VitaminDandMultipleHealthOutcomes: AnUmbrellaReviewofObservationalStudies, RandomizedControlledTrials,andMendelian RandomizationStudies

Abstract

Observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have yielded inconsistent results on the associations of vitamin D concentrations with multiple health outcomes. In the present umbrella review we aimed to evaluate the effects of low vitamin D concentrations and vitamin D supplementation on multiple health outcomes. We summarized current evidence obtained from meta-analyses of observational studies that examined associations between vitamin D concentrations and multiple health outcomes, metaanalyses ofRCTsthat investigatedtheeffect ofvitaminDsupplementationonmultiplehealth outcomes,andMRstudiesthat exploredthecausal associations of vitamin D concentrations with various diseases (international prospective register of systematic reviews PROSPERO registration number CRD42018091434). A total of 296 meta-analyses of observational studies comprising 111 unique outcomes, 139 meta-analyses of RCTs comprising46uniqueoutcomes,and73MRstudiescomprising43uniqueoutcomeswereincludedinthepresentumbrellareview.Twenty-eight diseaseoutcomeswereidentifiedbybothmeta-analysesofobservationalstudiesandMRstudies.Seventeenofthesereporteddiseaseoutcomes hadconsistentresults,demonstratingthatlowerconcentrationsofvitaminDwereassociatedwithahigherriskforall-causemortality,Alzheimer’s disease, hypertension, schizophrenia, and type 2 diabetes. The combinations of consistent evidence obtained by meta-analyses of observational studies and MR studies together with meta-analyses of RCTs showed that vitamin D supplementation was associated with a decreased risk for allcause mortality but not associated with the risk for Alzheimer’s disease, hypertension, schizophrenia, or type 2 diabetes. The results indicated that vitamin D supplementation is a promising strategy with long-term preventive effects on multiple chronic diseases and thus has the potential to decrease all-cause mortality. However, the current vitamin D supplementation strategy might not be an efficient intervention approach for these diseases,suggestingthatnewstrategiesarehighlyneededtoimprovetheinterventionoutcomes