Higher vitamin D concentrations have been proposed as a protective 'seasonal stimulus' against influenza, and there are suggestions for associations with other aspects of respiratory health. The aim ...of the present study was to investigate the relationship of current vitamin D status (measured by 25-hydroxyvitamin D, 25(OH)D) with respiratory infections and lung function. We used cross-sectional data from 6789 participants in the nationwide 1958 British birth cohort who had measurements of 25(OH)D, lung function (forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) and respiratory infections available from the age of 45 years. In this population, the prevalence of respiratory infections had a strong seasonal pattern in the opposite direction to the pattern for 25(OH)D concentrations. Each 10 nmol/l increase in 25(OH)D was associated with a 7 % lower risk of infection (95 % CI 3, 11 %) after adjustment for adiposity, lifestyle and socio-economic factors. For FEV1 and FVC, each 10 nmol/l increase in 25(OH)D was associated with 8 (95 % CI 3, 13) ml and 13 (95 % CI 7, 20) ml higher volume, respectively, after controlling for covariates. Associations of 25(OH)D with FEV1 and FVC were only slightly attenuated after further adjustment for infection and other respiratory illness. In conclusion, vitamin D status had a linear relationship with respiratory infections and lung function. Randomised controlled trials are warranted to investigate the role of vitamin D supplementation on respiratory health and to establish the underlying mechanisms.
Mendelian randomization (MR) studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems ...with confounding and reverse causality affecting other types of observational studies.
We evaluated genetic markers that index differences in 25-hydroxyvitamin D (25(OH)D) as instruments for MR studies on vitamin D.
We used data from up-to 6,877 participants in the 1958 British birth cohort with information on genetic markers and 25(OH)D. As potential instruments, we selected 20 single nucleotide polymorphisms (SNP) which are located in the vitamin D metabolism pathway or affect skin pigmentation/tanning, including 4 SNPs from genome-wide association (GWA) meta-analyses on 25(OH)D. We analyzed SNP associations with 25(OH)D and evaluated the use of allele scores dividing genes to those affecting 25(OH)D synthesis (DHCR7, CYP2R1) and metabolism (GC, CYP24A1, CYP27B1). In addition to the GWA SNPs, only two SNPs (CYP27B1, OCA2) showed evidence for association with 25(OH)D, with the OCA2 association abolished after lifestyle adjustment. Per allele differences varied between -0.02 and -0.08 nmol/L (P≤0.02 for all), with a 6.1 nmol/L and a 10.2 nmol/L difference in 25(OH)D between individuals with highest compared lowest number of risk alleles in synthesis and metabolism allele scores, respectively. Individual SNPs but not allele scores showed associations with lifestyle factors. An exception was geographical region which was associated with synthesis score. Illustrative power calculations (80% power, 5% alpha) suggest that approximately 80,000 participants are required to establish a causal effect of vitamin D on blood pressure using the synthesis allele score.
Combining SNPs into allele scores provides a more powerful instrument for MR analysis than a single SNP in isolation. Population stratification and the potential for pleiotropic effects need to be considered in MR studies on vitamin D.
Hypovitaminosis D and reduced IGF-1 are associated, individually, with metabolic syndrome. Physiological interactions between vitamin D and IGF-1 are reported; this is the first study to investigate ...their combined associations with metabolic syndrome prevalence.
Data on 25-hydroxyvitamin D (25(OH)D), IGF-1, and metabolic syndrome abnormalities (abdominal obesity; raised A1C, blood pressure, and triglycerides; and low HDL cholesterol) were collected from 6,810 British white subjects in the 1958 cohort, surveyed during 2002-2004 (age 45 years).
IGF-1 concentrations increased with 25(OH)D up to approximately 75-85 nmol/l but not thereafter. Both 25(OH)D and IGF-1 were inversely associated with metabolic syndrome. There was an interaction between 25(OH)D and IGF-1 (P = 0.025) on metabolic syndrome prevalence: IGF-1 was not significantly associated with metabolic syndrome among those with the lowest levels of 25(OH)D (P > 0.09), whereas higher 25(OH)D was associated with metabolic syndrome at all IGF-1 concentrations (P </= 0.006). Metabolic syndrome prevalence was lowest for participants with the highest concentrations of both 25(OH)D and IGF-1 (odds ratio for highest vs. lowest third of both 0.26 95% CI 0.17-0.40, P < 0.0001; adjusted for sex, month, hour, inactivity, alcohol consumption, smoking, and social class). 25(OH)D was associated with the prevalence of high A1C, blood pressure, and triglycerides after adjustment for IGF-1, obesity, and social and lifestyle variations (P </= 0.004 for all comparisons).
