Functional MRI (fMRI) and MRS (fMRS) can be used to noninvasively map cerebral activation and metabolism. Recently, hyperpolarized
C spectroscopy and metabolic imaging have provided an alternative ...approach to assess metabolism. In this study, we combined
H fMRI and hyperpolarized 1-
Cpyruvate MRS to compare cerebral blood oxygenation level-dependent (BOLD) response and real-time cerebral metabolism, as assessed with lactate and bicarbonate labelling, during nicotine stimulation. Simultaneous
H fMRI (multislice gradient echo echo-planar imaging) and
C spectroscopic (single slice pulse-acquire) data were collected in urethane-anaesthetized female Sprague-Dawley rats (n = 12) at 9.4 T. Animals received an intravenous (i.v.) injection of either nicotine (stimulus; 88 μg/kg, n = 7, or 300 μg/kg, n = 5) or 0.9% saline (matching volume), followed by hyperpolarized 1-
Cpyruvate injection 60 s later. Three hours later, a second injection was administered: the animals that had previously received saline were injected with nicotine and vice versa, both followed by another hyperpolarized 1-
Cpyruvate i.v. injection 60 s later. The low-dose (88 μg/kg) nicotine injection led to a 12% ± 4% (n = 7, t-test, p ~ 0.0006 (t-value -5.8, degrees of freedom 6), Wilcoxon p ~ 0.0078 (test statistic 0)) increase in BOLD signal. At the same time, an increase in
C-bicarbonate signal was seen in four out of six animals. Bicarbonate-to-total carbon ratios were 0.010 ± 0.004 and 0.018 ± 0.010 (n = 6, t-test, p ~ 0.03 (t-value -2.3, degrees of freedom 5), Wilcoxon p ~ 0.08 (test statistic 3)) for saline and nicotine experiments, respectively. No increase in the lactate signal was seen; lactate-to-total carbon was 0.16 ± 0.02 after both injections. The high (300 μg/kg) nicotine dose (n = 5) caused highly variable BOLD and metabolic responses, possibly due to the apparent respiratory distress. Simultaneous detection of
H fMRI and hyperpolarized
C-MRS is feasible. A comparison of metabolic response between control and stimulated states showed differences in bicarbonate signal, implying that the hyperpolarization technique could offer complimentary information on brain activation.
The genomics era has brought useful tools to dissect the genetic architecture of complex traits. Here we propose a multivariate reaction norm model (MRNM) to tackle genotype-covariate (G-C) ...correlation and interaction problems. We apply MRNM to the UK Biobank data in analysis of body mass index using smoking quantity as a covariate, finding a highly significant G-C correlation, but only weak evidence for G-C interaction. In contrast, G-C interaction estimates are inflated in existing methods. It is also notable that there is significant heterogeneity in the estimated residual variances (i.e., variances not attributable to factors in the model) across different covariate levels, i.e., residual-covariate (R-C) interaction. We also show that the residual variances estimated by standard additive models can be inflated in the presence of G-C and/or R-C interactions. We conclude that it is essential to correctly account for both interaction and correlation in complex trait analyses.
Observational and Mendelian randomization (MR) studies link obesity and cancer, but it remains unclear whether these depend upon related metabolic abnormalities.
We used information from 321,472 ...participants in the UK biobank, including 30,561 cases of obesity-related cancer. We constructed three genetic instruments reflecting higher adiposity together with either "unfavourable" (82 SNPs), "favourable" (24 SNPs) or "neutral" metabolic profile (25 SNPs). We looked at associations with 14 types of cancer, previously suggested to be associated with obesity.
