Mendelian randomization can lead to flawed conclusions about the effects of vitamin C

A Mendelian randomization (MR) study concluded that vitamin C was not effective for pneumonia. We showed that the MR study corresponds to the comparison of two groups with similar vitamin C levels of 47.3 vs. 52.7 μM, whereas the plasma vitamin C level range in the population is from 10 to 100 μM.
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In the early literature, low vitamin C intake was associated with increased risk of pneumonia (Hemilä 2007) and a few intervention trials indicated that vitamin C may have preventive and treatment effects on pneumonia (Hemilä 2013). With very low dietary vitamin C intakes, plasma vitamin C level can fall below 10 μM, whereas with particularly high dietary intakes, plasma level can increase to around 100 μM. Thus, to evaluate the effects of plasma vitamin C on specific conditions, the relevant plasma range should cover around 10 μM to 100 μM.

In a Mendelian randomization (MR) study, Hui (2001) concluded that there is no support for the use of vitamin C in the prevention and treatment of pneumonia or COVID-19. However, they used single nucleotide polymorphisms (SNPs) that were associated with plasma vitamin C levels in the genome-wide association study in 52,018 people of European ancestry. The cited study states “the variance of plasma vitamin C explained by the 11 lead SNPs was 1.87% on average”. Explaining such a very small proportion of the variance is not a valid measure of the possible effects of vitamin C.

We calculated that the analysis by Hui et al. corresponds to the comparison of two population groups of equal size with vitamin C levels of 47.3 vs. 52.7 μM. Such a very small difference in the mean vitamin C levels is not clinically meaningful. A study of vitamin C and pneumonia should ideally compare plasma levels between 10 μM and 100 μM.

MR can be powerful, but in the case of vitamin C, the difference between “low” and “high” levels is so small that it has no physiological relevance. Similarly, this very small variation renders MR studies on vitamin C and many other clinical conditions also uninformative (e.g. Hemilä 2022a, Hemilä 2022b). Other limitations of MR have also been published.

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