Epidemiological evidence for a role of UV-induced vitamin D in

cancer (and other disease) prevention  

William B. Grant, Ph.D.Sunlight, Nutrition, and

Health Research Center (SUNARC)San Francisco, CA

94109, USAwww.sunarc.org

Disclosure

• I am pleased to acknowledge funding from these organizations:– UV Foundation (McLean, Virginia)

(www.uvfoundation.org)– The Vitamin D Society (Canada)

(www.vitamindsociety.org)– The European Sunlight Association

(www.europeansunlight.eu)

Outline Health Effects of UV and Vitamin D• Cancer

– Ecologic and cohort studies– Prospective supplementation study– Internal cancers after diagnosis of skin cancer

• Respiratory viral diseases• Autoimmune diseases• Metabolic diseases• Effect of vitamin D on mortality rates• Effect of vitamin D on economic burden: Canada• Summary

Ecological Studies of UVB and Cancer Incidence and Mortality

• The UVB/vitamin D/cancer theory was proposed in 1980 by Cedric and Frank Garland after seeing the map of colon cancer mortality rates in the United States.

• They realized that cancer rates were lowest in the sunniest part of the country and highest in the least sunny part.

• They hypothesized that since vitamin D production is the most important physiological effect of solar radiation, vitamin D was likely the agent.

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Cohort Studies of Vitamin D and Cancer Risk

• Edward Giovannucci developed a vitamin D index based on vitamin D from oral intake and UVB production, and controlled for other factors.

• This index was used to examine risk of cancer among the 50,000 participants in their male health professionals cohort.

• Significant inverse correlations with vitamin D were found for colon, esophageal, oral, pancreatic, and rectal cancer and leukemia.

• Insignificant inverse correlations were found for bladder, gastric, lung, prostate, and renal cancer.

Prospective Study of Vitamin D and Calcium and Cancer Risk

• Recently, a randomized, double-blind, placebo-controlled prospective study was conduced with various arms of the study receiving supplementation of 1100 IU of vitamin D3 and/or 1400 mg of calcium per day or a placebo. The finding was that the all-cancer incidence for post-menopausal women over the age of 55 years at time of enrollment was reduced by 77% (OR = 0.23 (CI: 0.09, 0.60; P < 0.005) between the ends of the first and forth years of the study [Lappe et al., 2007]. The baseline serum calcidiol level for these women was 28 ng/mL.

• Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007 Jun;85(6):1586-91.

Studies Based on Indices of UVB Irradiance Rather than Dose

• Critics of ecological studies based on solar UVB doses related to geographic location of residence question whether UVB dose translates to UVB irradiance.

• There is a simple way to determine lifetime UVB irradiance at the personal or population level: development of non-melanoma skin cancer (NMSC).

Meta-analysis of Risk of Second Cancer After Diagnosis of NMSC

Colon Cancer Risk Ratio vs. Lung Cancer Risk Ratio After Diagnosis of Nonmelanoma Skin Cancer

Lung Cancer Risk Ratio

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When adjusted for smoking (lung cancer risk ratio = 1.0), diagnosisof NMSC is significantly inversely correlated with colon cancer risk

Meta-analysis of Risk of Second Cancer After Diagnosis of NMSC

• For a diagnosis of squamous cell carcinoma, relative risks (RRs) were significantly reduced for subsequent colon, gastric, and rectal cancer with that for renal cancer being marginally insignificant, also accounting for smoking.

• For NMSC, RRs for cervical, esophageal, gastric, and rectal cancer were significantly reduced; those for colon and gallbladder cancer were marginally insignificant, while those for female breast, laryngeal, ovarian, renal, and uterine corpus cancer were insignificantly reduced.

Cancer in Spain

• Based on the results of my study finding that diagnosis of NMSC cancer reduced the risk of second cancers, I investigated cancer mortality rates for Spain using data for 48 continental provinces for the period 1978-93.

• I used latitude and NMSC mortality rates for lifetime solar UVB irradiance and lung cancer mortality rates for smoking.

Cancer in Spain Results

• Seven cancers had mortality rates significantly inversely correlated with latitude for one or both sexes: brain, gastric, melanoma, pancreatic, pleural, rectal and thyroid cancer, and non-Hodgkin's lymphoma (NHL).

• Those 7 plus an additional 10 cancers were inversely correlated with NMSC: bladder, breast, colon, esophageal, gallbladder, lung, ovarian, and uterine corpus cancer, Hodgkin's lymphoma and multiple myeloma.

Spain: Breast cancer vs. NMSC

Non-melanoma Skin Cancer Mortality Rate (RR)

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Tuohimaa P, et al. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: Vitamin D as a possible explanation.

Eur J Cancer. 2007 May 29;43:1701-1712.

• Standardized incidence ratios for all solid tumours except lip and skin after diagnosis of various skin cancers

• In sunny countries:– SCC: 0.79; SCC: 0.86; melanoma: 1.03

• In less-sunny countries:– SCC: 1.36; BCC: 1.35; 1.14

Tuohimaa P, et al. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: Vitamin D as a possible explanation.

Eur J Cancer. 2007 May 29;43:1701-1712.

• The effect of smoking explains the correlations between second cancers and skin cancers for cancers associated with smoking.

• The results for the less sunny countries indicated that in such countries, solar UVB doses are generally insufficient to play an important role in determining other cancer rates.

• The correlations between other cancers with skin cancers were consistent with the variable role of UVA and UVB in the etiology of each type of skin cancer (melanoma – UVA; SCC – UVB; BCC – mixed UVA and UVB).