Serum 25(OH)D is inversely associated with metabolic syndrome, whereas the inverse association with IGF-1 was found only among those without hypovitaminosis D. These results suggest that metabolic syndrome prevalence is the lowest when both 25(OH)D and IGF-1 are high.
High body mass index (BMI) is an important predictor of mortality but estimating underlying causality is hampered by confounding and pre-existing disease. Here, we use information from the offspring ...to approximate parental BMIs, with an aim to avoid biased estimation of mortality risk caused by reverse causality.
The analyses were based on information on 9674 offspring-mother and 9096 offspring-father pairs obtained from the 1958 British birth cohort. Parental BMI-mortality associations were analysed using conventional methods and using offspring BMI as a proxy, or instrument, for their parents' BMI.
In the conventional analysis, associations between parental BMI and all-cause mortality were U-shaped (P
< 0.001), while offspring BMI had linear associations with parental mortality (P
< 0.001, P
> 0.46). Curvature was particularly pronounced for mortality from respiratory diseases and from lung cancer. Instrumental variable analyses suggested a positive association between BMI and mortality from all causes mothers: HR per SD of BMI 1.43 (95% CI 1.21-1.69), fathers: HR 1.17 (1.00-1.36) and from coronary heart disease mothers: HR 1.65 (1.15-2.36), fathers: HR 1.51 (1.17-1.97). These were larger than HR from the equivalent conventional analyses, despite some attenuation by adjustment for social indicators and smoking.
Analyses using offspring BMI as a proxy for parental BMI suggest that the apparent adverse consequences of low BMI are considerably overestimated and adverse consequences of overweight are underestimated in conventional epidemiological studies.
Summary Background & aims The relationship between vitamin D and common mental disorders (CMDs) remains unclear. We aimed to determine if behaviours affecting vitamin D concentrations differ between ...individuals with or without CMDs and evaluate, cross-sectionally and prospectively, the extent to which the association between 25(OH)D and CMDs are explained by these behaviours. Methods Data are from the 1958 British birth cohort ( n = 7401). Behaviours were ascertained by questionnaire at age 45 years. CMDs (depression, anxiety, panic, phobia) were assessed using the Clinical Interview Schedule-Revised at 45 years and depression using Mental Health Inventory-5 at 50 years. Results Participants with CMDs at 45 years differed from others on some but not all vitamin D related behaviours. There were inverse, cross-sectional associations at 45 years of 25(OH)D with depression and panic, which persisted after adjustment for vitamin D related behaviours (OR = 0.57, 95% CI: 0.40,0.81 and OR = 0.33, 95% CI: 0.40,0.81, respectively). Association between 25(OH)D and subsequent (50 years) risk of depression was non-linear ( p = 0.01), with lower risk for participants with 25(OH)D between 50 and 85 nmol/l compared with those with lower or higher concentrations. Conclusion This study provides support for an association of low 25(OH)D concentrations with current and subsequent risk of depression in mid-adulthood.
ObjectivesTo assess the association between working patterns and vitamin D status in men and women and to determine the potential influence of related lifestyle and socioeconomic factors.MethodsThe ...authors used data from the 1958 British birth cohort (aged 45 years) and 6154 participants, who were in full-time work, were included in current analyses. Vitamin D status was measured by circulating concentrations of 25-hydroxyvitamin D (25(OH)D). Information on working patterns and lifestyle factors was obtained using a structured questionnaire administered at 45 years.ResultsManual social class was strongly associated with vitamin D-related lifestyle factors, with those in manual classes not only spending more time outdoors, but also spending more time watching TV/using PC, consuming less supplements and oily fish. Associations between working patterns and vitamin D-related lifestyles were less clear: night work was not strongly associated with lifestyles in either gender, while working hours were associated with time spent outside, PC/TV leisure time and use of supplements in men but not in women. In men, working patterns were not associated with lower 25(OH)D concentrations. In women, 25(OH)D concentrations were 8% lower (95% CI 15% to 2%) in night workers compared with others, while women working less than 35 h/week had 5% higher concentrations of 25(OH)D (95% CI 1% to 8%) compared with those working 35–40 h/week after adjustment for season, social class and body mass index (BMI).ConclusionsWomen working nights and longer hours may be vulnerable to deficits in vitamin D status and associated health hazards.
