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Serum calcium and 25-hydroxyvitamin D in relation to longevity, cardiovascular disease and cancer: a Mendelian
Shuai Yuan1, John A Baron2,3,4,5, Karl Michaëlsson5
1Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Insights
Higher serum calcium (S-Ca) levels are linked to reduced longevity and increased cardiovascular disease risk. Serum 25-hydroxyvitamin D (S-25(OH)D) showed no significant associations with these outcomes.
Area of Science:
- Nutritional Epidemiology
- Genetic Epidemiology
- Cardiovascular Disease Research
Background:
- The relationship between serum calcium (S-Ca) and 25-hydroxyvitamin D (S-25(OH)D) concentrations and major health outcomes like longevity, cardiovascular disease (CVD), and cancer remains incompletely understood.
- Mendelian randomization (MR) offers a powerful approach to investigate causal relationships by utilizing genetic variants as instrumental variables, minimizing confounding factors.
Purpose of the Study:
- To investigate the potential causal associations of genetically predicted serum calcium (S-Ca) and 25-hydroxyvitamin D (S-25(OH)D) concentrations with longevity.
- To examine the associations of genetically predicted S-Ca and S-25(OH)D with the risk of developing cardiovascular disease and cancer.
Main Methods:
- A Mendelian randomization study design was employed using large-scale genome-wide association meta-analysis data.
- Primary genetic instruments for S-Ca and S-25(OH)D were derived from meta-analyses involving over 61,000 and 79,000 individuals, respectively.
- Confirmatory analyses utilized genetic variants from the UK Biobank, and outcome data for longevity, CVD, and cancer were sourced from the UK Biobank and FinnGen consortium.
Main Results:
- A one standard deviation increase in genetically predicted S-Ca concentration was associated with significantly lower odds of longevity (OR, 0.72; 95% CI, 0.55-0.95).
- Genetically predicted S-Ca was associated with an increased risk of cardiovascular disease (OR, 1.11; 95% CI, 1.03-1.20).
- No significant associations were found between genetically predicted S-Ca and cancer risk, nor between genetically predicted S-25(OH)D and any of the studied outcomes (longevity, CVD, cancer).
Conclusions:
- Lifelong higher serum calcium levels, as predicted by genetic factors, may be causally linked to reduced life expectancy.
- Elevated serum calcium concentrations appear to increase the risk of cardiovascular disease.
- Serum 25-hydroxyvitamin D concentrations do not seem to have a causal association with longevity, cardiovascular disease, or cancer risk.
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.
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