| Part?: Associations of serum 25(OH)D and calcium concentrations with all-cause and cause-specific mortalityBackground: Vitamin D and calcium have a wide range of biological functions in the human body.However,the associations of these two biomarkers with all-cause and cause-specific mortality are not consistent in previous studies,and the optimal serum concentration related to reduced mortality risk remains to be studied.Aim: To investigate the associations of serum 25(OH)D and calcium concentrations with the risk of all-cause and cause-specific mortality,determine the association shapes,and estimate the optimal concentrations of these two serum biomarkers.Methods: This study was based on UK Biobank,a large prospective cohort study with a half-million participants.We included 390,132 participants who had serum 25(OH)D or calcium measurements and no history of cancer,diabetes,or cardiovascular disease(CVD)at baseline(2006-2010).The main outcomes in this study were all-cause mortality and cause-specific mortality related to cancer,CVD,and respiratory diseases(RSD).Follow-up time was calculated for each participant from the date of attending an assessment center to the date of death or the date of last follow-up(31st January 2018 for England and Wales,and 30 th November 2016 for Scotland),whichever occurred first.Cox proportional hazard models were performed to estimate the hazard ratio(HR)and 95% confidence intervals(CI)for mortality.We used multivariate cubic regression splines to explore the dose-response relations of serum biomarker levels with all-cause and cause-specific mortality,and estimate the optimal concentrations on reducing mortality risk.We also evaluated the joint effects on mortality by cross-classifying participants based on the levels of serum 25(OH)D and calcium.Various stratified and sensitivity analyses were used to test the robustness of observed associations.Results: During a median follow-up of 8.9(interquartile range: 8.3-9.5)years,11,149 deaths occurred,including 6,288(56.4%)due to cancer,2,014(18.1%)due to CVD,and 728(6.5%)due to RSD.The multivariate analyses revealed non-linear inverse associations of serum 25(OH)D concentrations with all-cause mortality and mortality related to cancer,CVD,and RSD;positive linear associations between corrected calcium levels and mortality due to all-cause,cancer,and RSD were observed in the multivariate-adjusted results.In the continuous model,per 1-standard deviation(SD)increment in serum 25(OH)D concentrations was associated with a 13% lower risk for all-cause mortality(HR = 0.87,95% CI: 0.85-0.89),6% lower risk for cancer mortality(HR = 0.94,95% CI: 0.92-0.97),16% lower risk for CVD mortality(HR = 0.84,95% CI: 0.80-0.89),and 35% lower risk for RSD mortality(HR = 0.65,95% CI: 0.59-0.71);per 1-SD increment in corrected calcium levels was associated with a 6% higher risk for all-cause mortality(HR = 1.06,95% CI: 1.04-1.08),a 7% higher risk for cancer mortality(HR = 1.07,95% CI: 1.04-1.10),and a 14% higher risk for RSD mortality(HR = 1.14,95% CI: 1.06-1.23).The restricted cubic spline regression analyses suggested non-linear inverse associations(all Pnonlinear <0.0001),with a decrease in mortality risk appearing to level off between 45-60 nmol/L of 25(OH)D for overall deaths;we also found linear associations between corrected calcium and mortality due to all-cause,cancer,and RSD(all Plinear <0.005).In the joint effect analyses,participants with adequate vitamin D status(?50 nmol/L)and lower corrected calcium levels(<2.34 mmol/L)have the lowest risk for overall mortality(HR = 1.53,95% CI: 1.34-1.74;Pinteraction = 0.002).Conclusions: Higher 25(OH)D concentrations are non-linearly associated with a lower risk of all-cause,cancer,CVD,and RSD mortality.The thresholds of 45-60 nmol/L might represent an intervention target to reduce the overall risk of premature death,which needs further confirmation in large clinical trials.Higher corrected calcium levels are linearly positive associated with higher all-cause,cancer,and RSD mortality risk.In the participants with adequate vitamin D status,lower levels of corrected calcium levels were also associated with reduced overall mortality risk.This study provides important evidence for future clinical intervention trials.Part?: Associations of serum 25(OH)D and calcium concentrations with lung cancer riskBackground: Epidemiological studies evaluating associations of serum 25(OH)D and calcium concentrations with lung cancer risk have yielded inconsistent results.Aim: To systematically explore the associations of serum 25(OH)D and calcium with lung cancer risk,determine the association shapes,and investigate the potential interaction effect between these two biomarkers on lung cancer incidence.Methods: The observational analyses included 432,927 participants enrolled in the UK Biobank with serum 25(OH)D or calcium measured and no cancer history at baseline(2006-2010).Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries.Complete follow-up was available through 31 st March 2016 for participants in England and Wales,and 31 st October 2015 for participants in Scotland.HRs and 95% CIs were estimated using multivariable Cox proportional hazards models.Restricted cubic splines were used to assess dose-response relations.The joint analysis was used to evaluate the joint effect and potential interaction between serum 25(OH)D and calcium on lung cancer incidence.We also used various stratified and sensitivity analyses to test the robustness of observed associations.Results: During a median follow-up of 7.1(interquartile range: 6.4-7.7)years,2017 cases of lung cancer were recorded,including 825 adenocarcinoma cases and 406 squamous carcinoma cases.In a multivariable-adjusted model,25(OH)D levels were inversely associated with overall lung cancer risk(HR per SD increment = 0.91,95% CI: 0.87–0.96,Ptrend = 0.0001);and calcium levels were positively associated with overall lung cancer risk(HR per SD increment = 1.10,95% CI: 1.06–1.16,Ptrend <0.0001).The restricted cubic spline revealed a linear inverse association of 25(OH)D concentrations(Pnonlinear = 0.0002)and a linear positive association of calcium concentrations(Plinear = 0.001)with overall lung cancer risk.Stratified analyses showed the associations of 25(OH)D and calcium with lung cancer risk were basically consistent;however,the HRs were stronger in participants with BMI <25 kg/m2 and follow-up time ?5 years in 25(OH)D analysis.Besides,in the joint analysis,compared to the participants with adequate vitamin D status(?50 nmol/L)and lower corrected calcium levels(<2.34 mmol/L),participants with deficiency vitamin D status(<30 nmol/L)and high corrected calcium levels(?2.41 mmol/L)showed higher lung cancer risk(HR = 1.38,95% CI: 1.01-1.89),but no interaction effect was observed(Pinteraction = 0.07).These associations were largely consistent in the various stratified and sensitivity analyses.Conclusions: Serum concentrations of 25(OH)D and calcium are both linearly associated with lung cancer risk,with inverse relation for 25(OH)D and positive relation for calcium.No significant interaction effect is found between 25(OH)D and calcium on lung cancer incidence,and the protective association between 25(OH)D and lung cancer risk is only observed among participants with low blood calcium concentrations.This study provides important evidence for future intervention trials. |
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