Laura Perna

Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States

Objective To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences. Design Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US. Setting General population. Participants 26 018 men and women aged 50-79 years Main outcome measures All-cause, cardiovascular, and cancer mortality. Results 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses. Conclusions Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

Strong associations of 25-hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study

BACKGROUND Serum 25-hydroxyvitamin D [25(OH)D] concentration has been linked to mortality in several studies, but appropriate cutoffs to define risk categories are under debate. OBJECTIVE We aimed to conduct a repeated-measurements analysis on the association of serum 25(OH)D concentrations with all-cause and cause-specific mortality, with particular attention given to the shape of dose-response relations. DESIGN Concentrations of 25(OH)D were measured in n = 9578 baseline and n = 5469 5-y follow-up participants of the ESTHER study, which is a German population-based cohort aged 50-74 y at baseline. Deaths were recorded during 9.5 y of follow-up (median). Restricted cubic splines were used to assess dose-response relations, and Cox regression with time-dependent variables was used to estimate hazard ratios. RESULTS During follow-up, 1083 study participants died; of those, 350 individuals died of cardiovascular diseases, 433 individuals died of cancer, and 55 individuals died of respiratory diseases. The overall mortality [HR (95% CI)] of subjects with vitamin D deficiency [25(OH)D concentrations <30 nmol/L] or vitamin D insufficiency [25(OH)D concentrations from 30 to 50 nmol/L) was significantly increased [1.71 (1.43, 2.03) and 1.17 (1.02, 1.35), respectively] compared with that of subjects with sufficient 25(OH)D concentrations (>50 nmol/L)]. Vitamin D deficiency was also associated with increased cardiovascular mortality [1.39 (95% CI: 1.02, 1.89)], cancer mortality [1.42 (95% CI: 1.08, 1.88)] and respiratory disease mortality [2.50 (95% CI: 1.12, 5.56)]. The association of 25(OH)D concentrations with all-cause mortality proved to be a nonlinear inverse association with risk that started to increase at 25(OH)D concentrations <75 nmol/L. CONCLUSIONS In this large cohort study, serum 25(OH)D concentrations were inversely associated with all-cause and cause-specific mortality. In particular, vitamin D deficiency [25(OH)D concentration <30 nmol/L] was strongly associated with mortality from all causes, cardiovascular diseases, cancer, and respiratory diseases.

Vitamin D and cognitive functioning in the elderly population in Germany

OBJECTIVES To examine the relationship of serum 25-hydroxy vitamin D3 with cognitive functioning in higher age, using an instrument covering multiple cognitive domains in a population-based study. DESIGN Follow-up study with measurement of vitamin D levels at baseline and assessment of cognitive functioning at year 5 follow-up. SETTING AND PARTICIPANTS A subgroup of 1639 participants of the ongoing epidemiological ESTHER study of the elderly general population in Saarland State, Germany, aged 65+ years at baseline (2000-2002). INTERVENTION Observational study. MEASUREMENTS Cognitive functioning was assessed by the COGTEL phone interview developed by Kliegel et al., which was administered 5 years after ESTHER baseline. Vitamin D in baseline samples was measured by chemiluminescence methods. Additional information was obtained by standardised questionnaires. RESULTS In multiple linear regression adjusted for important confounders, women in the lowest sex-specific quintile of vitamin D showed an on average 2.1 (95% confidence interval: 0.4 to 3.9) units lower COGTEL score than women in the highest quintile. A similar, albeit slightly weaker, association was seen in males (difference of 1.7 [-0.4 to 3.8] units). Spline regression suggested non-linearity with a distinct decline in cognitive performance in the lower range of vitamin D levels. CONCLUSIONS Our findings support suggestions that low levels of vitamin D may be associated with reduced cognitive functioning in the elderly.

Serum 25-Hydroxyvitamin D and Incidence of Fatal and Nonfatal Cardiovascular Events: A Prospective Study With Repeated Measurements

CONTEXT Several studies suggested that low serum concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with an increased risk of cardiovascular disease (CVD). However, the evidence is still inconclusive, mostly based on CVD mortality and studies with single 25(OH)D measurements. OBJECTIVE We aimed to assess the association of 25(OH)D with fatal and nonfatal CVD in the same study population, using repeated 25(OH)D measurements and competing risks analysis. DESIGN This was a population-based cohort study (ESTHER study, baseline 2000-2002). Follow-up data, including survival status, were collected after 2, 5, and 8 years. The response rate for survival was 99.9%. SETTING Participants were recruited during a health screening examination by their general practitioners. 25(OH)D was measured in blood samples collected at baseline and the 5-year follow-up visit. PATIENTS OR OTHER PARTICIPANTS A total of 9949 men and women, aged 50 to 74 years at baseline, with sufficient knowledge of the German language and resident in the German state of Saarland were included in the study. MAIN OUTCOME MEASURES Outcomes included CVD, coronary heart disease (CHD), and stroke, in total and differentiated into fatal and nonfatal events. RESULTS Overall, 854 study participants had a nonfatal and 176 a fatal CVD event during 8 years of follow-up. Comparing subjects with 25(OH)D levels below 30 nmol/L and above 50 nmol/L resulted in a hazard ratio of 1.27 (95% confidence interval = 1.05-1.54) for total CVD and 1.62 (95% confidence interval = 1.07-2.48) for fatal CVD in a model adjusted for important potential confounders. No significant association for nonfatal CVD was observed. In dose-response analysis, we observed an increased cardiovascular risk at 25(OH)D levels below 75 nmol/L. Results for CHD and stroke were comparable to the results obtained for the composite outcome CVD. CONCLUSIONS Our results support evidence that low 25(OH)D levels are associated with moderately increased risk of CVD and indicate that the observed association is much stronger for fatal than for nonfatal events.

