Associations between FTO genotype and total energy and macronutrients intake: a systematic review and meta-analysis

Risk variants of the fat-mass and obesity-associated (FTO) gene have been associated with increased obesity. However, the evidence for associations between FTO genotype and macronutrients intake has not been reviewed systematically. Our aim was to evaluate potential associations between FTO genotype and intakes of total energy, fat, carbohydrate and protein. We undertook a systematic literature search in Medline, Scopus, EMBASE and Cochrane of associations between macronutrients intake and FTO genotype in adults. Beta coefficients and confidence intervals were used for per-allele comparisons. Random-effects models assessed the pooled effect sizes. We identified 56 eligible studies reporting on 213 173 adults. For each copy of the FTO risk allele, individuals reported 6.46 kcal/day (95% CI: 10.76, 2.16) lower total energy intake (P=0.003). Total fat (P=0.028) and protein (P=0.006), but not carbohydrate intakes, were higher in those carrying the FTO risk allele. After adjustment for body weight, total energy intakes remained significantly lower in individuals with the FTO risk genotype (P=0.028). The FTO risk allele is associated with a lower reported total energy intake and with altered patterns of macronutrients intake. Although significant, these differences are small and further research is needed to determine whether the associations are independent of dietary misreporting.

Neonatal environment exerts a sustained influence on the development of the intestinal microbiota and metabolic phenotype

The postnatal environment, including factors such as weaning and acquisition of the gut microbiota, has been causally linked to the development of later immunological diseases such as allergy and autoimmunity, and has also been associated with a predisposition to metabolic disorders. We show that the very early-life environment influences the development of both the gut microbiota and host metabolic phenotype in a porcine model of human infants. Farmpiglets were nursed by their mothers for 1 day, before removal to highly controlled, individual isolators where they received formula milk until weaning at 21 days. The experiment was repeated, to create two batches, which differed only in minor environmental fluctuations during the first day. At day 1 after birth, metabolic profiling of serum by 1H nuclear magnetic resonance spectroscopy demonstrated significant, systemic, inter-batch variation which persisted until weaning. However, the urinary metabolic profiles demonstrated that significant inter-batch effects on 3-hydroxyisovalerate, trimethylamine-N-oxide and mannitol persisted beyond weaning to at least 35 days. Batch effects were linked to significant differences in the composition of colonic microbiota at 35 days, determined by 16 S pyrosequencing. Different weaning diets modulated both the microbiota and metabolic phenotype independently of the persistent batch effects. We demonstrate that the environment during the first day of life influences development of the microbiota and metabolic phenotype and thus should be taken into account when interrogating experimental outcomes. In addition, we suggest that intervention at this early time could provide ‘metabolic rescue’ for at-risk infants who have undergone aberrant patterns of initial intestinal colonisation.

Ibuprofen inhibits migration and proliferation of human coronary artery smooth muscle cells by inducing a differentiated phenotype: role of peroxisome proliferator-activated receptor y

Objectives: The search for agents that are capable of preventing restenosis and reduce the risk of late thrombosis is of utmost importance. In this study we aim to evaluate the in vitro effects of ibuprofen on proliferation and migration of human coronary artery smooth muscle cells (HCASMCs) and on human coronary artery endothelial cells (HCAECs) migration. Methods: Cell proliferation was evaluated by direct cell counting using trypan blue exclusion. Cell migration was assessed by wound healing “scratch” assay and by time lapse video-microscopy. Protein expression was assessed by immunoblotting, and morphological changes were studied by immunocytochemistry. The involvement of the PPARγ pathway was studied with the selective agonist troglitazone, and the use of highly selective antagonists of PPARγ such as PGF2α and GW9662. Results: We demonstrate that ibuprofen inhibits proliferation and migration of HCASMCs and induces a switch in HCASMCs towards a differentiated and contractile phenotype, and that these effects are mediated through the PPARγ pathway. Importantly we also show that the effects of ibuprofen are cell type specific as it does not affect migration and proliferation of endothelial cells. Conclusions: Taken together, our results suggest that ibuprofen could be an effective drug for the development of novel drug eluting stents, which could lead reduced rates of restenosis and potentially other complications of DES stent implantation.