All genetic instruments had a strong association with BMI (p < 1 × 10
for all). The instrument reflecting unfavourable adiposity was also associated with higher CRP, HbA1c and adverse lipid profile, while instrument reflecting metabolically favourable adiposity was associated with lower HbA1c and a favourable lipid profile. In MR-inverse-variance weighted analysis unfavourable adiposity was associated with an increased risk of non-hormonal cancers (OR = 1.22, 95% confidence interval CI:1.08, 1.38), but a lower risk of hormonal cancers (OR = 0.80, 95%CI: 0.72, 0.89). From individual cancers, MR analyses suggested causal increases in the risk of multiple myeloma (OR = 1.36, 95%CI: 1.09, 1.70) and endometrial cancer (OR = 1.77, 95%CI: 1.16, 2.68) by greater genetically instrumented unfavourable adiposity but lower risks of breast and prostate cancer (OR = 0.72, 95%CI: 0.61, 0.83 and OR = 0.81, 95%CI: 0.68, 0.97, respectively). Favourable or neutral adiposity were not associated with the odds of any individual cancer.
Higher adiposity associated with a higher risk of non-hormonal cancer but a lower risk of some hormone related cancers. Presence of metabolic abnormalities might aggravate the adverse effects of higher adiposity on cancer. Further studies are warranted to investigate whether interventions on adverse metabolic health may help to alleviate obesity-related cancer risk.
Currently, there is a lack of clarity in the literature as to whether there is a definitive difference between the effects of vitamins D2 and D3 in the raising of serum 25-hydroxyvitamin D 25(OH)D.
...The objective of this article was to report a systematic review and meta-analysis of randomized controlled trials (RCTs) that have directly compared the effects of vitamin D2 and vitamin D3 on serum 25(OH)D concentrations in humans.
The ISI Web of Knowledge (January 1966 to July 2011) database was searched electronically for all relevant studies in adults that directly compared vitamin D3 with vitamin D2. The Cochrane Clinical Trials Registry, International Standard Randomized Controlled Trials Number register, and clinicaltrials.gov were also searched for any unpublished trials.
A meta-analysis of RCTs indicated that supplementation with vitamin D3 had a significant and positive effect in the raising of serum 25(OH)D concentrations compared with the effect of vitamin D2 (P = 0.001). When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation.
This meta-analysis indicates that vitamin D3 is more efficacious at raising serum 25(OH)D concentrations than is vitamin D2, and thus vitamin D3) could potentially become the preferred choice for supplementation. However, additional research is required to examine the metabolic pathways involved in oral and intramuscular administration of vitamin D and the effects across age, sex, and ethnicity, which this review was unable to verify.
We assigned 329,908 UK Biobank participants into six subgroups based on a self-organizing map of 51 biochemical measures (blinded for clinical outcomes). The subgroup with the most favorable ...metabolic traits was chosen as the reference. Hazard ratios (HR) for incident disease were modeled by Cox regression. Enrichment ratios (ER) of incident multi-morbidity versus randomly expected co-occurrence were evaluated by permutation tests; ER is like HR but captures co-occurrence rather than event frequency. The subgroup with high urinary excretion without kidney stress (HR = 1.24) and the subgroup with the highest apolipoprotein B and blood pressure (HR = 1.52) were associated with ischemic heart disease (IHD). The subgroup with kidney stress, high adiposity and inflammation was associated with IHD (HR = 2.11), cancer (HR = 1.29), dementia (HR = 1.70) and mortality (HR = 2.12). The subgroup with high liver enzymes and triglycerides was at risk of diabetes (HR = 15.6). Multimorbidity was enriched in metabolically favorable subgroups (3.4 ≤ ER ≤ 4.0) despite lower disease burden overall; the relative risk of co-occurring disease was higher in the absence of obvious metabolic dysfunction. These results provide synergistic insight into metabolic health and its associations with cardiovascular disease in a large population sample.
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.
The role of vitamin D beyond its importance for bone health is under much debate. In this article, we review recent evidence for genetic influences on 25-hydroxyvitamin D 25(OH)D and discuss the uses ...of this information and its importance for public health.