Public health implications of standardized 25-hydroxyvitamin D levels: A decrease in the prevalence of vitamin D deficiency among older women in Germany

OBJECTIVE To compare the public health implications of using unstandardized immunoassay measurements of serum 25-hydroxyvitamin D [25(OH)D] concentrations versus using measurements standardized by liquid chromatography tandem-mass spectrometry (LC-MS/MS) when assessing the prevalence of 25(OH)D insufficiency and deficiency in various subgroups of individuals. METHOD We standardized immunoassay-based measurements of 25(OH)D with LC-MS/MS in a population-based sample of 5386 women aged 50-74 recruited in 2000-2002 in Germany. We used multivariate regression to assess 25(OH)D determinants and the association of vitamin D deficiency with health status. RESULTS Prevalences of 25(OH)D levels <50 nmol/L (insufficiency) and <30 nmol/L (deficiency) decreased considerably by standardization. The decrease in vitamin D deficiency (from 64.4% to 17.9%) was particularly strong in March-May among women aged ≥ 65. Independent of season of blood draw and standardization, women ≥ 70 years, obese, or currently smoking had an increased risk of having 25(OH)D levels <30 nmol/L. CONCLUSION The proportion of older women with vitamin D deficiency in Germany is much lower than previously reported, but prevalence of vitamin D insufficiency is high. Standardization of 25(OH)D values by immunoassay methods to LC-MS/MS equivalent values or direct measurement by LC-MS/MS is indispensable in drawing valid conclusions about the health implications of vitamin D deficiency or insufficiency.

Cognitive impairment, all-cause and cause-specific mortality among non-demented older adults

BACKGROUND cognitive impairment is widespread among older adults even in the absence of dementia, but very little is known about the association between cognitive impairment not due or not yet converted to dementia and mortality. The association between cognitive impairment and mortality contributes to assessing cognitive impairment-related risk constellation in old age in the absence of manifest dementia. OBJECTIVE to assess the impact of cognitive impairment on all-cause and cause-specific mortality among non-demented older adults and to explore the nature of the association between cognitive impairment and mortality. DESIGN an observational cohort study (ESTHER study; 2000-present). SETTING German state of Saarland. SUBJECTS a subsample of 1,622 participants aged ≥70 with measurement of cognitive function through the Cognitive Telephone Screening Instrument (COGTEL) and exclusion of a possible dementia diagnosis at both COGTEL baseline (2005-08) and over the mortality follow-up (2005-13). RESULTS during an average follow-up of 6.1 years, 231 participants (14.2%) died. Participants with low COGTEL total scores had ∼60% increased mortality compared with participants with higher COGTEL total scores in Cox regression models adjusting for a wide range of possible confounders (hazard ratio = 1.62; confidence interval 1.13-2.33). Dose-response analyses with restricted cubic splines indicate a monotonic inverse relationship between cognitive function and mortality. CONCLUSION cognitive impairment in the absence of manifest dementia is an important independent predictor of mortality, especially among men. The administration of cognitive tests among older adults may provide relevant information for patient care and treatment decisions. SOURCES OF FUNDING financial sponsors played no role in the design, execution, analysis and interpretation of data.

Genetic variations in the vitamin D binding protein and season-specific levels of vitamin D among older adults.

Background: Vitamin D insufficiency is common among older adults. Genome-wide association studies have found an association between variants in the vitamin D binding protein and serum levels of vitamin D. The quantification of this association among older women and men and its potential variation by season remain unexplored. Methods: Serum levels of 25-hydroxyvitamin D [25(OH)D] and genetic variants in the vitamin D binding protein were analyzed in 2160 women and 1581 men age 50 to 74 years participating in a large population-based cohort study (ESTHER study—epidemiologic study assessing chances of prevention and early detection of various chronic diseases, including cancer among older adults) in Germany. Serum levels of 25(OH)D were assessed in relation to four single nucleotide polymorphisms (SNPs; rs4588, rs2282679, rs1155563, and rs12512631) by descriptive and multivariate analysis. Results: Both heterozygous and homozygous women and men carrying the rare allele with SNPs rs4588, rs2282679, or rs1155563 had lower levels of 25(OH)D in summer months than those homozygous for the wild-type alleles. Adjusted differences ranged from 5.1 to 5.4 nmol/l among heterozygous carriers of the rare alleles and from 8.8 to 9.6 nmol/l among homozygous carriers of the rare alleles. During winter months, 25(OH)D differences by genotype were smaller among women and not apparent among men. Conclusions: Older women and men living in a high-latitude region and carrying the rare alleles of SNPs rs4588, rs2282679, or rs1155563 seem to benefit less from higher levels of ultraviolet radiation during the summer season.

