Serum 25-Hydroxyvitamin D and Risks of Colon and Rectal Cancer in Finnish Men

Stephanie J. Weinstein; Kai Yu; Ronald L. Horst; Jason Ashby; Jarmo Virtamo; Demetrius Albanes

Disclosures

Am J Epidemiol. 2011;173(5):499-508. 

In This Article

Discussion

Neither colon cancer risk nor rectal cancer risk was inversely associated with circulating 25(OH)D concentrations. In fact, most odds ratios for categories below the referent level (50–<75 nmol/L) suggested lower risk. Results from analyses using season-specific and seasonally adjusted 25(OH)D cutpoints yielded similar patterns, with significantly elevated risks of colon cancer in the higher quartiles, although rectal cancer risk was significantly reduced in the second quartile versus the first quartile. Across all models, risk patterns did not differ consistently by season of blood collection.

Vitamin D plays a role in calcium homeostasis and regulation of bone mineralization by enhancing the absorption of calcium in the kidney and intestine,[15] and higher calcium intake has been associated with reduced colorectal cancer risk.[5] Besides its impact on calcium metabolism, higher vitamin D status may protect against cancer by reducing cellular proliferation and angiogenesis or inducing differentiation and apoptosis.[15] Vitamin D could also act locally in the colon to inhibit carcinogenesis, since both 1-α-vitamin D hydroxylase, the enzyme that metabolizes 25(OH)D to 1,25(OH)2D, and the vitamin D receptor, which binds the active 1,25(OH)2D molecule, are expressed in the colon and elsewhere,[15] and direct binding of harmful secondary bile acids by vitamin D receptor and activation of detoxifying enzymes has been shown.[32] However, our findings are not consistent with these hypotheses of a protective association for vitamin D.

Clinical trials of vitamin D supplementation and colorectal cancer have been limited, and results do not support a beneficial effect for higher exposure.[14,33,34] For example, in the Women's Health Initiative, the hazard ratio for colorectal cancer incidence after 7 years of supplementation with vitamin D (400 IU) and calcium (1,000 mg) was 1.08 (95% CI: 0.86, 1.34); however, all participants were permitted to self-supplement, complicating the trial's interpretation.[14] Research on polymorphisms in vitamin D pathway genes, especially the vitamin D receptor, is inconsistent for colorectal cancer,[35] as is evidence for an association with vitamin D intake.[36] In only 4 of 12 prospective studies did investigators report lower colorectal cancer risk with higher vitamin D intakes,[2] and risk was decreased by only 6% in a meta-analysis of dietary vitamin D.[37]

Because the substantial contribution of sun exposure to vitamin D status is not captured in dietary studies, circulating 25(OH)D is a more accurate measure of overall vitamin D exposure. Prospective studies generally indicate an association between higher 25(OH)D concentrations and reduced colorectal cancer risk[6–14,38] or mortality[39] or improved survival[40]—findings that are also supported by a recent meta-analysis.[41] However, many reported risk estimates are not statistically significant, and some differ within study by anatomic subsite. While the majority of studies have observed inverse associations for 25(OH)D, risks or trends were significantly inverse in only 4[11–14] of 7 prospective colorectal cancer studies,[7,9–14] 2[10,12] of 8 colon cancer studies,[6–13] and 3[9] (men only)[11,13] of 6 rectal cancer studies.[7,9–13] Investigators in 2 studies reported nonsignificant positive associations for colon cancer (OR = 2.1, P-trend = 0.12)[9] and rectal cancer (OR = 3.32, P-trend = 0.08).[10] By far the largest study was the European Prospective Investigation into Cancer and Nutrition (EPIC), with 785 colon cancer cases and 463 rectal cancer cases; however, even with such large numbers, the inverse association for rectal cancer failed to reach statistical significance.[12] With regard to subsite differences, inverse associations were significant for colon cancer only in EPIC[12] and the Health Professionals Follow-up Study[10] and, for rectal cancer, only in the Multiethnic Cohort Study[11] and a Japanese cohort study.[9] Our findings indicate a significant positive association for colon cancer only. Interestingly, the 2 studies with significant inverse findings for rectal cancer either included a large percentage of Japanese Americans [11] or consisted entirely of Japanese participants.[9] Other than the Multiethnic Cohort Study, which also included participants from Latino, African-American, and white populations but showed no evidence of heterogeneity among the racial/ethnic groups,[11] data on minority groups are lacking.

