Low vitamin D status is often associated with systemic low-grade inflammation as reflected by elevated C-reactive protein (CRP) levels. We investigated the causality and direction of the association ...between vitamin D status and CRP using linear and non-linear Mendelian randomization (MR) analyses.
MR analyses were conducted using data from 294 970 unrelated participants of White-British ancestry from the UK Biobank. Serum 25-hydroxyvitamin D 25(OH)D and CRP concentrations were instrumented using 35 and 46 genome-wide significant variants, respectively.
In non-linear MR analysis, genetically predicted serum 25(OH)D had an L-shaped association with serum CRP, where CRP levels decreased sharply with increasing 25(OH)D concentration for participants within the deficiency range (<25 nmol/L) and levelled off at ∼50 nmol/L of 25(OH)D (Pnon-linear = 1.49E-4). Analyses using several pleiotropy-robust methods provided consistent results in stratified MR analyses, confirming the inverse association between 25(OH)D and CRP in the deficiency range (P = 1.10E-05) but not with higher concentrations. Neither linear or non-linear MR analysis supported a causal effect of serum CRP level on 25(OH)D concentration (Plinear = 0.32 and Pnon-linear = 0.76).
The observed association between 25(OH)D and CRP is likely to be caused by vitamin D deficiency. Correction of low vitamin D status may reduce chronic inflammation.
Coffee is one of the most widely consumed stimulants worldwide and is generally considered to be safe or even beneficial for health. However, increased risk of myocardial infarction and hypertension ...has been suggested for individuals who carry a functional variant at cytochrome P450 1A2 (CYP1A2), which makes them less effective at metabolizing caffeine.
The aim of this study was to examine if the CYP1A2 genotype or a genetic score for caffeine metabolism (caffeine-GS) modifies the association between habitual coffee consumption and the risk of cardiovascular disease (CVD).
Genetic data and information on habitual coffee intake and relevant covariates were available for 347,077 individuals in the UK Biobank, including 8368 incident CVD cases. We used logistic regression to test for the association between coffee intake and CVD risk, and whether the association varies with CYP1A2 genotype or caffeine-GS.
The association between habitual coffee intake and CVD risk was nonlinear, and, compared with participants drinking 1–2 cups/day, the risk of CVD was elevated for nondrinkers, drinkers of decaffeinated coffee, and those who reported drinking >6 cups/day (increase in odds by 11%, 7%, and 22%, respectively, P-curvature = 0.013). CYP1A2 genotype and caffeine-GS were not associated with CVD (P ≥ 0.22 for all comparisons). There was no evidence for an interaction between the CYP1A2 genotype or caffeine-GS and coffee intake with respect to risk of CVD (P ≥ 0.53).
Heavy coffee consumption was associated with a modest increase in CVD risk, but this association was unaffected by genetic variants influencing caffeine metabolism.
Increased awareness of the importance of vitamin D to health has led to concerns about the prevalence of hypovitaminosis D in many parts of the world.
We aimed to determine the prevalence of ...hypovitaminosis D in the white British population and to evaluate the influence of key dietary and lifestyle risk factors.
We measured 25-hydroxyvitamin D 25(OH)D in 7437 whites from the 1958 British birth cohort when they were 45 y old.
The prevalence of hypovitaminosis D was highest during the winter and spring, when 25(OH)D concentrations <25, <40, and <75 nmol/L were found in 15.5%, 46.6%, and 87.1% of participants, respectively; the proportions were 3.2%, 15.4%, and 60.9%, respectively, during the summer and fall. Men had higher 25(OH)D concentrations, on average, than did women during the summer and fall but not during the winter and spring (P = 0.006, likelihood ratio test for interaction). 25(OH)D concentrations were significantly higher in participants who used vitamin D supplements or oily fish than in those who did not (P < 0.0001 for both) but were not significantly higher in participants who consumed vitamin D-fortified margarine than in those who did not (P = 0.10). 25(OH)D concentrations <40 nmol/L were twice as likely in the obese as in the nonobese and in Scottish participants as in those from other parts of Great Britain (ie, England and Wales) (P < 0.0001 for both).
