Genetically Low Vitamin D Not Linked to CV Death

Miriam E. Tucker

November 19, 2014

Genetically low vitamin D concentrations are associated with deaths due to cancer and other causes but not cardiovascular disease mortality, a new study finds.

Published online November 18 in the BMJ by Dr Shoaib Afzal (Copenhagen University Hospital, Denmark) and colleagues, the results suggest that associations between low vitamin D and cardiovascular mortality previously seen in observational trials could be because of confounding.

“In previous studies, a close statistical relationship has been established between low vitamin D levels and increased mortality rates. However, the fact that vitamin D deficiency can be a marker for unhealthy lifestyles and poor health in general may have distorted the results," principal investigator Dr Børge G Nordestgaard (University of Copenhagen, Herlev Hospital, Denmark) told Medscape Medical News.

"This led to our current study, which was based on an examination of the participants' genes — genes that cannot be explained by unhealthy lifestyles or hidden disease," he added.

He said that he was surprised by the protective effect of vitamin D observed for some conditions.

"My expectation was that genetically low vitamin D would not be associated with mortality, because I always thought that the association between low vitamin D and high mortality was due to confounding by poor lifestyle. Thus, the finding of no association between low vitamin D and cardiovascular mortality was what I expected. The surprising finding was the increased cancer and other mortality."

In an accompanying editorial, Dr Paul Welsh (British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Scotland) and Dr Naveed Sattar (University of Glasgow) praised the approach taken by the authors, harnessing genetics to investigate the issue.

But they cautioned that "the borderline significance of the findings means that we should be careful not to overinterpret" and that this new study "in isolation cannot therefore be taken as sufficient evidence to change clinical practice."

For that, both the investigators and editorialists point to the results of two randomized vitamin D supplementation trials anticipated 2017, the American Vitamin D and Omega-3 Trial (VITAL) and Finnish Vitamin D Trial (FIND).

Until those results are reported, "increasing vitamin D via modest sun exposure of your skin and by eating foods rich in vitamin D, like fatty fish," is all that can be advised, Dr Nordestgaard told Medscape Medical News.

Groundhog Day: Is There Any More to Say on Vitamin D?

In their editorial, Drs Welsh and Sattar say readers would be "forgiven for experiencing a sense of déjà vu — another study investigating the role of vitamin D in chronic disease, another editorial. They might also be forgiven for thinking that little is left to say about vitamin D that has not already become a cliché."

The wealth of recent research articles on vitamin D "is not the result of a comedic temporal loop designed to make one feel like Bill Murray relentlessly reliving the same experience in the 1993 cult movie Groundhog Day." Rather it "reflects the collective will of the academic community to investigate this topical public-health question as rapidly as possible."

Consequently, Dr Afzal and colleagues need make no apology for coming back to the vitamin D question using a Mendelian randomization approach, they note. Such studies are now being used to clarify cause and effect when reliable evidence from randomized controlled trials is difficult to obtain, they explain.

The researchers analyzed 95,766 white participants of Danish descent from three study cohorts, with median follow-up times of 19.1, 5.8, and 7.9 years, respectively.

All participants were genotyped for genetic variants in DHCR7 and CYP2R1 — the two variants that most strongly affect the metabolite measured as a marker of 25-hydroxyvitamin D. In total, 35,334 of the participants had 25-hydroxyvitamin D measurements taken. From study entry through 2013, 10,349 participants died.

As expected, vitamin D concentrations were associated with a number of health-related potentially confounding factors, including smoking, physical activity, systolic blood pressure, body mass index, diabetes, and plasma cholesterol, as well as income. The genetic alleles were not associated with those factors.

Overall, a 20 nmol/L lower vitamin D concentration was associated with all-cause and cause-specific mortality. Hazard ratios (HRs) were 1.19 for all-cause mortality, 1.18 for cardiovascular death, 1.12 for cancer mortality, and 1.27 for other mortality.

Small Effect Size for Each Genetic Variant

Each increase in DHCR7/CYP2R1 allele score of 0 to 8 was associated with a 1.9-nmol/L lower vitamin D concentration and with increased all cause, cancer, and other mortality, but not cardiovascular mortality.

HRs per one increase in DHCR7/CYP2R1 allele score were 1.02 (P = .03) for all-cause mortality, 0.98 for cardiovascular mortality (P not reported), 1.03 (P = .04) for cancer mortality, and 1.03 (P = .07) for other mortality.

Drs Welsh and Sattar write, "The small effect sizes do not diminish the potential importance of these findings in the search for evidence of a causal link between low [vitamin D] concentrations, disease, and death."

Because of the small effect, the authors modeled the anticipated effect of a genetically determined 20-nmol/L reduction in vitamin D. Here, the odds ratio for all-cause mortality was 1.30.

The two ongoing trials, which expect a 50-nmol/L increase in vitamin D, should therefore be sufficiently powered to detect reduced cancer mortality, Dr Afzal and colleagues write.

However, Drs Welsh and Sattar point out, "These predictions...hinge on the primary findings being valid and reliable."

Nevertheless, they say, "Afzal and colleagues' findings provide some cause for optimism about the impending results of large vitamin D trials, more so if they are rapidly confirmed by additional Mendelian randomization studies with greater power."

"Trials of vitamin D supplementation such as VITAL and FIND will start reporting in 2017, so we do not have to wait too long to see whether Mendelian randomization studies and large-scale trials are in agreement."

Dr Nordestgaard told Medscape Medical News, "Like Welsh and Sattar, I advise to wait for the VITAL and FIND studies to report in 2017. Also, I hope to see other reports of the importance of genetically low vitamin D on risk of morbidity and mortality to confirm the results of our study."

The studies from which these data were obtained were supported by the Danish Heart Foundation, Danish Medical Research Council, Copenhagen County Foundation, and Herlev Hospital, Copenhagen University Hospital. Drs Nordestgaard, Welsh, and Sattar have reported no relevant financial relationships.

BMJ. Published online November 18, 2014. Full article, Editorial

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