Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study
Guillaume Butler-Laporte, Tomoko Nakanishi, Vincent Mooser, David R Morrison, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Annarita Giliberti, Alessandra Renieri, Yiheng Chen, Sirui Zhou, Vincenzo Forgetta, J Brent Richards
PLOS Medicine, doi:10.1371/journal.pmed.1003605
Background Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity.
Methods and findings Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on
Supporting information
S1 STROBE Checklist. STROBE case-control study checklist. (DOC)
Author Contributions Visualization: Guillaume Butler-Laporte, Tomoko Nakanishi. Writing -original draft: Guillaume Butler-Laporte, Tomoko Nakanishi, J. Brent Richards.
Writing -review & editing: Guillaume Butler-Laporte, Tomoko Nakanishi, Vincent Mooser, David R. Morrison, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Annarita Giliberti, Alessandra Renieri, Yiheng Chen, Sirui Zhou, Vincenzo Forgetta, J. Brent Richards.
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'abstract': '<jats:sec id="sec001">\n'
'<jats:title>Background</jats:title>\n'
'<jats:p>Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) '
'measurements, have been proposed to protect against COVID-19 based on in vitro, '
'observational, and ecological studies. However, vitamin D levels are associated with many '
'confounding variables, and thus associations described to date may not be causal. Vitamin D '
'Mendelian randomization (MR) studies have provided results that are concordant with '
'large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence '
'supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and '
'severity.</jats:p>\n'
'</jats:sec>\n'
'<jats:sec id="sec002">\n'
'<jats:title>Methods and findings</jats:title>\n'
'<jats:p>Genetic variants strongly associated with 25OHD levels in a genome-wide association '
'study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK '
'Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, '
'hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as '
'outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 '
'without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory '
'testing or medical chart review. Population controls without COVID-19 were also included in '
'the control groups for all outcomes, including hospitalization and severe disease. Analyses '
'were restricted to individuals of European descent when possible. Using inverse-weighted MR, '
'genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no '
'significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, '
'1.08; <jats:italic>p</jats:italic> = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; '
'<jats:italic>p =</jats:italic> 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; '
'<jats:italic>p =</jats:italic> 0.77). We used an additional 6 meta-analytic methods, as well '
'as conducting sensitivity analyses after removal of variants at risk of horizontal '
'pleiotropy, and obtained similar results. These results may be limited by weak instrument '
'bias in some analyses. Further, our results do not apply to individuals with vitamin D '
'deficiency.</jats:p>\n'
'</jats:sec>\n'
'<jats:sec id="sec003">\n'
'<jats:title>Conclusions</jats:title>\n'
'<jats:p>In this 2-sample MR study, we did not observe evidence to support an association '
'between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, '
'vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not '
'supported by genetic evidence. Other therapeutic or preventative avenues should be given '
'higher priority for COVID-19 randomized controlled trials.</jats:p>\n'
'</jats:sec>',
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