Number of Observational Studies on UVB and Cancer Risk Reduction

• 10+: breast, colon, ovarian, pancreatic, prostate rectal cancer, NHL

• 7-9: esophageal, lung cancer• 5-6: gastric, renal, uterine corpus cancer,

Hodgkin’s lymphoma• 3-4: bladder, gallbladder cancer, multiple

myeloma• 2: cervical, oral, thyroid cancer, leukemia• 1: biliary, pleural, small intestine, soft tissue,

vulvar cancer

Dose-Response Relations

• It is important to determine the dose-response relations between vitamin D and cancer risk:– To verify that the effect is causal;– To be able to make policy recommendations.

• This has been done for breast and colorectal cancer through meta-analyses of published studies of prediagnostic serum calcidiol.

Respiratory Viral Diseases

• Cannell et al. [2006] hypothesized that epidemic influenza is seasonal in part due to seasonal variations of solar UVB and vitamin D.

• Aloia and Li-Ng [2007] provided experimental verification of this hypothesis.

• Yusuf et al. [2007] showed that solar UVB modulates the incidence of respiratory syncytical virus (bronchitis)

Aloia JF, Li-Ng M. Links Correspondence.Epidemiol Infect. 2007 Mar 12;:1-4 [Epub ahead of print]

Results of a prospective double blind vitamin D supplementation study involving 208 African-American post-menopausal women living in or near Mineola, New York. The numbers refer to cases of common cold or influenza.

Human Cathelicidin

• The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D (calcitriol) can induce the production of cathelicidin, a component of the innate immune system.

• The process of producing cathelicidin involves the microbe or viral activation of the enzyme 25(OH)D3-1-α-hydroxylase in macrophages, other immune cells, or epithelial cells, which increases local calcitriol levels from circulating calcidiol, which then activates the cathelicidin antimicrobial peptide (CAMP) gene [Gombart, 2006].

Vitamin D and Innate Immune System

• Cathelicidin induction from vitamin D seems to explain the beneficial role of UVB and vitamin D for bacterial and viral infections that peak in winter, including tuberculosis.

Sepsis

• Sepsis (infectious blood disease related to bacterial and viral infections) has these epidemiological features in the United States:– Highest in the Northeast, lowest in the Southwest;– Highest in winter, lowest in fall;– Higher in black Americans than white Americans;– Rapid increase with advancing age;– Comorbid diseases are vitamin D sensitive.

• These features are explained by the epidemiological features of solar UVB and vitamin D.

Extension to Autoimmune Diseases

• There are a number of diseases for which viral infections are a risk factor.

• The virus can embed itself in various tissues and live for many years with few symptoms.

• However, it does cause inflammation, which can lead to cancer.

• It may generate an autoimmune response.

Multiple Sclerosis (MS)

• Risk of MS is linked to viral diseases such as infectious mononucleosis linked to Epstein-Barr virus.

• UVB and vitamin D reduce the risk of MS.

• The prevalence of MS increases with increasing latitude in Australia, Europe south of Nordic countries, and the United States.

Multiple Sclerosis Prevalence for U.S. WWII, KC Veterans at Time of Entery into the Armed Forces vs. Latitude

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Hypothesis for MS

• UVB, through production of vitamin D, reduces the risk of MS primarily by fighting the viral infections that lead to MS, especially in youth, when such viral infections are more common.

• The simple latitudinal gradient in disease outcome is linked to wintertime solar UVB, when infectious diseases are more common, as opposed to summertime UVB, which has an asymmetrical pattern in the U.S.

Metabolic Diseases

• The evidence of beneficial effects for metabolic diseases are primarily observational to date:– Myocardial infarction; calcidiol [Scragg, 1990]– Hypertension; calcidiol [Forman et al., 2007]– Stroke incidence; calcidiol [Poole et al., 2006]– Incidence of type 2 diabetes mellitus; vitamin

D and calcium supplementation [Pittas, 2006]– Prevalence of type 2 diabetes; serum calcidiol

[Scragg, 2004]

Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Autier P. Gandini S.

Arch Intern Med. 2007 Sep 10;167(16):1730-7.

• BACKGROUND: Ecological and observational studies suggest that low vitamin D status could be associated with higher mortality from life-threatening conditions including cancer, cardiovascular disease, and diabetes mellitus that account for 60% to 70% of total mortality in high-income countries. We examined the risk of dying from any cause in subjects who participated in randomized trials testing the impact of vitamin D supplementation on any health condition.

• METHODS: The literature up to November 2006 was searched without language restriction.

• RESULTS: We identified 18 independent randomized controlled trials, including 57 311 participants. A total of 4777 deaths from any cause occurred during a trial size-adjusted mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to 2000 IU. The trial size-adjusted mean daily vitamin D dose was 528 IU. In 9 trials, there was a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D between the intervention and control groups. The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87-0.99). The summary relative risk did not change according to the addition of calcium supplements in the intervention.

• CONCLUSIONS: Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates.

Estimated Health Benefit of 2000 IU of Vitamin D3 per day - Canada • I have just completed an analysis of the

role of vitamin D in reducing the risk of various diseases and applied the findings to Canada.

• Conclusions:– The mortality rate would be reduced by 12%

(range: 6-18%)– The total economic burden would be reduced

by 8% (range: 4-12%)

Summary and Conclusion

• 1000-2000 IU/day of vitamin D3 is essential for optimal health.

• Solar UVB is the primary source for most people. Irradiance to the point of Skin cancer development is not required.

• Other sources include diet (inadequate), supplements (efficient), and artificial sources of UVB such as sunbeds.

• Public health policies on UVB and vitamin D should be revised in light of the emerging scientific findings.