Abstract
Associations of serum calcium (S-Ca) and 25-hydroxyvitamin D (S-25(OH)D) concentrations with longevity, cardiovascular disease, and cancer are not clear. We conducted a Mendelian randomization study to examine the associations of S-Ca and S-25(OH)D with longevity and risk of cardiovascular disease and cancer. The primary genetic instruments for S-Ca and S-25(OH)D were obtained from genome-wide association meta-analyses that included 61,054 individuals for S-Ca and up to 79,366 individuals for S-25(OH)D. Genetic variants associated with S-Ca and S-25(OH)D in the UK Biobank were used as confirmatory instruments. We obtained summary-level data for associations of these instruments with individual survival later than the 90th versus at most the 60th percentile of expected age at death from a genome-wide association meta-analysis including 11,262 cases and 25,483 controls, and with parental longevity (both parents in top 10% percentile) from the UK Biobank including 7,182 cases and 79,767 controls. Data for cardiovascular disease (111,108 cases and 107,684 controls) and cancer (38,036 cases and 180,756 controls) were obtained from the FinnGen consortium. A one standard deviation increase in genetically-predicted S-Ca concentration was associated with lower odds of longevity (odds ratio, 0.72; 95% CI, 0.55-0.95) and increased risk of cardiovascular disease (odds ratio, 1.11; 95% CI, 1.03-1.20). The associations were consistent in confirmatory analyses. There was no evidence supporting an association between genetically-predicted S-Ca and cancer, and no associations of genetically-predicted S-25(OH)D with the studied outcomes. Lifelong higher levels of S-Ca but not S-25(OH)D may shorten life expectancy and increase the risk of cardiovascular disease.
Highlights
Calcium and vitamin D supplements are frequently used for the prevention and treatment of osteoporosis despite weak and inconsistent evidence that they prevent fractures in communitydwelling women and men[1,2,3,4]
Summary-level data for longevity were available from a discovery metaanalysis of 18 GWAS cohorts of longevity
Long-lived cases were 11,262 European-descent participants who lived to an age ≥90th survival percentile based on individual cohort life tables from census data from each country, by sex and birth cohort
Summary
Calcium and vitamin D supplements are frequently used for the prevention and treatment of osteoporosis despite weak and inconsistent evidence that they prevent fractures in communitydwelling women and men[1,2,3,4]. Epidemiological evidence regarding the associations of these nutrients with all-cause and cardiovascular disease mortality is inconsistent and data on longevity are scarce[8,9,10,11,12,13,14]. Supplementation with calcium and vitamin D, alone or together, leads to increases in serum calcium (S-Ca) concentration with a peak 4 h after each ingestion and a more long-lasting elevation in serum 25-hydroxyvitamin D (S-25(OH)D), the marker metabolite for vitamin D status[15,16,17,18]. We first explored the long-term effects of calcium and calcium plus vitamin D supplementation on S-Ca concentrations in a meta-analysis. We used the MR design to assess the associations of genetically predicted lifelong small increases of S-Ca and S-25(OH)D concentrations with longevity as well as with risk of overall cardiovascular disease and cancer
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