Field phenotyping of potato to assess root and shoot characteristics associated with drought tolerance

Aims Potatoes are a globally important source of food whose production requires large inputs of fertiliser and water. Recent research has highlighted the importance of the root system in acquiring resources. Here measurements, previously generated by field phenotyping, tested the effect of root size on maintenance of yield under drought (drought tolerance). Methods Twelve potato genotypes, including genotypes with extremes of root size, were grown to maturity in the field under a rain shelter and either irrigated or subjected to drought. Soil moisture, canopy growth, carbon isotope discrimination and final yields were measured. Destructively harvested field phenotype data were used as explanatory variables in a general linear model (GLM) to investigate yield under conditions of drought or irrigation. Results Drought severely affected the small rooted genotype Pentland Dell but not the large rooted genotype Cara. More plantlets, longer and more numerous stolons and stolon roots were associated with drought tolerance. Previously measured carbon isotope discrimination did not correlate with the effect of drought. Conclusions These data suggest that in-field phenotyping can be used to identify useful characteristics when known genotypes are subjected to an environmental stress. Stolon root traits were associated with drought tolerance in potato and could be used to select genotypes with resilience to drought.

Theoretical insight into diagnosing observation error correlations using observation-minus-background and observation-minus-analysis statistics

To improve the quantity and impact of observations used in data assimilation it is necessary to take into account the full, potentially correlated, observation error statistics. A number of methods for estimating correlated observation errors exist, but a popular method is a diagnostic that makes use of statistical averages of observation-minus-background and observation-minus-analysis residuals. The accuracy of the results it yields is unknown as the diagnostic is sensitive to the difference between the exact background and exact observation error covariances and those that are chosen for use within the assimilation. It has often been stated in the literature that the results using this diagnostic are only valid when the background and observation error correlation length scales are well separated. Here we develop new theory relating to the diagnostic. For observations on a 1D periodic domain we are able to the show the effect of changes in the assumed error statistics used in the assimilation on the estimated observation error covariance matrix. We also provide bounds for the estimated observation error variance and eigenvalues of the estimated observation error correlation matrix. We demonstrate that it is still possible to obtain useful results from the diagnostic when the background and observation error length scales are similar. In general, our results suggest that when correlated observation errors are treated as uncorrelated in the assimilation, the diagnostic will underestimate the correlation length scale. We support our theoretical results with simple illustrative examples. These results have potential use for interpreting the derived covariances estimated using an operational system.

Effects of a web-based personalized intervention on physical activity in European adults: a randomized controlled trial

Background: The high prevalence of physical inactivity worldwide calls for innovative and more effective ways to promote physical activity (PA). There are limited objective data on the effectiveness of Web-based personalized feedback on increasing PA in adults. Objective: It is hypothesized that providing personalized advice based on PA measured objectively alongside diet, phenotype, or genotype information would lead to larger and more sustained changes in PA, compared with nonpersonalized advice. Methods: A total of 1607 adults in seven European countries were randomized to either a control group (nonpersonalized advice, Level 0, L0) or to one of three personalized groups receiving personalized advice via the Internet based on current PA plus diet (Level 1, L1), PA plus diet and phenotype (Level 2, L2), or PA plus diet, phenotype, and genotype (Level 3, L3). PA was measured for 6 months using triaxial accelerometers, and self-reported using the Baecke questionnaire. Outcomes were objective and self-reported PA after 3 and 6 months. Results: While 1270 participants (85.81% of 1480 actual starters) completed the 6-month trial, 1233 (83.31%) self-reported PA at both baseline and month 6, but only 730 (49.32%) had sufficient objective PA data at both time points. For the total cohort after 6 months, a greater improvement in self-reported total PA (P=.02) and PA during leisure (nonsport) (P=.03) was observed in personalized groups compared with the control group. For individuals advised to increase PA, we also observed greater improvements in those two self-reported indices (P=.006 and P=.008, respectively) with increased personalization of the advice (L2 and L3 vs L1). However, there were no significant differences in accelerometer results between personalized and control groups, and no significant effect of adding phenotypic or genotypic information to the tailored feedback at month 3 or 6. After 6 months, there were small but significant improvements in the objectively measured physical activity level (P<.05), moderate PA (P<.01), and sedentary time (P<.001) for individuals advised to increase PA, but these changes were similar across all groups. Conclusions: Different levels of personalization produced similar small changes in objective PA. We found no evidence that personalized advice is more effective than conventional “one size fits all” guidelines to promote changes in PA in our Web-based intervention when PA was measured objectively. Based on self-reports, PA increased to a greater extent with more personalized advice. Thus, it is crucial to measure PA objectively in any PA intervention study.

Loss of Dictyostelium HSPC300 causes a scar-like phenotype and loss of SCAR protein.

HSPC300 is essential for most SCAR complex functions. The phenotype of HSPC300 knockouts is most similar to mutants in scar, not the other members of the SCAR complex, suggesting that HSPC300 acts most directly on SCAR itself.

