Intended for healthcare professionals

CCBYNC Open access
Research

Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study

BMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j4761 (Published 31 October 2017) Cite this as: BMJ 2017;359:j4761

Are their limitations to Mendelian randomization studies? Re: Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study

Eczema and problems with vitamin D Mendelian randomization studies
Excerpt:
John Cannell MD
1/30/2018

I was bothered by eczema for decades. I never had it bad - and it can get bad. Instead, every winter, like clockwork, itchy, dry areas on my skin would breakout. All the dermatologist could do was tell me to use moisturizing lotion, but that never really helped much. But just as it appeared like clockwork in winter, it disappeared like clockwork in the spring. Then, when I began taking 10,000 IU/day (250 mcg) of vitamin D3, my eczema disappeared, never to return.

But my case doesn't interest scientists. They want "proof". Mendelian randomization (MR) analyses are all the "proof" rage; some say they are more accurate than randomized controlled trials. They are being used to disprove vitamin D's involvement in various diseases, even when randomized controlled trials and meta-analyses show a direct cause/effect treatment relationship.

MR studies are a way of seeing if a lifetime of slightly lower vitamin D levels affect the prevalence of a disease. MR studies compare the prevalence of a disease between a population that has genetically lower 25(OH)D levels with a population without genetically lower 25(OH)D. The difference in 25(OH)D between the two groups is small, usually 1-3 ng/ml.

However, MR studies have limitations, especially when there is a strong genetic/environmental interaction as there is with vitamin D. Studies evaluating this interaction have found anywhere from 30% to 70% of 25(OH)D levels are heritable; for our purposes assume the variation in 25(OH)D levels are 50% genetic and 50% environmental. What studies should we believe, MR studies, or meta-analysis of randomized controlled trials?

Eczema is a good example.

Two large meta-analyses published in 2016 found supplemental vitamin D helps treat eczema:

Kim MJ, Kim SN, Lee YW, Choe YB, Ahn KJ. Vitamin D Status and Efficacy of Vitamin D Supplementation in Atopic Dermatitis: A Systematic Review and Meta-Analysis. Nutrients. 2016 Dec 3;8(12). pii: E789. Review.

Kim MJ, Kim SN, Lee YW, Choe YB, Ahn KJ. Vitamin D Status and Efficacy of Vitamin D Supplementation in Atopic Dermatitis: A Systematic Review and Meta-Analysis. Nutrients. 2016 Dec 3;8(12). pii: E789. Review.

However, a recent Mendelian randomization study found no evidence that vitamin D is involved with eczema.

Manousaki D, Paternoster L, Standl M, Moffatt MF, Farrall M, Bouzigon E, Strachan DP, Demenais F, Lathrop M, Cookson WOCM, Richards JB. Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study. PLoS Med. 2017 May 9;14(5):e1002294.

Which study to believe, the two meta-analyses or the Mendelian randomization?

I'd believe the two meta-analyses for a number of reasons:

" An assumption of MR analyses is that the effect of a vitamin D polymorphism (genetic variant) on a disease outcome functions only via 25(OH)D exposure. However, a genetic variant may result in multiple biological alterations (pleiotropy). Hence, if these alterations also independently affect the disease in question, does this lead to bogus conclusions? No one knows.

" Violation of MR assumptions may occur when closely located genetic variants are inherited together (linkage disequilibrium). Does this affect the prevalence of disease outside of the mechanism of 25(OH)D exposure? No one knows.

" The polymorphism genes usually assessed in vitamin D MR studies have been assessed in a vitamin D deficient population, usually with levels below 20 ng/ml (50 nmol/l). Does a slightly higher vitamin D level in one group help protect against a disease when both groups remain vitamin D deficient? No one knows.

" Unlike other vitamins, vitamin D concentrations in blood varies in relation to both genetic (direct genetic influence, gender, ethnicity, polymorphisms) and environmental factors (sunlight exposure, diet, food-related or direct vitamin D supplementation, season, latitude and skin pigmentation). In fact, vitamin D has very high, perhaps the highest, genetic/environmental interactions of any nutrient. The environmental effects can completely and easily obviate the genetic influence on vitamin D levels. How do all these various factors together affect 25(OH)D in MR studies? No one knows.

" MR studies assume the behaviors of the two groups that are compared do not differ. Genes certainly can influence behavior, and if any of the genes studied in MR studies affect vitamin D behavior, then vitamin D MR studies may be invalid. How does genetically influenced behavior affect MR studies? No one knows.

" Most of the genes affecting 25(OH)D levels are yet to be discovered. Until all or the majority of genes affecting 25(OH)D levels are identified, it cannot be known for certain how much individual genes affect 25(OH)D levels. How does this effect MR studies? No one knows.

" Dramatic effects of epigenetic phenomenon, such as methylation, on vitamin D (vitamin D receptor) are not assessed in MR studies. How can epigenetic phenomenon effect MR studies? No one knows.

RCTs have been the gold standard for decades. They answer a simple question. Does giving vitamin D help reduce the incidence of or treat the symptoms of various diseases. Of course, those RCTS must use an adequate dose, study the disease in question, have low baseline 25(OH)D levels, obtain adequate 25(OH)D levels, to have any value
.
MR studies are new to science and should be treated with healthy skepticism until the answers to the numerous problems with them are known.

Competing interests: No competing interests

30 January 2018
John Cannell
physician
John J Cannell MD
Vitamin D Council
11549 Los Osos Valley Road