Background Vitamin D may regulate the innate immune system, and randomised controlled trials suggest a beneficial effect of vitamin D supplementation against acute respiratory tract infections. By using a Mendelian randomisation approach, we tested the hypothesis that low 25-hydroxyvitamin D is associated with increased risk of bacterial pneumonia in observational and genetic analyses.
Methods We genotyped 116 335 randomly chosen white Danes aged 20 to 100 from the Copenhagen City Heart Study and Copenhagen General Population Study for plasma 25-hydroxyvitamin D decreasing genetic variants around CYP2R1 (rs117913124, rs12794714 and rs10741657), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458) and HAL (rs3819817). Information on plasma 25-hydroxyvitamin D was available on 35 833 individuals. Individuals were followed from 1981 through 2018 for hospital diagnoses of bacterial pneumonias.
Results During up to 38 years follow-up, we observed 6342 bacterial pneumonias in observational analyses and 13 916 in genetic analyses. In observational analyses, multivariable adjusted HR for bacterial pneumonias was 1.27 (95% CI: 1.16 to 1.40) for individuals with 25-hydroxyvitamin D<25 nmol/L compared with those with ≥25 nmol/L. In genetic analyses, the OR for bacterial pneumonia per 10 nmol/L lower plasma 25-hydroxyvitamin D was 1.12 (95% CI: 1.02 to 1.23) in Wald’s ratio, 1.12 (95% CI: 1.04 to 1.20) in inverse-variance weighted, 1.63 (95% CI: 0.96 to 2.78) in MR-Egger and 1.15 (95% CI: 1.05 to 1.26) in weighted median instrumental variable analysis. This association was strongest for genetic variants around CYP2R1. There was no observational or genetic evidence to support that 25-hydroxyvitamin D is associated with risk of urinary tract infections, skin infections, sepsis or gastroenteritis, which were used as negative control outcomes.
Conclusions Low vitamin D is associated observationally and genetically with increased risk of bacterial pneumonias.
- clinical epidemiology
- respiratory infection
- bacterial infection
- innate immunity
Statistics from Altmetric.com
Contributors YÇ and SA had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses. YÇ, BGN and SA contributed to the study concept and design. YÇ, BGN and SA collected, analysed or interpreted the data. YÇ wrote the draft manuscript and did the statistical analyses. YÇ, BGN and SA revised the manuscript for important intellectual content. BGN obtained funding. BGN provided administrative, technical or material support. BGN and SA supervised the study.
Funding The Lundbeck Foundation. The funding source had no role in the design and conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.
Competing interests YÇ reports personal fees from Boehringer Ingelheim, AstraZeneca, Sanofi Genzyme outside the submitted work. BGN and SA have nothing to disclose.
Patient consent for publication Not required.
Ethics approval Both studies were approved by Danish ethical committees and conducted according to the Declaration of Helsinki (approval numbers: KF-V-100-2039/91 and H-KF-01-144/01). All individuals provided written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Additional data regarding technical details, statistical code and derivative data are available from the corresponding author. Data access for further analyses is possible through direct collaborative agreement or through locally managed access arranged through the study’s principal investigator.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.