Background
Population‐based research on vitamin D has increased dramatically in recent years. Such studies are typically reliant on assay procedures to measure reliable and comparable levels of ...25‐hydroxyvitamin D 25(OH)D concentrations.
Methods
Concentrations of 25(OH)D3 and 25(OH)D2 were measured using LC‐MS/MS in 5,915 participants (aged 31 years) of Northern Finland Birth Cohort 1966. Blood samples were assayed in batches over a course of 18 months. As anomalies were present in the measurements, 200 samples were reassayed using Diasorin RIA. Agreement between measurements was assessed by Passing–Bablok regression and limits of agreement (LoA). To harmonize LC‐MS/MS with Diasorin RIA measurements, formulae were derived from the LoA.
Results
Concentrations measured by LC‐MS/MS were much higher than those measured by Diasorin RIA, with a mean difference of 12.9 ng/ml. Constant variation was evident between batch measurements after log transformation. Statistical formula was applied separately for each batch of LC‐MS/MS measurements, enabling us to remove both the constant and proportional bias that was evident prior to the transformation.
Conclusion
Despite the introduction of schemes/programs to improve accuracy of assays to measure 25(OH)D, significant differences can still happen. In these instances, methods to harmonize measurements based on a relatively small number of replicates can be successfully applied to establish confidence and to enable between‐study comparisons.
Seasonal variations in health outcomes are commonly used to hypothesize a link with nutritional vitamin D (25-hydroxyvitamin D, 25(OH)D) status. The majority of vitamin D intake is from skin exposure ...to sunlight and varies seasonally in countries at a distance away from the Equator. However, despite the strong seasonality of vitamin D intake, no statistical method using cyclical patterns has been proposed to deduce an association between 25(OH)D and health indicators. Our motivation was to overcome the influence of related confounders, such as obesity, between 25(OH)D and health indicators: obesity would be expected to have little or no effect on the seasonal variations in 25(OH)D and in five inflammatory/hemostatic health outcomes (fibrinogen, tissue plasminogen activator tPA, von Willebrand factor vWF, C-reactive protein CRP, and D-dimer). The data analyzed was from the 1958 British birth cohort biomedical survey (n = 6195) and the biomarkers were ascertained from blood drawn over an 18-mo period. We used mediation analysis to determine whether the seasonal variations of the outcomes were mediated by 25(OH)D to infer an association. The assumptions of mediation analysis fit naturally into the study's cross-sectional setting, where day of year of blood collection is the independent variable transformed by the harmonic function, and 25(OH)D is the mediator of the seasonal variation of the outcomes. The harmonic terms were tested to establish the presence of seasonal variation in the outcomes and 25(OH)D in order to determine whether the statistical mediation test could be applied. The data were collected over an 18-mo period and assayed in multiple batches to measure the serum biomarkers. When the assay batches were modeled as fixed effects, significant correlation was found with date of when blood was drawn. Thus, variation in assay batches was accounted for as random effects terms on the intercept in linear mixed-effects models. Inferences were based on tests from mediation analysis defined by the product of regression coefficients; we extended this test to allow for harmonic functions with multiple frequencies in order to statistically test the mediated effect through 25(OH)D. This was done using parametric bootstrap when the models were run in the Frequentist setting. We also replicated the analyses in the Bayesian setting to ascertain the change in amplitude of the seasonal variation that was due to 25(OH)D. Out of the five health outcomes, three (tPA, D-dimer, and fibrinogen) had significant seasonal associations that were partially mediated through 25(OH)D, one (vWF) had a seasonal pattern not mediated through 25(OH)D, and finally another (CRP) had no significant seasonal pattern. The association of 25(OH)D was strongest for tPA, and less so for D-dimer and fibrinogen. Our results and adaption of the mediation test show that there is broad potential in using seasonal variations of health indicators to deduce an association that may have not been affected by nonseasonal confounding.
Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and ...25-hydroxyvitamin D 25(OH)D using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.
We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% 95% CI -0.10 to -0.02, p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 95% CI -7.1 to -1.3, p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).
On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
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