Prevalence of hypovitaminosis D in the general population was alarmingly high during the winter and spring, which warrants action at a population level rather than at a risk group level.
Depression affects all aspects of an individual's life but evidence relating to the causal effects on health is limited. We used information from 337,536 UK Biobank participants and performed ...hypothesis-free phenome-wide association analyses between major depressive disorder (MDD) genetic risk score (GRS) and 925 disease outcomes. GRS-disease outcome associations passing the multiple-testing corrected significance threshold (P < 1.9 × 10
) were followed by Mendelian randomisation (MR) analyses to test for causality. MDD GRS was associated with 22 distinct diseases in the phenome-wide discovery stage, with the strongest signal observed for MDD diagnosis and related co-morbidities including anxiety and sleep disorders. In inverse-variance weighted MR analyses, MDD was associated with several inflammatory and haemorrhagic gastrointestinal diseases, including oesophagitis (OR 1.32, 95% CI 1.18-1.48), non-infectious gastroenteritis (OR 1.25, 95% CI 1.06-1.48), gastrointestinal haemorrhage (OR 1.26, 95% CI 1.11-1.43) and intestinal E.coli infections (OR 3.24, 95% CI 1.74-6.02). Signals were also observed for symptoms/disorders of the urinary system (OR 1.36, 95% CI 1.19-1.56), asthma (OR 1.23, 95% CI 1.06-1.44), and painful respiration (OR 1.28, 95% CI 1.14-1.44). MDD was associated with disorders of lipid metabolism (OR 1.22, 95% CI 1.12-1.34) and ischaemic heart disease (OR 1.30, 95% CI 1.15-1.47). Sensitivity analyses excluding pleiotropic variants provided consistent associations. Our study indicates a causal link between MDD and a broad range of diseases, suggesting a notable burden of co-morbidity. Early detection and management of MDD is important, and treatment strategies should be selected to also minimise the risk of related co-morbidities.
Low vitamin D status is associated with a higher risk for cardiovascular diseases (CVDs). Although most existing linear Mendelian randomization (MR) studies reported a null effect of vitamin D on CVD ...risk, a non-linear effect cannot be excluded. Our aim was to apply the non-linear MR design to investigate the association of serum 25-hydroxyvitamin D 25(OH)D concentration with CVD risk.
The non-linear MR analysis was conducted in the UK Biobank with 44 519 CVD cases and 251 269 controls. Blood pressure (BP) and cardiac-imaging-derived phenotypes were included as secondary outcomes. Serum 25(OH)D concentration was instrumented using 35 confirmed genome-wide significant variants.We also estimated the potential reduction in CVD incidence attributable to correction of low vitamin D status. There was a L-shaped association between genetically predicted serum 25(OH)D and CVD risk (Pnon-linear = 0.007), where CVD risk initially decreased steeply with increasing concentrations and levelled off at around 50 nmol/L. A similar association was seen for systolic (Pnon-linear = 0.03) and diastolic (Pnon-linear = 0.07) BP. No evidence of association was seen for cardiac-imaging phenotypes (P = 0.05 for all). Correction of serum 25(OH)D level below 50 nmol/L was predicted to result in a 4.4% reduction in CVD incidence (95% confidence interval: 1.8- 7.3%).
Vitamin D deficiency can increase the risk of CVD. Burden of CVD could be reduced by population-wide correction of low vitamin D status.
Excessive coffee consumption can lead to unpleasant sensations such as tachycardia and heart palpitations.
Our aim was to investigate if cardiovascular symptoms can lead to alterations in habitual ...patterns of coffee consumption.
We used information from up to 390,435 European ancestry participants in the UK Biobank, aged 39–73 y. Habitual coffee consumption was self-reported, and systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were measured at baseline. Cardiovascular symptoms at baseline were based on hospital diagnoses, primary care records, and/or self-report. Mendelian randomization (MR) was used to examine genetic evidence for a causal association between SBP, DBP, and heart rate with habitual coffee consumption.
