Genes associated with low vitamin D levels linked to greater premature mortality risk

Tuesday, December 9, 2014. A study reported on November 19, 2014 in the British Medical Journal has uncovered an association between genetically low vitamin D levels and an increased risk of mortality over follow-up among Danish men and women.

"In previous studies, a close statistical relationship has been established between low vitamin D levels and increased mortality rates," explained study coauthor Børge Nordestgaard, who is a Clinical Professor at the Faculty of Health and Medical Sciences, University of Copenhagen, and Chief Physician at Copenhagen University Hospital. "However, the fact that vitamin D deficiency can be a marker for unhealthy lifestyles and poor health in general may have distorted the results. This led to our current study, which was based on an examination of the participants' genes - genes which cannot be explained by unhealthy lifestyles."

The investigation included 95,766 participants in the Copenhagen City Heart Study, the Copenhagen General Population Study and The Copenhagen Ischemic Heart Disease Study. Over the studies' median follow-up times of 19.1, 5.8 and 7.9 years, 10,349 deaths occurred. After evaluating the association between 25-hydroxyvitamin D levels and mortality over follow-up, Dr Nordestgaard and colleagues analyzed the relationship between genotypes that decrease plasma vitamin D and the risk of mortality.

"We have conducted a major Danish study, in which we have examined the connection between genes associated with permanent low levels of vitamin D and mortality," reported lead author Shoaib Afzal. We can see that genes associated with low vitamin D levels involve an increased mortality rate of 30 percent and, more specifically, a 40 percent higher risk of cancer-related deaths. An important factor in our study is that we have established a causal relationship."

"What is mendelian randomisation, and why might it be better than classical observational epidemiology?" ask Paul Welsh of the British Heart Foundation and Naveed Sattar in an accompanying editorial. "We now know that approaches linking circulating 25-hydroxyvitamin D [25(OHD)] to health outcomes are seriously hampered by confounding and reverse causality. The circulating concentration of 25(OH)D is influenced by factors such as time spent outdoors, diet, adiposity, smoking, and acute phase response. Mendelian randomisation attempts to eliminate such problems by exploiting the random allocation of genetic material at conception."

Since several trials of vitamin D supplementation will begin reporting in 2017, Drs Welsh and Sattar note that "We do not have to wait too long to see whether mendelian randomisation studies and large scale trials are in agreement."

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Lower risk of mortality over thirteen year period in association with higher levels of vitamin D

The American Journal of Clinical Nutrition published an article on September 17, 2014 that revealed a lower risk of dying over a 13 year average follow-up period among those whose serum vitamin D levels were highest in comparison with those whose were lowest.

Researchers at the University of Cambridge measured 25-hydroxyvitamin D [25(OH)D] levels in stored serum samples from 14,641 participants in the European Prospective Investigation into Cancer and Nutrition, who were between the ages of 42 and 82 years from 1997 to 2000. Subjects were followed until December 2012.

For men and women whose serum vitamin D levels were among the highest one-fifth of participants at an average of 36 ng/mL or more, there was a 27% lower adjusted risk of dying from all causes over follow-up in comparison with those whose levels were among the lowest fifth at less than 12 ng/mL. Those whose vitamin D levels were highest had a lower risk of death from cardiovascular disease, respiratory disease and other causes, and cardiovascular events, respiratory disease events and fractures were also reduced.

"This 13-year prospective study in a free-living, middle-aged and older British population provides additional support for the hypothesis that vitamin D status is associated with a range of important health outcomes including respiratory disease, cardiovascular disease, fractures, and total mortality," Kay-Tee Khaw and colleagues write. "Only 1% of the population had concentrations greater than 120 nmol/L [48 ng/mL]. Within this observed population range, there was no evidence for increased mortality for 25(OH)D greater than 90 [36 ng/mL] or greater than 120 nmol/L [48 ng/mL], suggesting that a moderate increase in population mean concentrations may have a potential health benefit for preventing deficiency without increasing risk."

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Complementary Alternative Cancer Therapies

Vitamin D is formed in the skin of animals and humans by the action of shortwave UV light, the so-called fast-tanning sunrays. Precursors of vitamin D in the skin are converted into cholecalciferol, a weak form of vitamin D3, which is then transported to the liver and kidneys where enzymes convert it to 1,25-dihydroxycholecalciferol, the more potent form of vitamin D3 (Sardi 2000). Although vitamin D exists in two molecular forms, vitamin D3 (cholecalciferol) found in animal skin and vitamin D2 (ergocalciferol) found in yeast, vitamin D3 is believed to exhibit more potent cancer-inhibiting properties and is therefore the preferred form.

Dark-skinned people require more sun exposure to produce vitamin D because the thickness of the skin layer (the stratum corneum) affects the absorption of UV radiation. Black human skin is thicker than white skin and thus transmits only about 40% of the UV rays needed for vitamin D production. Darkly pigmented individuals who live in sunny equatorial climates experience a higher mortality rate from breast and prostate cancer when they move to geographic areas that are deprived of sunlight exposure in winter months (Angwafo 1998; Sardi 2000).

Identifying the at-risk groups, through the assessment of genetic variations in the vitamin D receptor, appears to be a forthcoming tool for planning intervention strategies.

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