, as in African Americans and Native Hawaiians, can reduce cutaneous vitamin D production through sun exposure by up to 99·9 % due to filtering of UV-B and, therefore, dietary intake of vitamin D might be much more relevant for these ethnic groups(Reference Giovannucci5, Reference Holick16). The slightly elevated risk observed in Latinos, despite their darker skin pigmentation, is hard to explain and might be due to chance.
The suggestive inverse association with follicular lymphoma in women is consistent with a previous study that found a 70 % lowered follicular lymphoma risk associated with high dietary vitamin D(Reference Polesel, Talamini and Montella14). Unfortunately, there is a lack of literature on the effect of dietary vitamin D on NHL subgroups. However, a large pooled analysis of sun exposure and NHL suggested similar inverse associations across all NHL subtypes(Reference Kricker, Armstrong and Hughes3).
Strengths of the present study include the use of Surveillance, Epidemiology, and End Results tumour registries, which ensured accurate NHL classification despite the many different institutions involved in diagnosing the cases. We are confident that the majority of pathologic diagnoses was accurate since all NHL cases occurred after the implementation of the WHO classification(Reference Jaffe, Harris and Stein9). Furthermore, the present study included a multiethnic population with a wide variety of dietary exposures. However, dietary sources of vitamin D are limited to oily fish (e.g. salmon, mackerel and sardines), fish oils (e.g. cod liver oil) and egg yolk, as well as to fortified food items (e.g. milk, cereals and orange juice) and the use of dietary supplements(Reference Holick16). Despite the large size of the multiethnic cohort, the present study was still limited in power for stratified analyses by ethnicity and subtypes. Especially, because of the multiple comparisons, it is possible that the few significant results were due to chance.
To our knowledge, the present study is the first on dietary vitamin D and NHL risk among different ethnic groups. We conclude that the effect of dietary vitamin D on NHL risk might be ethnic specific and call for more prospective investigations involving non-Caucasian subjects.
Acknowledgements
The present work was supported by the US National Cancer Institute (Grant Number R37 CA54281) and surveillance, epidemiology, and end results contract N01-PC-35 137. There are no conflicts of interest. E. E. collated all statistical information and wrote the manuscript; G. M. and U. L. wrote and reviewed the manuscript; and L. N. K. designed the study and reviewed the manuscript. All authors read and approved the findings of the study.
