Long time readers of this weblog will know I have an interest in Vitamin D. It has been hypothesized to be one of the major causal factors in generating human skin color variation, and we know from evolutionary genomics that the genes which underly skin color have been under very recent & powerful selection pressures. There is also data that Vitamin D levels may have a relationship to endemic diseases such as flu, and chronic ones such as arthritis. And then we find out nuggets such as the fact that most non-whites in Canada are Vitamin D deficient.

But what if we're putting the cart before the horse? Vitamin D Deficiency Study Raises New Questions About Disease And Supplements:

"Our disease model has shown us why low levels of vitamin D are observed in association with major and chronic illness," Marshall added. "Vitamin D is a secosteroid hormone, and the body regulates the production of all it needs. In fact, the use of supplements can be harmful, because they suppress the immune system so that the body cannot fight disease and infection effectively."

Marshall's research has demonstrated how ingested vitamin D can actually block VDR activation, the opposite effect to that of Sunshine....

...

Vitamin D deficiency, long interpreted as a cause of disease, is more likely the result of the disease process, and increasing intake of vitamin D often makes the disease worse. "Dysregulation of vitamin D has been observed in many chronic diseases, including many thought to be autoimmune," said J.C. Waterhouse, Ph.D., lead author of a book chapter on vitamin D and chronic disease.

"We have found that vitamin D supplementation, even at levels many consider desirable, interferes with recovery in these patients."

"We need to discard the notion that vitamin D affects a disease state in a simple way," Marshall said. "Vitamin D affects the expression of over 1,000 genes, so we should not expect a simplistic cause and effect between vitamin D supplementation and disease. The comprehensive studies are just not showing that supplementary vitamin D makes people healthier."

The original paper is Vitamin D discovery outpaces FDA decision making. You can find a preprint here. The article actually states "Vitamin D activates the VDR [Vitamin D receptor] to transcribe (or repress) 913 genes, and the possibility that it might affect expression of as many as 27,091...." It is interesting to me, from an evolutionary perspective, that Vitamin D production might be interrelated with numerous biochemical processes. That being said, I can't but help feel throwing out "27,091" genes affected is an attempt to interject a large number into the argument to puff up the case. Modeling evolutionary genetics as a system where alleles operate independently and additively is an ideal, and it only is truly relevant in the case of loci where extant genetic variation is related to the normal range of phenotypic variation. Molecular biology and biochemistry make clear that as a matter of mechanism our physiology is characterized by an incredibly complex network of interdependent processes mediated by a bewildering array of biomolecules. The key is not that Vitamin D (through VDR) modulates thousands of genes, but whether this is atypical for a major biomolecule. My impression is that it's not, so the authors impress me more when they stick to their molecular bread & butter, as opposed to placing their work in a systematic perspective. We're modulating so many inputs simultaneously that arguments about "thousands and thousands" don't sound convincing in the bigger picture.

The paper also delves into a pretty controversial area:

It has been assumed that the obesity epidemic is due to unhealthy lifestyle choices. Surprisingly, however, several carefully controlled studies have failed to confirm that assumed causal link between lifestyle and childhood obesity...Additionally, other studies are showing an association between lowered levels of 25-D and obesity...indicating the alternative hypothesis of metabolic homeostasis should be considered alongside the customary assumption of deficiency.

The VDR is responsible for expression of key antimicrobial peptides. Both cathelicidin and defensin antimicrobial peptides are active in the GI tract, and are known to regulate the composition of bacterial flora...in addition to their role of responding to known pathogens. The activity of, particularly, cathelicidin, is important in the neonatal gut...Cathelicidin and defB2 are both expressed...by the VDR when it is activated by 1,25-D.

Is it possible that the chronic addition of immunomodulatory 'Vitamin D' to the diet of Homo sapiens has disturbed the historic composition of gut microbiota, and thus is at least partly responsible for the current epidemic of obesity? Physicians know that chronic administration of corticosteroids encourages obesity. More research is needed to better define the immunomodulatory activities of this secosteroid, before encouraging even more of it to be added to the food chain.

I'm open to the idea of pathogens having a greater phenotypic affect on us than we're aware of, but this seems a bit extreme. Like the earlier assertion about 27,000 genes it seems like the author is trying to go for broke and make a really grand hypothesis when the molecular talking points are good enough to capture interest. It would have been nice if they tried to correlate obesity rates internationally with the level of Vitamin D supplementation; or run some multiple regression on American ethnic groups and regions, who do vary a fair amount in between population obesity. And just as there are tens of thousands of genes potentially affected by VDR, there are hundreds of dietary and lifestyle shifts which might account for the obesity epidemic.

All that being said, this paper has made me think. I've been reading up about the biochemical complexities of this pathway lately, and it's too easy to just pretend it's a black-box and play evolutionary games. Details matter. I think that the paper points out some molecular processes which need to be accounted for, but it would have been nice if they left it at that instead of trying to throw out a bunch of wild conjectures which seem superfluous to their main argument.