Blood concentrations of 25(OH)D vary substantially by season,[42] and we noted such a pattern, with the highest 25(OH)D concentrations being observed in the summer and fall. We used a multifaceted approach to adjust for this variation in our analyses, including tightly matching controls to cases on the date of blood collection (within 30 days), conducting season-stratified analyses, and using season-specific cutpoints, to decrease the influence of date of blood collection on quantile placement. In a simulation study, the association between 25(OH)D and disease risk was biased toward the null when seasonal variation was ignored but biased away from the null when results were adjusted for season of blood collection, but quantiles were not based on season-specific cutpoints.[43] We also calculated season-standardized 25(OH)D values as residuals from a regression on date of blood collection. Our findings were generally similar across all approaches, although the positive association for colon cancer was statistically significant only in the season-specific and season-standardized models, which may have more precisely adjusted for season-related sun exposure. All but 1[12] of the previous prospective serologic studies matched subjects on the date of blood collection, but only 4 included additional adjustment for seasonal variation in 25(OH)D:[9–12] EPIC adjusted for season of blood collection and used season-standardized values,[12] 1 study tested season-specific cutpoints,[11] and 2 studies conducted season-stratified analyses.[9,10] In the Health Professionals Follow-up Study, an inverse relation between 25(OH)D and colorectal cancer was observed based only on blood collected during the winter months.[10]

In contrast to the present findings, an early analysis within the ATBC Study suggested an inverse association, particularly for 25(OH)D and rectal cancer, although risk estimates were based on only 146 cases and up to 8 years of follow-up and were not statistically significant.[7] The earlier study used a radioimmunoassay to measure 25(OH)D, but the coefficients of variation and the average 25(OH)D concentrations were similar to those presented here, and applying similarly derived cutpoints from the earlier analysis to the present data yielded risk patterns consistent with the current findings. For example, odds ratios for quartiles 1–4 were 1.0 (reference), 1.41, 1.86, and 1.71 (95% CI for quartile 4: 0.95, 3.07) for colon cancer and 1.0, 0.58, 1.02, and 1.41 (95% CI for quartile 4: 0.72, 2.76) for rectal cancer. Given the shorter observation period, reverse causality could have influenced the previous results to some degree; however, exclusion of cases diagnosed within 2 years of blood collection did not attenuate those risks, and we found no evidence of reduced risks with higher 25(OH)D for subjects in the present analysis with shorter follow-up.

Our findings could have been due to the low vitamin D status of the study population, which was a consequence of the high latitude's limiting synthesis of vitamin D in skin, especially during the winter,[44] very few blood collections in the summer months, and low use of supplemental vitamin D. However, 2 other studies that observed a nonsignificantly increased risk with higher 25(OH)D for colon[9] and rectal[10] cancer had higher 25(OH)D concentrations than were found in ATBC. Other studies have reported increased risk of pancreatic[30,45,46] and upper gastrointestinal[47,48] cancer with higher 25(OH)D concentrations in ATBC and other populations. The risk patterns in the current ATBC colorectal analysis differed from those in the EPIC analysis of Europeans,[12] which used similar a priori defined cutpoints and the same referent category as our analysis. More than half of the EPIC participants were current or former smokers, and while adjustment for smoking status did not appear to alter the risk estimates, results stratified on smoking status were not presented in the published article.[12]

The 25(OH)D biomarker integrates vitamin D exposure from diet, supplements, and sunlight, with an approximately 2- to 3-week half-life.[2] The prospective evaluation of 25(OH)D 8–20 years after baseline minimized any effect of cancer on vitamin D status, but the long follow-up could be a limitation if exposures changed over time. Differences in the length of follow-up among studies do not appear to explain inconsistencies in the results found across studies. As with most prospective studies, we relied on a single measurement of 25(OH)D to represent long-term vitamin D exposure; however, correlations of 0.52–0.70 have been reported for 25(OH)D measured in samples collected 3–14 years apart.[49–51] Another limitation, due to the design of the parent study, was that the analysis included only male smokers, leaving open the possibility that the vitamin D-colorectal cancer relation is somehow altered among smokers and that our findings may not be generalizable to nonsmoking populations or to women. Some investigators have reported gender differences in the vitamin D-colorectal cancer association,[9,10] while others have not.[11,12] Whether an interaction with smoking exists has not been adequately addressed, and future researchers should examine this issue, especially given that approximately 20% of the US population currently smokes.[52] Few cohort studies will have the statistical power to prospectively examine vitamin D-cancer associations among smokers; however, planned pooled analyses should be able to address this issue.

In summary, high 25(OH)D concentrations were not associated with lower risk of colorectal cancer in this prospective study. In fact, our data suggested greater colon cancer risk in men with higher circulating 25(OH)D concentrations. This could have resulted from the very long period of observation, the fact that the cohort consisted solely of smokers, or the low overall vitamin D status of this population, although insufficiently high levels might be expected to yield a null finding. In future studies, researchers should specifically examine the association by smoking status, sex, and race/ethnicity and should employ rigorous methods to adjust and control for seasonal variation in circulating vitamin D concentrations.

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