Participants with essential hypertension, angina, or heart arrhythmia were all more likely to drink less caffeinated coffee and to be non-habitual or decaffeinated coffee drinkers compared with those who did not report related symptoms (P ≤ 3.5 × 10−8 for all comparisons). Higher SBP and DBP were associated with lower caffeinated coffee consumption at baseline, with consistent genetic evidence to support a causal explanation across all methods MR-Egger regression (MREggr) β: −0.21 cups/d (95% CI: −0.34, −0.07) per 10 mm Hg higher SBP and −0.33 (−0.61, −0.07) per 10 mm Hg higher DBP). In genetic analyses, higher resting heart rate was associated with a greater odds of being a decaffeinated coffee drinker (MREggr OR: 1.71; 95% CI: 1.31, 2.21) per 10 beats/min).
We provide causal genetic evidence for cardiovascular system–driven influences on habitual coffee intakes, suggesting that people tend to naturally regulate their coffee consumption based on blood pressure levels and heart rate. These findings suggest that observational studies of habitual coffee intakes are prone to influences by reverse causation, and caution is required when inferred health benefits result from comparisons with coffee abstainers or decaffeinated coffee drinkers.
Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking.
To assess genetic evidence for the causal role of low vitamin D ...status in mortality.
Nonlinear Mendelian randomization analyses.
UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010.
307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data.
Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease CVD, cancer, and respiratory) were recorded up to June 2020.
There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (
for nonlinearity < 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (
≤ 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 95% CI, 1.16 to 1.35) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L.
Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate.
Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated with low vitamin D levels.
National Health and Medical Research Council.
There is evidence that long-term heavy coffee consumption may adversely affect individuals’ cardiovascular disease (CVD) risk. As hyperlipidemia is a well-established contributor to CVD risk, we ...investigated the association between habitual coffee intake and plasma lipid profile.
We used data from up to 362,571 UK Biobank participants to examine phenotypic associations between self-reported coffee intake and plasma lipid profiles, including low-density-lipoproteins cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (total-C), triglycerides, and apolipoproteins A1 and B (ApoA1 and ApoB). Mendelian randomization (MR) analysis using genetically instrumented coffee intake was used to interrogate the causal nature of coffee–lipid associations.
We observed a positive dose-dependent association between self-reported coffee intake and plasma concentration of LDL-C, ApoB and total-C, with the highest lipid levels seen among participants reported drinking >6 cups/day (Plinear trend≤ 3.24E-55 for all). Consistently, in MR analyses using genetically instrumented coffee intake one cup higher coffee intake was associated with a 0.07 mmol/L (95% CI 0.03 to 0.12), 0.02 g/L (95% CI 0.01 to 0.03), and 0.09 mmol/L (95% CI 0.04 to 0.14) increase in plasma concentration of LDL-C, ApoB, and total-C, respectively.
Our phenotypic and genetic analyses suggest that long-term heavy coffee consumption may lead to unfavourable lipid profile, which could potentially increase individuals’ risk for CVD. These findings may have clinical relevance for people with elevated LDL cholesterol.
This review was conducted to clarify both the complex interrelationship between adiposity and vitamin D and the clinical implications of vitamin D status on metabolic abnormalities associated with ...obesity. Obesity increases the risk of vitamin D deficiency, a finding consistently reported across all ages and in different population groups. According to genetic studies, this is driven by the effect of higher adiposity, which causes a reduction in circulating concentrations of 25-hydroxyvitamin D 25(OH)D, used as an indicator of vitamin D status. Conversely, higher concentrations of 25(OH)D do not appear to affect the risk of obesity. Evidence from clinical trials using vitamin D supplementation to achieve weight reduction is limited. Some trials, however, have suggested that concomitant supplementation with vitamin D and calcium potentially reduces central fat deposits, especially in individuals with low dietary calcium intakes. Adiposity has important implications for the efficacy of vitamin D supplementation, and increases in 25(OH)D concentrations are generally lower in obese than in normal-weight individuals. Active hormonal vitamin D has many mechanistic effects, both physiologically and biochemically, that could counteract the harmful effects of obesity on metabolism and reduce the risks of metabolic abnormalities and tissue damage consequent to adiposity. Whether improvements in the overall obesogenic metabolic profile can be achieved by vitamin D supplementation, however, is still unknown.
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