Designing a sampling scheme to reveal correlations between weeds and soil properties at multiple spatial scales

Weeds tend to aggregate in patches within fields and there is evidence that this is partly owing to variation in soil properties. Because the processes driving soil heterogeneity operate at different scales, the strength of the relationships between soil properties and weed density would also be expected to be scale-dependent. Quantifying these effects of scale on weed patch dynamics is essential to guide the design of discrete sampling protocols for mapping weed distribution. We have developed a general method that uses novel within-field nested sampling and residual maximum likelihood (REML) estimation to explore scale-dependent relationships between weeds and soil properties. We have validated the method using a case study of Alopecurus myosuroides in winter wheat. Using REML, we partitioned the variance and covariance into scale-specific components and estimated the correlations between the weed counts and soil properties at each scale. We used variograms to quantify the spatial structure in the data and to map variables by kriging. Our methodology successfully captured the effect of scale on a number of edaphic drivers of weed patchiness. The overall Pearson correlations between A. myosuroides and soil organic matter and clay content were weak and masked the stronger correlations at >50 m. Knowing how the variance was partitioned across the spatial scales we optimized the sampling design to focus sampling effort at those scales that contributed most to the total variance. The methods have the potential to guide patch spraying of weeds by identifying areas of the field that are vulnerable to weed establishment.

Interaction between BMI and APOE genotype is associated with changes in the plasma long-chain-PUFA response to a fish-oil supplement in healthy participants

BACKGROUND: Carriers of the apolipoprotein E ɛ4 (APOE4) allele are lower responders to a docosahexaenoic acid (DHA) supplement than are noncarriers. This effect could be exacerbated in overweight individuals because DHA metabolism changes according to body mass index (BMI; in kg/m²). OBJECTIVES: We evaluated the plasma fatty acid (FA) response to a DHA-rich supplement in APOE4 carriers and noncarriers consuming a high-saturated fat diet (HSF diet) and, in addition, evaluated whether being overweight changed this response. DESIGN: This study was part of the SATgenɛ trial. Forty-one APOE4 carriers and 41 noncarriers were prospectively recruited and consumed an HSF diet for 8-wk followed by 8 wk of consumption of an HSF diet with the addition of DHA and eicosapentaenoic acid (EPA) (HSF + DHA diet; 3.45 g DHA/d and 0.5 g EPA/d). Fasting plasma samples were collected at the end of each intervention diet. Plasma total lipids (TLs) were separated into free FAs, neutral lipids (NLs), and phospholipids by using solid-phase extraction, and FA profiles in each lipid class were quantified by using gas chromatography. RESULTS: Because the plasma FA response to the HSF + DHA diet was correlated with BMI in APOE4 carriers but not in noncarriers, the following 2 groups were formed according to the BMI median: low BMI (<25.5) and high BMI (≥25.5). In response to the HSF + DHA diet, there were significant BMI × genotype interactions for changes in plasma concentrations of arachidonic acid and DHA in phospholipids and TLs and of EPA in NLs and TLs (P ≤ 0.05). APOE4 carriers were lower plasma responders to the DHA supplement than were noncarriers but only in the high-BMI group. CONCLUSIONS: Our findings indicate that apolipoprotein E genotype and BMI may be important variables that determine the plasma long-chain PUFA response to dietary fat manipulation. APOE4 carriers with BMI ≥25.5 may need higher intakes of DHA for cardiovascular or other health benefits than do noncarriers

Diagnosing observation error correlations for Doppler radar radial winds in the Met Office UKV model using observation-minus-background and observation-minus-analysis statistics

With the development of convection-permitting numerical weather prediction the efficient use of high resolution observations in data assimilation is becoming increasingly important. The operational assimilation of these observations, such as Dopplerradar radial winds, is now common, though to avoid violating the assumption of un- correlated observation errors the observation density is severely reduced. To improve the quantity of observations used and the impact that they have on the forecast will require the introduction of the full, potentially correlated, error statistics. In this work, observation error statistics are calculated for the Doppler radar radial winds that are assimilated into the Met Office high resolution UK model using a diagnostic that makes use of statistical averages of observation-minus-background and observation-minus-analysis residuals. This is the first in-depth study using the diagnostic to estimate both horizontal and along-beam correlated observation errors. By considering the new results obtained it is found that the Doppler radar radial wind error standard deviations are similar to those used operationally and increase as the observation height increases. Surprisingly the estimated observation error correlation length scales are longer than the operational thinning distance. They are dependent on both the height of the observation and on the distance of the observation away from the radar. Further tests show that the long correlations cannot be attributed to the use of superobservations or the background error covariance matrix used in the assimilation. The large horizontal correlation length scales are, however, in part, a result of using a simplified observation operator.

