We found no overall association between serum 25(OH)D and lymphoid cancers or their components of NHL, multiple myeloma, and Hodgkin lymphoma. Higher serum 25(OH)D levels were, however, associated with lower incidence of NHL cases with shorter time to diagnosis, especially among participants whose baseline blood was drawn in less sunny seasons.
It is biologically plausible that higher levels of serum 25(OH)D may reduce the risk of lymphomagenesis. Activated lymphocytes express 1α-hydroxylase, which converts the circulating inert form, 25-hydroxyvitamin D (25(OH)D), to the functional hormone, 1,25-dihydroxyvitamin D (1,25(OH)2
). Lymphocytes contain nuclear receptors for the hormone as well, which suggests their autocrine/paracrine capacity to respond to the hormone’s anti-neoplastic effects (37
). Vitamin D receptor knockout mice have shown an accelerated rate of mitogen-induced malignant transformations in the thymus gland and lymph nodes (39
). In humans, a small clinical trial of 1,25(OH)2
D analog showed ~25% remission of low-grade NHL (40
). In addition, the active vitamin D may be protective through its immunity-modulating effects (41
), such as selectively down-regulating helper T1 cells (Th1) and suppressing their systemic release of pro-inflammatory cytokines (20
), and thereby, reducing the autoimmunity-induced risk of lymphoma (44
). Alternatively, UV-B exposure, which is the principal source of vitamin D levels, may exert similar immunosuppression independently of vitamin D, by, for example, lowering the secretion of melatonin and elevating melanocyte stimulating hormone, which in turn attenuates Th1-mediated immunity (45
A possible explanation for a protective association between serum 25(OH)D and NHL with shorter, but not longer, time to diagnosis from baseline is that exposure to vitamin D close to diagnosis has a stronger protective effect than earlier exposures. Our finding is consistent with the pooled analysis in the InterLymph Consortium, where sunlight exposure in the last decade prior to NHL diagnosis had a stronger inverse association with NHL than sun exposure in teen years or early to mid-adulthood (19
). Similarly, studies of other cancers have reported stronger protective associations for vitamin D indicators in relation to cancer diagnoses that are close temporally: e.g., baseline dietary vitamin D and breast cancer in the first 5 years than later years of a follow-up (48
) and serum 25(OH)D and colon cancer in the first 10 years compared with later follow-up (49
). If a protective effect was limited to exposures close in time to the diagnosis, we would not expect to see a uniform relationship over time unless 25(OH)D levels in individuals were fairly constant over time. However, intra-individual variability of serum 25(OH)D over time was evidenced in a study of adult women who were followed up for repeat measures at 1, 2 and 5 years from the baseline (51
). The 19% variation detected in the study was not entirely accounted for by the measurement error in the enzyme immunoassay (10% CV), supporting the notion that a one-time measure of serum 25(OH)D may poorly predict vitamin D status many years after blood collection.
Alternatively, a covariate that changes over the several years prior to diagnosis may account for the disparate results. Because abnormal lipid metabolism is common in latent lymphoma (52
), and because we previously observed an inverse association between serum HDL cholesterol and NHL in diminishing magnitude with follow-up time (31
), we considered HDL as such a covariate. However, the 25(OH)D-NHL association was confounded by neither HDL nor total serum cholesterol, and the strength of the association remained consistent for the early follow-up. Likewise, adjusting for other risk factors for NHL or correlates of serum 25(OH)D did not alter the association. We, however, cannot rule out possible vitamin D-lowering effects of latent lymphoma, although normal levels of 25(OH)D with high 1,25(OH)2
D in some patients have been clinically observed (53
). We also cannot disregard the possibility of residual confounding by known or unknown risk factors or, in this observational study, that the disparate pattern of associations might have been due to chance.
The 25(OH)D-NHL association was more inverse for CLL/SLL than other common subtypes of NHL among cases with shorter time to diagnosis from baseline. Whether this is an indication of true heterogeneity, i.e., a stronger involvement of vitamin D status in CLL/SLL etiology over other subtypes’ (54
), or due to chance requires further research. The literature is inconsistent on the effects of sun exposure or vitamin D on multiple myeloma (15
), and the non-significant positive association we observed regardless of time to diagnosis remains inconclusive due to small numbers.
Our findings were based on a population with lower serum 25(OH)D levels compared to the US and other populations (56
), likely due to the high latitude, older age, and smoking status. For example, levels below 37.5nmol/L were found in 27% of this versus <10% of the U.S. population among white men of 60–79 years (56
). Similarly, levels above 62.5nmol/L were found in 28% versus ~65% of the respective populations. This may or may not have contributed to a stronger inverse association in our data if serum 25(OH)D exhibits a threshold for protective effects. In addition, our observation of a stronger inverse association for 25(OH)D measured in winter/spring compared with the summer/fall months implicates the importance of considering year-round levels, and not simply high values limited to a part of the year.
Some of the suggested confounding or modifying associations (25
) were not observed in our study population. For example, the range of the latitude from mostly Southwestern counties of Finland was narrow (60.1–62.5°) and was not correlated with serum 25(OH)D. Physical activity, especially intensity of leisure-time activity, was positively correlated with serum 25(OH)D, but was not associated with NHL. The proposed antagonistic or modifying effects of obesity and high levels of serum retinol on vitamin D (25
) were not evident in this study. This may be because the heavy smokers’ BMI was likely distorted as an indicator of positive energy balance or obesity-related etiology and their baseline serum retinol levels were low to exhibit such modifying effects (58
). Also, we did not detect any influence of beta-carotene or alpha-tocopherol intervention treatments, which were randomized and evenly distributed across baseline serum 25(OH)D levels. Although substantially lower serum 25(OH)D levels have been reported among smokers (59
), smoking has not shown to modify the 25(OH)D association with NHL or any cancers, to the best of our knowledge, and thus, we do not have a reason to question the generalizability of our findings.
As the first investigation of serum 25(OH)D and lymphoma risk, this study was conducted within a prospective cohort with excellent case ascertainment and reliable histology information, which minimized selection bias and allowed subtype analyses. We applied different analytic approaches to better adjust for seasonal variation in serum 25(OH)D at blood draw and found confirmatory estimates for those obtained from using overall tertile cutpoints on all raw measurement values. Nevertheless, this study had some limitations. Serum 25(OH)D derives from solar and dietary exposures in recent weeks (24
), and thus is not necessarily correlated with historic 25(OH)D levels. We could not determine how well the baseline serum 25(OH)D was correlated with individuals’ typical or cumulative sun exposure or sun-seeking behavior in the past, with only limited information available in a subgroup of all participants. For example, the number of vacation days in the sunny south, but not host susceptibility, was correlated with serum 25(OH)D, and adjustment of this antecedent factor did not change the 25(OH)D-NHL association.
These results warrant further evaluation in other prospective data, ideally with a large number of lymphoid neoplasm cases to examine histological and molecular subtypes, lifetime history of sunlight exposure, and DNA to enable assessment of genes involved in the metabolism and functional pathways of vitamin D. In addition, the differences in our findings by proximity to blood collection calls for further investigations of repeat measures of 25(OH)D to determine the intra-individual variability over time and to clarify the potential influence of disease progression on the marker.