When Mendelian randomisation fails

Kohlmeier, Martin; Baah, Emmanuel

doi:10.1136/bmjnph-2021-000265

Cited by 6 publications

(5 citation statements)

References 21 publications

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“…To explore the causal role of vitamin D in COVID-19 risk, there have been at least three Mendelian Randomisation studies using the genetic variants associated with serum 25OHD as instrumental variables [6][7][8] . It is shown that genetic predisposition for lower levels of vitamin D is not causally associated with infection from SARS-CoV-2 or severe COVID-19 disease [6][7][8][9] . It is important to note that genetic heritability of vitamin D status is high in winter, but in the summer the vitamin D status might be predominantly determined by environmental factors regulating exposure (including season, geographical latitude) to ultraviolet B (UVB) radiation 10 .…”

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confidence: 99%

An observational and Mendelian randomisation study on vitamin D and COVID-19 risk in UK Biobank

Geffen

Weele

et al. 2021

Sci Rep

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A growing body of evidence suggests that vitamin D deficiency has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes. We used logistic regression to identify associations between vitamin D variables and COVID-19 (risk of infection, hospitalisation and death) in 417,342 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to look for evidence of a causal effect. In total, 1746 COVID-19 cases (399 deaths) were registered between March and June 2020. We found no significant associations between COVID-19 infection risk and measured 25-OHD levels after adjusted for covariates, but this finding is limited by the fact that the vitamin D levels were measured on average 11 years before the pandemic. Ambient UVB was strongly and inversely associated with COVID-19 hospitalization and death overall and consistently after stratification by BMI and ethnicity. We also observed an interaction that suggested greater protective effect of genetically-predicted vitamin D levels when ambient UVB radiation is stronger. The main MR analysis did not show that genetically-predicted vitamin D levels are causally associated with COVID-19 risk (OR = 0.77, 95% CI 0.55–1.11, P = 0.160), but MR sensitivity analyses indicated a potential causal effect (weighted mode MR: OR = 0.72, 95% CI 0.55–0.95, P = 0.021; weighted median MR: OR = 0.61, 95% CI 0.42–0.92, P = 0.016). Analysis of MR-PRESSO did not find outliers for any instrumental variables and suggested a potential causal effect (OR = 0.80, 95% CI 0.66–0.98, p-val = 0.030). In conclusion, the effect of vitamin D levels on the risk or severity of COVID-19 remains controversial, further studies are needed to validate vitamin D supplementation as a means of protecting against worsened COVID-19.

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confidence: 99%

An observational and Mendelian randomisation study on vitamin D and COVID-19 risk in UK Biobank

Geffen

Weele

et al. 2021

Sci Rep

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“…One application of genetically modulated nutrition status is as instrumental variables for Mendelian Randomisation to examine whether the nutrition status impacts particular disease outcomes. [7][8][9] As soon as substantial and corroborated evidence emerges for a particular variable that indicates the stratification of a nutritional response, there is no going back to the assumption of uniform behaviour. Whether the candidate variant ends up being causal itself or linked to another, ultimately causal variant is of lesser importance in this context.…”

Section: Martin Kohlmeiermentioning

confidence: 99%

“…For most of the nutritional relationships with a significant genetic component,6 impactful categorical variables remain hidden in the jungle of other common genetic variants, often involving multiple loci or genes and typically hundreds of variants across each of them. One application of genetically modulated nutrition status is as instrumental variables for Mendelian Randomisation to examine whether the nutrition status impacts particular disease outcomes 7–9…”

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confidence: 99%

One size does not fit all: on the need for categorical stratification in nutrition science, practice and policy

Kohlmeier

2023

BMJNPH

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“…The vitamin D status of otherwise healthy individuals is strongly influenced by habitual sun exposure and skin pigmentation [4]. Genetic factors also appear to have a significant impact, particularly in carriers of the common GC rs4588 genotype TT associated with lower vitamin D status [5]. Obese individuals tend to have poorer vitamin D status as do people living at high latitude (Canada, UK, Central and Northern Europe).…”

Section: Essential Nutrients For a Balanced Immune Responsementioning

confidence: 99%

Nutrition and Immunity

Kohlmeier,

Agwara,

Baah

2023

Nestlé Nutrition Institute Workshop Series

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Both the constantly active innate immune system and the later acting humoral defenses depend on adequate supplies of vitamins and trace elements. An array of essential micronutrients, specifically omega-3 polyunsaturated fatty acids (PUFAs), the vitamins A, D and E, as well as iron, copper, zinc, and selenium are of critical importance for protection against many contagious diseases, including viral infections of the upper respiratory tract. Balanced, micronutrient-rich food choices are an important foundation for a strong immune system and resilience against disease. A good vitamin D status appears to play a significant role in the protection against the upper respiratory tract infection COVID-19 caused by SARS-CoV-2, particularly at the time of initial exposure to the virus. The likelihood of infection and mortality risk during the first months of the pandemic was closely linked to skin pigmentation and how far north (latitude) the people lived, pointing to a potential role of sunlight (UV-B) exposure and vitamin D status. The excess risk of people with obesity may be explained at least in part by their typically lower vitamin D concentrations in blood. Habitual use of dietary supplements with moderate amounts of vitamin D was associated with slightly reduced disease risk in some studies.

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When Mendelian randomisation fails

Cited by 6 publications

References 21 publications

An observational and Mendelian randomisation study on vitamin D and COVID-19 risk in UK Biobank

An observational and Mendelian randomisation study on vitamin D and COVID-19 risk in UK Biobank

One size does not fit all: on the need for categorical stratification in nutrition science, practice and policy

Nutrition and Immunity

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