Fat mass-and obesity-associated genotype, dietary intakes and anthropometric measures in European adults: the Food4Me study

The interplay between the fat mass- and obesity-associated (FTO) gene variants and diet has been implicated in the development of obesity. The aim of the present analysis was to investigate associations between FTO genotype, dietary intakes and anthropometrics among European adults. Participants in the Food4Me randomised controlled trial were genotyped for FTO genotype (rs9939609) and their dietary intakes, and diet quality scores (Healthy Eating Index and PREDIMED-based Mediterranean diet score) were estimated from FFQ. Relationships between FTO genotype, diet and anthropometrics (weight, waist circumference (WC) and BMI) were evaluated at baseline. European adults with the FTO risk genotype had greater WC (AAv. TT: +1·4 cm; P=0·003) and BMI (+0·9 kg/m2; P=0·001) than individuals with no risk alleles. Subjects with the lowest fried food consumption and two copies of the FTO risk variant had on average 1·4 kg/m2 greater BMI (Ptrend=0·028) and 3·1 cm greater WC (Ptrend=0·045) compared with individuals with no copies of the risk allele and with the lowest fried food consumption. However, there was no evidence of interactions between FTO genotype and dietary intakes on BMI and WC, and thus further research is required to confirm or refute these findings.

Exploring the effects of genotypical and phenotypical variations in bitter taste sensitivity on perception, liking and intake of brassica vegetables in the UK

Brassicaceous vegetables (BV) have chemoprotective effects and yet consumption of BV in the UK is low. Previous studies suggest perception, liking and intake of BV are influenced by bitter taste sensitivity which this study further explores. Phenotypical taste sensitivity of 136 subjects was classified using propythiouracil (PROP) and sodium chloride and fungiform papillae density (FPD) was measured from tongue images. Polymorphisms of TAS2R38 and gustin (CA6) genes were analysed. Liking and bitterness of four raw vegetables (two BV (broccoli and white cabbage) and two non-BV (spinach and courgette)), as well as habitual consumption, were evaluated. There was a significant association between TAS2R38 genotype and PROP taster status (p<0.0001) and between FPD and PROP taster status (p=0.029). Individuals with greater sensitivity for PROP predominantly had TAS2R38 PAV/PAV genotype and greater FPD. BV were perceived as more bitter than non-BV (p<0.0001) with PAV/PAV subjects perceiving significantly stronger bitter intensity. There was a significant difference in liking for the four vegetables (p=0.002), and between consumers of different TAS2R38 genotype (p=0.0024). Individuals with TAS2R38 AVI/AVI genotype liked BV more. Regarding intake, both PAV/PAV and AVI/AVI individuals consumed more total vegetables and BV than PAV/AVI. Although PROP nontasters tended to consume more vegetables and BV than the other two phenotype groups, liking and vegetable intake were not significantly affected by taste phenotype. Although there was not a significant effect of CA6 genotype on bitterness ratings, there was a significant interaction between CA6 and TAS2R38, and in addition CA6 genotype was significantly associated with BV intake. However, these effects require validation as the proportions of the population with the CA6 G/G genotype was extremely small (7%). Our results confirmed that bitter taste perception in vegetables was influenced by both genotype and phenotype of bitter taste sensitivity. Moreover, our findings demonstrated that neither genotype nor phenotype of taste sensitivity alone accurately predict vegetable liking and intake as demographic factors were found to have a substantial influence.

Acute benefits of the microbial-derived isoflavone metabolite equol on arterial stiffness in men prospectively recruited according to equol producer phenotype: a double-blind randomized controlled trial

