The findings from this pooled nested case-control study of data from 8 cohorts do not support the hypothesis that higher circulating vitamin D concentrations reduce the risk of pancreatic cancer. Indeed, a statistically significant 2-fold increased risk of pancreatic cancer was observed among subjects with circulating 25(OH)D concentrations greater than or equal to 100 nmol/L as compared with those with 25(OH)D concentrations of 50–<75 nmol/L. The positive association persisted when each cohort was excluded from the analysis in turn. The association was independent of race/ethnicity, sex, smoking history, obesity, and diabetes. Positive associations were observed in men, women, smokers, never smokers, and nonusers of multivitamin supplements. Although there were no statistically significant interactions, positive associations appeared more pronounced in Caucasians, participants residing in areas at latitudes above 35°N, and those who had their blood collected during the summer months. No significant associations were observed among participants with lower 25(OH)D status.
These pooled results are consistent with previously published findings from both the ATBC (27
) and PLCO (28
) cohorts, as all showed some evidence of positive associations, and effects appeared stronger among persons residing at high latitudes. In the previous nested case-control study conducted in the ATBC cohort, a population of male Finnish smokers, prediagnostic serum 25(OH)D concentrations greater than 65.5 nmol/L were associated with a nearly 3-fold increased risk of pancreatic cancer compared with concentrations of 32.0 nmol/L or less (OR = 2.92, 95% CI: 1.56, 5.48; P
-trend = 0.001) (27
). Although the previous PLCO nested case-control study showed an overall non-statistically significant 45% increased risk of pancreatic cancer for the highest fifth of 25(OH)D concentrations as compared with the lowest fifth, statistically significant 4-fold increased risks were observed with increasing 25(OH)D concentrations (>78.4 nmol/L vs. <49.3 nmol/L) only among participants living at northern US latitudes (i.e., Michigan, Minnesota, and Wisconsin) (28
). Persons who live at low latitudes with warm, sunlit environments might maintain efficient vitamin D status throughout the year (28
). This could contribute to more within-person variability in ambulatory populations and attenuate risk estimates (28
). Further, participants in the Shanghai and MEC studies, who lived at low latitudes, tended to have lower 25(OH)D concentrations overall (i.e., Shanghai) or because of race/ethnicity (e.g., African Americans). As a result, few participants residing at low latitudes had 25(OH)D concentrations greater than 100 nmol/L (; 5 cases and 8 controls), which limited our statistical power to observe associations.
The present analysis differs from the previous 2 studies (27
) in that clinically relevant vitamin D status cutpoints were used to examine associations, with 50–<75 nmol/L being used as the referent category, rather than quintiles based on the distribution among study controls (27
). In the current pooled analysis, a threshold pattern of association was observed, with an increased risk being seen only at the highest vitamin D concentrations (≥100 nmol/L), which corresponds to the top 2.3% of the distribution in the controls. In contrast, the previous ATBC Study showed a significant positive trend with increasing quintiles of vitamin D concentration (27
). On average, men in the ATBC Study had lower 25(OH)D concentrations than those of the US-based cohorts (), and in a range where positive associations were not observed in the VDPP. Few ATBC participants were in the high 25(OH)D category (≥100 nmol/L). Excluding the ATBC participants from the present analysis increased the strength of the association (>100 nmol/L vs. 50–<75 nmol/L: OR = 2.95, 95% CI: 1.47, 5.93), because the ATBC men were removed from the referent category. Therefore, the increased pancreatic cancer risk with high vitamin D status in the present pooled study is not explained by the ATBC Study participants. The PLCO Study contributed 19% of the cases (n
= 183) and 27% of the controls (n
= 364), with both cases and controls having higher 25(OH)D concentrations than the other cohorts (). With the PLCO participants excluded, the association remained positive but nonsignificant because of reduced study power (OR = 1.60, 95% CI: 0.83, 3.08). Excluding both the ATBC and PLCO participants (52% of the cases and 67% of the controls) resulted in no change in the strength of the association, but the significance was diminished (OR = 2.23, 95% CI: 0.82, 6.08) also because of reduced statistical power. The VDPP's advantage for examining pancreatic cancer is the “pooling” of data from 8 cohorts covering multiple geographic regions, which in total includes a larger number of cases and a wider range of vitamin D concentrations than the individual studies alone and provides greater power to observe associations.
A major strength of the VDPP is the prospective design, thereby reducing the likelihood of reverse causality. In addition, the cohort study investigators followed a protocol for case-control selection, and 25(OH)D levels were measured centrally at the same laboratory (except in the ATBC Study). Conclusions concerning associations among Asians or African Americans separately are limited because of their small numbers in the present analysis. The measurement of serum 25(OH)D concentration reflects internal dose and actual vitamin D status and is considered more valid than evaluation of vitamin D intake alone or predictors of vitamin D status. Although a single measure of 25(OH)D in adulthood may not correspond to long-term vitamin D status, it can reflect exposure over the past several weeks or months (44
). In addition, high intraclass correlations ranging from 0.70 to 0.78 have been observed in both men and women for measures taken over several years (45
), suggesting that 1 sample may provide a good measure of long-term status. Controls were matched to the cases by month of blood collection to reduce misclassification of vitamin D status due to seasonal variation. Residual confounding by cigarette smoking is not likely, because there was no significant interaction of the vitamin D association with smoking status, and positive associations were observed among never smokers. Both men and women were included in this study, as well as never, former, and current smokers; therefore, our results should be generalizable to Caucasian populations.
The biologic basis for the observed associations is speculative, because there is an incomplete understanding of the molecular mechanisms by which the vitamin D receptor–1,25-dihydroxyvitamin D3
) complex regulates the expression of genes involved in pancreatic carcinogenesis. The active form of vitamin D is a steroid hormone, and it is likely that the vitamin D receptor–1,25(OH)2
complex affects and interacts with other regulators and endogenous hormones (47
), particularly in an autocrine or paracrine manner within the pancreas and/or pancreatic tumor tissue. The active form of vitamin D, 1,25(OH)2
, might influence growth factors (19
) which promote tumor growth (27
). Toxic effects of hypervitaminosis D are thought to be mediated through hypercalcemia, including calcification of soft tissues; however, the range of 25(OH)D levels associated with risk in this study was below that considered to reflect hypervitaminosis D (400–1,250 nmol/L) (49
). Alternatively, a mechanism directly related to solar ultraviolet radiation or an unknown surrogate risk factor that is correlated with sun exposure is possible.
In conclusion, the previously reported positive association between 25(OH)D and pancreatic cancer observed in the earlier studies (27
) was confirmed in this large pooled study; however, the increased risk was observed only among subjects with the highest circulating 25(OH)D concentrations. Before any conclusions regarding vitamin D's potential role(s) in the etiology of pancreatic cancer can be reached, more research is needed, including prospective studies and laboratory investigations of biologically plausible mechanisms that may explain the observations. Given the present study's pooled results and research gaps in the understanding of vitamin D's role in carcinogenesis, recommendations to increase vitamin D concentrations in healthy persons for cancer prevention seem premature.