Findings from large-scale genome-wide association meta-analyses on 25(OH)D confirmed the associations for loci nearby genes encoding vitamin D binding protein (GC, group component), 7-dehydrochlesterol reductase (DHCR7), 25-hydroxylase (CYP2R1) and 24-hydroxylase (CYP24A1), all influencing key sites for vitamin D metabolism. Findings from candidate gene studies have been inconsistent, with some implicating an association with 25(OH)D for loci near the gene encoding the hormonal vitamin D activation enzyme (CYP27B1).
The amount of variation in 25(OH)D explained by genetic determinants is small compared with environmental exposures. Information on genetic variants affecting 25(OH)D can be used as tools for Mendelian randomization analyses on vitamin D, and they provide some potential for the use as drug targets.
Mendelian randomisation allows for the testing of causal effects in situations where clinical trials are challenging to do. In this hypothesis-free, data-driven phenome-wide association study ...(PheWAS), we sought to assess possible associations of high body-mass index (BMI) with multiple disease outcomes.
For this registry-based case-control PheWAS, we used genome-wide data available from the UK Biobank to construct a genetic risk score of 76 variants related to BMI. Eligible UK Biobank participants were aged 37-73 years during recruitment, were white British, were unrelated to each other, and had available genetic information. Disease outcomes from these participants were mapped to a phenotype code (phecode). Participants with a phecode of interest were recoded as cases, whereas participants without a phecode of interest or any codes under a parent phecode were classified as controls. We did a PheWAS to analyse possible associations between the BMI genetic risk score and a range of disease outcomes. Disease associations passing stringent correction for multiple testing (Bonferroni corrected threshold p<5·4 × 10
, false discovery rate corrected p<0·0074) were assessed for causal association with use of inverse-variance weighted mendelian randomisation. We did sensitivity analyses to assess pleiotropy and stability of estimation with use of weighted median, weighted mode, Egger regression, and mendelian randomisation pleiotropy residual sum and outlier methods.
Our study population comprised 337 536 UK Biobank participants, and analyses were done for 925 unique phecodes from 17 different disease categories. After Bonferroni correction, PheWAS identified that BMI genetic risk score was associated with hospital-diagnosed obesity and 58 other outcomes; 30 distinct disease associations were supported by the mendelian randomisation analyses. 30 distinct disease associations were supported by the mendelian randomisation analyses. In inverse-variance weighted mendelian randomisation, genetically determined BMI was associated with endocrine disorders (odds ratio per one SD or 4·1 kg/m
higher BMI 2·72, 95% CI 2·33-3·29 for type 2 diabetes; 2·11, 1·62-2·76 for type 1 diabetes; and 1·46, 1·25-1·70 for hypothyroidism), circulatory diseases (1·96, 1·53-2·51 for phlebitis and thrombophlebitis; 1·89, 1·39-2·57 for cardiomegaly; 1·68, 1·35-2·09 for congestive heart failure; 1·55, 1·37-1·76 for hypertension; 1·31, 1·13-1·52 for ischaemic heart disease; and 1·25, 1·14-1·37 for cardiac dysrhythmias), and inflammatory or dermatological conditions (2·00, 1·72-2·23 for superficial cellulitis and abscess; 3·37, 2·17-5·25 for chronic ulcers of leg and foot; 4·99, 2·54-9·82 for gangrene; and 2·24, 1·53-3·28 for atopy). Mendelian randomisation analyses provided further support for a causal effect of BMI on renal failure, osteoarthrosis, neurological (insomnia and peripheral nerve disorders) and respiratory diseases (asthma and chronic bronchitis), structural problems (hernias and knee derangement), and chemotherapy treatment. Mendelian randomisation with Egger regression produced consistently wider CIs compared with those of other methods. 26 of 72 distinct diseases detected under false discovery rate correction produced consistent estimates across at least four mendelian randomisation methods, and consistent evidence across all five approaches was obtained for 14 diseases.
Our data-driven approach identified a range of diseases as possibly affected by high BMI. This population-level screening approximated the accumulated consequences of high BMI, whereas the true effects might be more complex and vary by life stage. Our results highlight the importance of obesity prevention and effective management of obesity-related comorbidities.
National Health and Medical Research Council of Australia.
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