There is much speculation with regard to the potential cardioprotective benefits of equol, a microbial-derived metabolite of the isoflavone daidzein, which is produced in the large intestine after soy intake in 30% of Western populations. Although cross-sectional and retrospective data support favorable associations between the equol producer (EP) phenotype and cardiometabolic health, few studies have prospectively recruited EPs to confirm this association. The aim was to determine whether the acute vascular benefits of isoflavones differ according to EP phenotype and subsequently investigate the effect of providing commercially produced S-(–)equol to non-EPs. We prospectively recruited male EPs and non-EPs (n = 14/ group) at moderate cardiovascular risk into a double-blind, placebocontrolled crossover study to examine the acute effects of soy isoflavones (80-mg aglycone equivalents) on arterial stiffness [carotid-femoral pulse-wave velocity (cfPWV)], blood pressure, endothelial function (measured by using the EndoPAT 2000; Itamar Medical), and nitric oxide at baseline (0 h) and 6 and 24 h after intake. In a separate assessment, non-EPs consumed 40 mg S-(–)equol with identical vascular measurements performed 2 h after intake. After soy intake, cfPWV significantly improved in EPs at 24 h (cfPWV change from 0 h: isoflavone, 20.2 6 0.2 m/s; placebo, 0.6 6 0.2 m/s; P , 0.01), which was significantly associated with plasma equol concentrations (R = 20.36, P = 0.01). No vascular effects were observed in EPs at 6 h or in non-EPs at any time point. Similarly, no benefit of commercially produced S-(–)equol was observed in non-EPs despite mean plasma equol concentrations reaching 3.2 mmol/L. Acute soy intake improved cfPWV in EPs, equating to an 11–12% reduced risk of cardiovascular disease if sustained. However, a single dose of commercially produced equol had no cardiovascular benefits in non-EPs. These data suggest that the EP phenotype is critical in unlocking the vascular benefits of equol in men, and long-term trials should focus on confirming the implications of EP phenotype on cardiovascular health. This trial was registered at clinicaltrials.gov as NCT01530893. Am J Clin Nutr doi: 10.3945/ajcn.115.125690.

Positive phenotypic selection inferred from phylogenies

Rates of phenotypic evolution vary widely in nature and these rates may often reflect the intensity of natural selection. Here we outline an approach for detecting exceptional shifts in the rate of phenotypic evolution across phylogenies. We introduce a simple new branch-specific metric ∆V/∆B that divides observed phenotypic change along a branch into two components: (1) that attributable to the background rate (∆B), and (2) that attributable to departures from the background rate (∆V). Where the amount of expected change derived from variation in the rate of morphological evolution doubles that explained by to the background rate (∆V/∆B > 2), we identify this as positive phenotypic selection. We apply our approach to six datasets, finding multiple instances of positive selection in each. Our results support the growing appreciation that the traditional gradual view of phenotypic evolution is rarely upheld, with a more episodic view taking its place. This moves focus away from viewing phenotypic evolution as a simple homogeneous process and facilitates reconciliation with macroevolutionary interpretations from a genetic perspective, paving the way to novel insights into the link between genotype and phenotype. The ability to detect positive selection when genetic data are unavailable or unobtainable represents an attractive prospect for extant species, but when applied to fossil data it can reveal patterns of natural selection in deep time that would otherwise be impossible.

MEF2C-MYOCD and leiomodin1 suppression by miRNA-214 promotes smooth muscle cell phenotype switching in pulmonary arterial hypertension

Background Vascular hyperproliferative disorders are characterized by excessive smooth muscle cell (SMC) proliferation leading to vessel remodeling and occlusion. In pulmonary arterial hypertension (PAH), SMC phenotype switching from a terminally differentiated contractile to synthetic state is gaining traction as our understanding of the disease progression improves. While maintenance of SMC contractile phenotype is reportedly orchestrated by a MEF2C-myocardin (MYOCD) interplay, little is known regarding molecular control at this nexus. Moreover, the burgeoning interest in microRNAs (miRs) provides the basis for exploring their modulation of MEF2C-MYOCD signaling, and in turn, a pro-proliferative, synthetic SMC phenotype. We hypothesized that suppression of SMC contractile phenotype in pulmonary hypertension is mediated by miR-214 via repression of the MEF2C-MYOCD-leiomodin1 (LMOD1) signaling axis. Methods and Results In SMCs isolated from a PAH patient cohort and commercially obtained hPASMCs exposed to hypoxia, miR-214 expression was monitored by qRT-PCR. miR-214 was upregulated in PAH- vs. control subject hPASMCs as well as in commercially obtained hPASMCs exposed to hypoxia. These increases in miR-214 were paralleled by MEF2C, MYOCD and SMC contractile protein downregulation. Of these, LMOD1 and MEF2C were directly targeted by the miR. Mir-214 overexpression mimicked the PAH profile, downregulating MEF2C and LMOD1. AntagomiR-214 abrogated hypoxia-induced suppression of the contractile phenotype and its attendant proliferation. Anti-miR-214 also restored PAH-PASMCs to a contractile phenotype seen during vascular homeostasis. Conclusions Our findings illustrate a key role for miR-214 in modulation of MEF2C-MYOCD-LMOD1 signaling and suggest that an antagonist of miR-214 could mitigate SMC phenotype changes and proliferation in vascular hyperproliferative disorders including PAH.