Vitamin D Receptor Genotype rs731236 (Taq1) and Breast Cancer Prognosis

Several studies have suggested that the anticancerogenous effects of vitamin D might be modulated by genetic variants in the vitamin D receptor (VDR) gene. The association of VDR polymorphisms with breast cancer–specific and all-cause mortality after a breast cancer diagnosis remains, however, largely unexplored. We assessed the association of genetic variants in VDR (rs731236, rs1989969, rs2228570, and 11568820) with breast cancer survival in a sample of 498 patients with breast cancer with a mean age at diagnosis of 61 years from Saarland, Germany, who were followed for up to 5 years with respect to total and breast cancer–specific mortality (56 and 48 events, respectively). Adjusted HRs with 95% confidence intervals (CI) were estimated by Cox regression models. We found that patients with breast cancer homozygous for the rare allele of rs731236 (15% of the women in our cohort) had a tendency toward an increased risk for breast cancer–specific mortality. The HR (95% CI) adjusted for age and breast cancer stage was 2.8 (1.1–7.2) for breast cancer–specific mortality and 2.1 (0.9–4.9) for total mortality. Additional adjustment for family history of breast cancer, radical mastectomy, and body mass index only marginally changed the estimates. No association was found for rs1989969, rs2228570, and rs11568820. Our analysis suggests that VDR polymorphism rs731236 might be associated with breast cancer–specific mortality, and if our findings are confirmed in future bigger studies rs731236 might deserve consideration as a prognostic factor in clinical care of patients with breast cancer. Cancer Epidemiol Biomarkers Prev; 22(3); 437–42. ©2012 AACR.

Vitamin D receptor polymorphism and colorectal cancer-specific and all-cause mortality.

BACKGROUND The vitamin D receptor (VDR) gene is present in colorectal cancer (CRC) cells and its genetic variants have been associated with an increased risk of CRC. The association with colorectal cancer prognosis remains widely unexplored. METHODS 1397 colorectal cancer patients participating in two cancer cohorts (ESTHER II and VERDI) and in a population-based case-control study (DACHS) were followed for 5 years. Unadjusted and adjusted hazard ratios for all-cause mortality (469 events) and CRC-specific mortality (336 events) were estimated for VDR variants rs731236 (TaqI), rs2228570 (FokI), rs11568820 (Cdx2), and rs1989969 (VDR-5132). RESULTS No association was found between VDR polymorphism and CRC specific and all-cause mortality. Adjusted hazard ratios ranged from 0.79 (95% CI 0.57-1.12) to 1.14 (95% CI 0.89-1.46) for CRC-specific mortality and from 0.89 (95% CI 0.67-1.18) to 1.22 (95% CI 0.99-1.50) for all-cause mortality. All 95% confidence intervals included the null value. CONCLUSIONS Our findings do not support the hypothesis that the common VDR gene variants investigated in this study are of clinical relevance with respect to CRC prognosis.

Serum 25-Hydroxyvitamin D and Cognitive Decline: A Longitudinal Study among Non-Demented Older Adults

Background/Aims: Very few studies have investigated the longitudinal association between serum levels of 25-hydroxyvitamin D [25(OH)D] and cognitive impairment not due to dementia. This longitudinal study analysed 25(OH)D and the risk of cognitive decline among non-demented older adults. Methods: A subsample of the ESTHER cohort study, aged ≥70 years, was assessed with the Cognitive Telephone Screening Instrument (COGTEL) and underwent 25(OH)D measurements standardized with a reference method (n = 1,302). After an average follow-up of 4.6 years, 527 participants had repeated COGTEL testing and were eligible for analysis. Linear regression models were used to assess longitudinal associations between 25(OH)D levels and cognitive function. Possible practice effects of repeated cognitive testing were addressed with the reliable change index. Results: A trend of a more pronounced cognitive decline with lower vitamin D levels was observed among both women and men, with a statistically significant difference in COGTEL scores in the lowest vitamin D quintile of the total sample. Conclusions: This study indicates that low levels of vitamin D might be associated with cognitive decline among non-demented elderly individuals and highlights the need for further large-scale prospective studies to clarify the potential role of vitamin D in cognitive function at an old age.