Gene–environment interactions and vitamin D effects on cardiovascular risk

Background
Mendelian randomization is the random collection of genes from parent to progeny that occurs during gamete formation. It represents a kind of natural randomization in large populations, where the combination of variants of one or more genes determines the intensity of a phenotype [1]. Plasma 25-hydroxyvitamin D (pVitD) concentrations are affected by polymorphisms of DHCR7 and CYP2R1 genes, so clustering of a population by its haplotypes allows stratification of lifelong exposure to low or high pVitD levels. Such a natural experiment was described by Afzal et al. [2] to show that in a large European cohort, lifelong exposure to reduced pVitD levels is associated with an increased risk of all-cause mortality.

In the human quest for immortality, this evidence would mean that vitamin D supplementation is an easy way to increase life expectancy - a sort of elixir of longevity. However, the results of clinical trials that have challenged this issue remain inconclusive, especially those that assess the effect of vitamin D supplementation on cardiovascular deaths and the risk of cardiovascular events [3]. In this scenario, Huang et al. [4] further impact expectations of vitamin D enthusiasts. The authors confirm that genetically elevated pVitD levels, when examined in a comprehensive analysis of European and Chinese Han populations, do not provide protection against cardiovascular events. However, the manuscript contains further interesting discussion points.

Comparison of European and Chinese cohorts
The study by Huang et al. [4] combined the results of two extensive studies in Europe (Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS)) and one in China (China Kadoorie Biobank (CKB)). However, the European and Chinese cohorts appear to differ in terms of their genetic background as well as in terms of age, sex, body mass index, concurrent morbidities, follow-up therapies and overall and mean pVitD scores. In fact, the latter was 50% higher in the Chinese than in the European cohorts (84 nM / L vs. ~ 50 nM / L). Although the authors have not provided a definitive explanation for this difference, this can easily be interpreted by a possible role of non-genetic determinants of pVitD levels, such as solar radiation, food intake, microbiome, and age. Regardless of the cause of the difference in pVitD levels between the European and Chinese cohorts, the study by Huang et al. [4] However, there was a difference in the incidence of cardiovascular events in the CCHS and CGPS ​​studies compared to the CKB cohort.

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European cardiovascular risk (CVR) has been shown to be affected by the combined genetics of DHCR7 and CYP2R1, with an increase in the number of cardiovascular events among those with genetically determined lower pVitD levels. In addition, changes in pVitD levels caused by Mendelian clustering were more significant in the European sample than in the Chinese cohort, confirming that the genetic-environmental interaction plays a role in the final phenotype. Dietary habits or trends in Chinese sun exposure are likely to offset the genetic effects on pVitD levels, while their impact on the environment in Northern Europe is less significant. In addition, many other studies in the general population of southern Europe, including ours in southern Italy [5], suggest that the range of pVitD levels in the general population is wider in Europe than in the CKB cohort. Therefore, there is a broader range of pVitD scores in Europe than in the CKB study. In view of the greater difference, it can be deduced that Europeans' CVR phenotypes are more sensitive to extremely low pVitD values.

Vitamin D and its physiological role
Vitamin D plays a role in many homeostatic mechanisms in physiology, especially calcium metabolism. Low vitamin D levels affect calcium absorption and are associated with increased parathyroid hormone (PTH) levels. PTH and CVR correlate directly with such a correlation, which is consistently observed in studies of primary and secondary hyperparathyroidism [6, 7]. The underlying pathophysiology is in turn attributed to various mechanisms, from increased cardiac damage [8] to endothelial dysfunction [9]. At any age, pVitD and plasma PTH levels are inversely correlated, so reduced vitamin D levels can lead to hyperparathyroidism and thus an increased risk of cardiovascular events [5]. It is therefore possible that the CCHS and CGPS ​​populations, which are older and have a broader range of pVitD levels, have higher PTH levels, leading to an increased risk of cardiovascular events. On the contrary, the Chinese cohort had higher and more homogeneous pVitD values, and such a stabilizing effect might then have prevented the identification of an effect on the CVR.

Conclusions
In the future, a better definition of the normal pVitD regions, which also takes into account the interaction with other CVR mechanisms such as PTH, could help to model a more detailed scenario and more accurate effects on CVR. This definition is needed to identify the populations for which vitamin D supplementation would actually be a beneficial therapeutic intervention.

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