To D or not to D? Now we know!
The causal role of circulating vitamin D concentrations in human complex traits and diseases: a large-scale Mendelian randomization study
Jiang, X., Ge, T., Chen, C. Y.
Science Reports; (2021) 11:184; ePub: January 10, 2021
Vitamin D is implicated as playing a role in multiple sclerosis (MS). Low levels of this hormone are associated with an increased risk for developing MS and of having more active disease. However, treatment trials with vitamin D have not shownb consistent benefits. Thus, the role of vitamin D is MS is not clear and raises the possibility of “reverse causality,” that is that low levels of vitamin D are secondary to having MS, and not the reverse. An unbiased and more direct way of determining whether vitamin D plays a role in causing MS is to study genes that control levels of vitamin D. Such genes are randomly distributed in the population and 69 different vitamin D-regulator genes are identified. These genes have more than 130 genetic variations called SNPs (“single nucleotide polymorphisms”). Certain SNPs or gene variations are associated with higher levels of vitamin D. Other SNPs are associated with lower levels of vitamin D. The authors of the above paper used a technique called “Mendelian randomization” to determine whether vitamin D regulating genes with were linked to 190 different diseases. These ranged from Alzheimer’s disease to stroke to a variety of autoimmune diseases in which altered immune function is believed to involved. MS was one of these autoimmune diseases. Using genetic data from hundreds of genome wide associations studies (GWAS) involving hundreds of thousands of persons, the researchers looked for linkages of vitamin D-regulating gene variations to the diseases in their large databases. They found only one such linkage, a highly statistically significant association of vitamin D-regulating genes with multiple sclerosis. SNPs that were associated with raised levels of vitamin D decreased the risk of MS by 60%. SNPs associated with lower levels of vitamin D increased the risk of MS. No other diseases, including other autoimmune diseases, showed such linkages. These unbiased observations, the largest to date, using multiple gene databases involving hundreds of thousands of individuals, strongly implicates vitamin D as being a unique causal factor in the development of MS. It is not the only factor, since in this large study vitamin D only accounted for 18% of susceptibility. There are some cautionary aspects of the study that are described below; nevertheless, the data strongly suggest that changes in vitamin D levels play an important causative role in the development of MS and that understanding how vitamin D deficiency leads to the development of MS would be a major breakthrough.
1. Multiple factors contribute to the development of MS. These include environmental factors such infections, one’s geographic location early in life, metabolic features such as obesity, and most importantly, one’s genes.
2. The observation that the prevalence of MS increasaed in populations that lived further from the equator led to the theory that exposure to sunlight was an important disease-contributing factor that could be related to levels of the hormone, vitamin D.
3. Subsequent studies showed that lower levels of vitamin D were associated with both an increased risk of developing MS and for having more active disease, supporting the concept that this hormone was important in the pathogenesis or cause of MS.
4. However, clinical trials involving the administration of varying doses of vitamin D to persons with MS did not show consistent benefits. The reasons are not clear but suggested that biases in patient selection (“unknown confounding variables”) may have played a role. These observations also raised the possibility of “reverse causation,” namely that low vitamin D levels didn’t contribute to the cause of MS but were secondary to having MS.
5. One way to obtain an unbiased insight into the role of vitamin D in MS is to study the effects of genes that regulate levels of vitamin D and see if these relate to the risks of developing MS or any other diseases.
6. This can be done with a technique called “Mendelian randomization.” Other researchers used this technique to suggest a causal relationship between low levels of vitamin D and the risk for developing MS, but numbers of persons and genes studied (4-6 genes versus 138 in the above study) were relatively small. The paper cited above is the largest and most compelling study implicating genes controlling vitamin D levels to risks of developing MS and its role in susceptibility.
7. Using three different statistical programs, the authors of the above paper found that the only disease out of the hundreds studied that linked to levels of circulating vitamin D was MS. This finding was unique to MS, with none of the 190 other diseases, including multiple autoimmune diseases, showing such linkage.
8. Genes associated with higher levels of vitamin D were associated with a 60% reduction in the probability of developing MS (odds ratio of ~0.4). However, vitamin D levels contributed only 18% overall to susceptibility of developing the disease. This relatively small contribution to susceptibility suggests that multiple other factors are involved in the pathogenesis of this illness.
9. There are several limitations to the above study. Most individuals whose genes were studied were white, with no data available for other populations. All individuals were adults, so effects of vitamin D levels on children and pre-adolescents are not known. The GWAS data used involved multiple studies and some participants may have been duplicated in different databases. Finally, there remains the possibility that vitamin D is not directly involved in the development of MS but is a marker for another process linked to vitamin D, an effect called “horizontal pleiotropy.” The authors tried to control for this and felt it unlikely given their analyses with three different statistical programs.
10. In spite of the limitations noted above, this study provides the strongest evidence that vitamin D is uniquely involved in the development of MS and is not just a general feature involved in other autoimmune diseases. Understanding the mechanisms by which vitamin D effects the pathogenesis of MS could lead to major advances in prevention and therapy.
One of the initial observations suggesting a role for vitamin D in the pathogenesis or development of MS were studies showing that the prevalence of MS in populations that were further from the equator was increased. While there are several possible reasons for this, such as differences in environmental infectious agents or age of exposure to regional infections, another possibility was differences in exposure to sunlight, resulting in lower levels of vitamin D in persons in northern regions. Subsequent studies showed that lower levels of vitamin D early in life increased the risk of developing MS , and that lower levels of this hormone were associated with more active disease. Such studies led to multiple treatment trials involving administration of varying doses of vitamin D, but results were inconsistent, with some showing benefit while others did not. All the above studies are observational, and establish a correlation of levels of vitamin D with the development of MS and with levels of disease activity, but they do not prove that vitamin D is directly involved in causing MS. There could be “reverse causality,” with the disease itself causing lower vitamin D levels. Alternatively, vitamin D could just be a marker, linked to another more fundamental disease mechanism, a phenomenon called “horizontal pleiotropy.” What is needed is an unbiased analysis of large numbers of persons with MS for evidence of a direct association of the disease with levels of vitamin D.
One way to do this is with a technique called “Mendelian randomization.” More than 130 variants involving 69 different genetic sites are involved in controlling vitamin D levels. These variants are distributed randomly among individuals. Some of the variants result in higher levels of vitamin D. Some result in lower levels of this hormone. Mendelian randomization looks at the distribution of these different variants and correlates them with clinical outcomes, i.e., specific diseases.
Using data from the largest number of available gene data sets (gene wide association studies or GWAS), involving hundreds of thousands of individuals, with a wide spectrum of different diseases, ranging from degenerative diseases such as Alzheimer’s, to psychiatric diseases, to a variety of autoimmune diseases such as lupus erythematosis and rheumatoid arthritis, the investigators looked at the distribution of vitamin D regulating genes to see if any were linked to the more than 100 illnesses. Three different analytic programs were used, each with a different approach. All arrived at the same conclusion. The only disease that showed a correlation with vitamin D levels was multiple sclerosis. The observation that none of the other autoimmune disease showed such a correlation makes it highly unlikely that levels of vitamin D affect more general immune functions in a disease non-specific fashion. The data also showed that gene variants associated with higher levels of vitamin D reduced the risk of developing MS by up to 60% (odds ratios of ~0.4), though vitamin D was only responsible for 18% of susceptibility.
As noted above in Key Point #9, there are some limitations of the study. Nevertheless, the data now firmly establish that vitamin D levels play a unique causal role in the pathogenesis of MS. What now must be done is to define the exact mechanisms for how this occurs, knowledge that could lead to new approaches to prevention and treatment.