4.1 Key Results
This study aims at assessing the strength of the inverse relationship between UVB exposure and CRC incidence with increasing age. The DINOMIT model(16) proposes an explanation of how vitamin D deficiency increases the risk of developing colorectal cancer. However, it is expected to take years for these phases to occur, and hence we expect increasing age to have a major role in explaining the inverse relationship between UVB estimates and incidence of colorectal cancer. Thus, older age groups can be expected to have a stronger inverse association between vitamin D status and crude incidence rate of colorectal cancer. Though there is mixed evidence for this inverse association, our study aims at taking into consideration the effect of age on this association. In this country-specific analysis, we have shown an increasing trend in the strength of the inverse association between adjusted UVB estimates and crude incidence rate of colorectal cancer. The proportion of variability in the outcome (crude incidence rate of CRC) explained by the adjusted UVB estimate also increased with age. This study assesses the age-dependent inverse association between vitamin D status and incidence of colorectal cancer globally. This is the first study to the authors’ knowledge to have explored the age-related effect in this inverse association. UVB estimates decrease with increasing latitude, and higher incidence of colorectal cancer has been reported at higher latitudes.(24) Another recent study mentions low vitamin D status as a possible explanation to higher incidence rates of colon cancer in cold countries (higher latitudes).(25) This study demonstrates a significant inverse association between UVB exposure and CRC incidence in all age groups. Age-related differences in vitamin D status have been observed in the regions of Asia/Pacific and Middle East/Africa(26) and reduced vitamin D status with increasing age has been reported in previous studies.(27) Also, vitamin D deficiency has been observed across all age groups globally including countries with low latitude.(28) UVB exposure is strongly correlated with the serum 25(OH)D levels and previous studies have shown significant associations between 25(OH)D levels and overall CRC incidence.(29) Photosynthesized vitamin D released from erythemal solar radiation to the skin has been found to have a greater effect on serum 25(OH)D levels than dietary vitamin D ingestion.(30) The tissue stores of cholecalciferol which are obtained through exposure to UVB radiation help in sustaining serum 25(OH)D levels.(30)
4.2 Interpretation
Previous ecological studies have reported an inverse association between UVB exposure and incidence as well as mortality of various cancers, including colon cancer.(31,32) In one of the prior ecological studies, a significant inverse association was observed for colon cancer (among ten other cancers), and the relative risk of colon cancer incidence related to solar UVB exposure was found to be 1.11 in males and 1.14 in females.(31) In another ecological study, inverse associations with UVB were found for 15 different cancers, including colon cancer.(32) The standardized regression coefficient for age-adjusted mortality rates of colon cancer versus UVB irradiance was found to be -0.71 (p < 0.001) for males and -0.76 (p < 0.001) for females. However, not all ecological studies have been able to demonstrate a significant inverse association between UV exposure and colon cancer.(33) The association between UVB exposure and global incidence of colorectal cancer was first analyzed in an ecological study(24) where simple linear regression and multiple linear regression methods were used to study the inverse association between UVB exposure and incidence of CRC. In this study, the age-adjusted crude incidence rates of colorectal cancer were higher at latitudes distant from the equator (R2 = 0.50, p < 0.001).(24) In the adjusted model of that study, UVB exposure (adjusted for cloudiness) was inversely associated with age adjusted CRC crude incidence rates (p = 0.01), after controlling for covariates.(24) However, age-dependent strength of the inverse association between UVB exposure and colorectal cancer was not explored in that study.(24)
Various studies have demonstrated the effect of diet on risk of colorectal cancer. Increased consumption of red meat and total meat were associated with higher risk of developing colorectal cancer in a study which analyzed data from a Japanese cohort.(34) Also, intake of fruits and vegetables have shown to have a protective effect against cancer.(35) Results from other studies suggest that changes in dietary pattern, specifically with increased meat consumption, can increase the risk of developing CRC.(36) A recent study observed highest number and proportion of diet-related cases for colorectal cancer.(37) Smoking is known to increase the risk of both colon and rectal cancer, with a stronger association for rectal cancer.(38,39) The duration of smoking had a significant association with the risk of colorectal cancer.(40)
A nested case-control study from the Women’s Health Study (WHS) found a significant inverse association between pre-diagnostic 25(OH)D levels and risk of CRC.(41) This case-control study with 274 controls and 274 colorectal cases observed a significant inverse association between plasma vitamin D and odds of colorectal cancer in multivariable adjusted logistic regression models.(41) MEG3 (non-coding RNA maternally expressed gene) functions as a tumor suppressor in CRC by regulating the activity of clusterins, which is stimulated by the binding of vitamin D receptor to its promoter.(42) Meta-analysis of the relationship between serum 25(OH)D and mortality of patients with colorectal cancer has shown that higher serum 25(OH)D was associated with lower mortality of patients with colorectal cancer.(5) Mortality rates were also decreased in summertime, where UVB wavelengths of solar radiation are more available.(43)
The main strength of this study is the novelty of assessing the age-dependent inverse relationship between UVB exposure and CRC incidence. The unadjusted analysis included 166 countries in comparison to 139 countries in a previous study.(24) The results of this analysis are in line with the previous study(24) in having obtained a significant inverse association between UVB exposure and incidence of colorectal cancer. As with prior analyses, this analysis employed multiple linear regression to account for other risk-modifying factors. UVB estimates were significantly associated with the risk of colorectal cancer in age groups over 45 years after adjusting for covariates. These findings are consistent with other studies which have found significantly different risk factors for individuals receiving a diagnosis of CRC prior to age 50, compared to those receiving a diagnosis after age 50.(44) We suggest that several risk factors for later-age development of CRC may derive from chronic exposures, and we suggest that vitamin D deficiency is among these. The significant increase in the strength of this inverse association with age was observed in the analysis, as hypothesized. Also, the proportion of variation in the age-specific crude incidence rates due to UVB exposure (R2) increased consistently with age.
4.3 Limitations
Data for all variables that were included in the multiple linear regression were available for only 148 countries. Some other influential risk-modifying factors, such as clothing and number of hours spent indoors, were not included in the adjusted model due to limited availability of data. The inherent limitations of the data used in this study include use of neighboring country’s CRC estimate in some cases of unavailability, as well as some uses of hospital-based data instead of population/registry-based data. Furthermore, countries which lacked data for UVB estimates were mostly countries with lower per capita income and limited access to healthcare, which were also closer to equator with high UVB exposure. Exclusion of these countries from the study could have reduced the strength of associations.
4.4 Generalizability
The results of the study cannot be applied directly at the level of individuals due to ecological fallacy. However, the study findings do reveal a significant effect of age on the inverse association between UVB exposure and colorectal cancer incidence rates. The multivariate models with modeled 25(OH)D had lower R2 values compared to those with the UVB estimates adjusted for cloud cover, reducing the proportion of variability in the crude incidence of CRC explained by vitamin D levels. Also, adjusted UVB estimate was statistically significant in the age group of 45-60 years, whereas modeled 25(OH)D was only marginally significant although both the covariates retained statistical significance in age groups above 60 years. Though our study used the modeled 25(OH)D data calculated from 28 publications, there was a mean difference of 5.26 nmol/L between the values used in the study and the published annual values of 25(OH)D.(26,27)