Relationship between genome and epigenome - challenges and requirements for future research

Understanding the links between genetic, epigenetic and non-genetic factors throughout the lifespan and across generations and their role in disease susceptibility and disease progression offer entirely new avenues and solutions to major problems in our society. To overcome the numerous challenges, we have come up with nine major conclusions to set the vision for future policies and research agendas at the European level.

ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer

There are currently no approved targeted therapies for advanced KRAS mutant (KRASMT) colorectal cancer (CRC). Using a unique systems biology approach, we identified JAK1/2-dependent activation of STAT3 as the key mediator of resistance to MEK inhibitors in KRASMT CRC in vitro and in vivo. Further analyses identified acute increases in c-MET activity following treatment with MEK inhibitors in KRASMT CRC models, which was demonstrated to promote JAK1/2-STAT3-mediated resistance. Furthermore, activation of c-MET following MEK inhibition was found to be due to inhibition of the ERK-dependent metalloprotease ADAM17, which normally inhibits c-MET signaling by promoting shedding of its endogenous antagonist, soluble "decoy" MET. Most importantly, pharmacological blockade of this resistance pathway with either c-MET or JAK1/2 inhibitors synergistically increased MEK-inhibitor-induced apoptosis and growth inhibition in vitro and in vivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients.

Seasonality of cardiovascular risk factors: an analysis including over 230 000 participants in 15 countries

Objective: To assess the seasonality of cardiovascular risk factors (CVRF) in a large set of population-based studies.

Methods: Cross-sectional data from 24 population-based studies from 15 countries, with a total sample size of 237 979 subjects. CVRFs included Body Mass Index (BMI) and waist circumference; systolic (SBP) and diastolic (DBP) blood pressure; total, high (HDL) and low (LDL) density lipoprotein cholesterol; triglycerides and glucose levels. Within each study, all data were adjusted for age, gender and current smoking. For blood pressure, lipids and glucose levels, further adjustments on BMI and drug treatment were performed.

Results: In the Northern and Southern Hemispheres, CVRFs levels tended to be higher in winter and lower in summer months. These patterns were observed for most studies. In the Northern Hemisphere, the estimated seasonal variations were 0.26 kg/m2 for BMI, 0.6 cm for waist circumference, 2.9 mm Hg for SBP, 1.4 mm Hg for DBP, 0.02 mmol/L for triglycerides, 0.10 mmol/L for total cholesterol, 0.01 mmol/L for HDL cholesterol, 0.11 mmol/L for LDL cholesterol, and 0.07 mmol/L for glycaemia. Similar results were obtained when the analysis was restricted to studies collecting fasting blood samples. Similar seasonal variations were found for most CVRFs in the Southern Hemisphere, with the exception of waist circumference, HDL, and LDL cholesterol.

Conclusions: CVRFs show a seasonal pattern characterised by higher levels in winter, and lower levels in summer. This pattern could contribute to the seasonality of CV mortality.

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.

The role of adiposity in cardiometabolic traits:a Mendelian randomization analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2)

Outgassing Behavior of C/2012 S1 (ISON) from 2011 September to 2013 June

We report photometric observations for comet C/2012 S1 (ISON) obtained during the time period immediately after discovery (r = 6.28 AU) until it moved into solar conjunction in mid-2013 June using the UH2.2 m, and Gemini North 8 m telescopes on Mauna Kea, the Lowell 1.8 m in Flagstaff, the Calar Alto 1.2 m telescope in Spain, the VYSOS-5 telescopes on Mauna Loa Hawaii and data from the CARA network. Additional pre-discovery data from the Pan STARRS1 survey extends the light curve back to 2011 September 30 (r = 9.4 AU). The images showed a similar tail morphology due to small micron sized particles throughout 2013. Observations at submillimeter wavelengths using the James Clerk Maxwell Telescope on 15 nights between 2013 March 9 (r = 4.52 AU) and June 16 (r = 3.35 AU) were used to search for CO and HCN rotation lines. No gas was detected, with upper limits for CO ranging between 3.5-4.5 × 1027 molecules s-1. Combined with published water production rate estimates we have generated ice sublimation models consistent with the photometric light curve. The inbound light curve is likely controlled by sublimation of CO2. At these distances water is not a strong contributor to the outgassing. We also infer that there was a long slow outburst of activity beginning in late 2011 peaking in mid-2013 January (r ~ 5 AU) at which point the activity decreased again through 2013 June. We suggest that this outburst was driven by CO injecting large water ice grains into the coma. Observations as the comet came out of solar conjunction seem to confirm our models.

Microbial community of the deep-sea brine Lake Kryos seawater-brine interface is active below the chaotropicity limit of life as revealed by recovery of mRNA

Within the complex of deep, hypersaline anoxic lakes (DHALs) of the Mediterranean Ridge, we identified a new, unexplored DHAL and named it ‘Lake Kryos’ after a nearby depression. This lake is filled with magnesium chloride (MgCl2)-rich, athalassohaline brine (salinity > 470 practical salinity units), presumably formed by the dissolution of Messinian bischofite. Compared with the DHAL Discovery, it contains elevated concentrations of kosmotropic sodium and sulfate ions, which are capable of reducing the net chaotropicily of MgCl2-rich solutions. The brine of Lake Kryos may therefore be biologically permissive at MgCl2 concentrations previously considered incompatible with life. We characterized the microbiology of the seawater–Kryos brine interface and managed to recover mRNA from the 2.27–3.03 MMgCl2 layer (equivalent to 0.747–0.631 water activity), thereby expanding the established chaotropicity window-for-life. The primary bacterial taxa present there were Kebrit Deep Bacteria 1 candidate division and DHAL-specific group of organisms, distantly related toDesulfohalobium. Two euryarchaeal candidate divisions, Mediterranean Sea Brine Lakes group 1 and halophilic cluster 1, accounted for > 85% of the rRNA-containing archaeal clones derived from the 2.27–3.03 M MgCl2 layer, but were minority community-members in the overlying interface-layers. These findings shed light on the plausibility of life in highly chaotropic environments, geochemical windows for microbial extremophiles, and have implications for habitability elsewhere in the Solar System.

Tephrochronology and the extended intimate (integration of ice‐core, marine and terrestrial records) event stratigraphy 8-128kab2k

The comparison of palaeoclimate records on their own independent timescales is central to the work of the INTIMATE (INTegrating Ice core, MArine and TErrestrial records) network. For the North Atlantic region, an event stratigraphy has been established from the high-precision Greenland ice-core records and the integrated GICC05 chronology. This stratotype provides a palaeoclimate signal to which the timing and nature of palaeoenvironmental change recorded in marine and terrestrial archives can be compared. To facilitate this wider comparison, without assuming synchroneity of climatic change/proxy response, INTIMATE has also focussed on the development of tools to achieve this. In particular the use of time-parallel marker horizons e.g. tephra layers (volcanic ash). Coupled with the recent temporal extension of the Greenland stratotype, as part of this special issue, we present an updated INTIMATE event stratigraphy highlighting key tephra horizons used for correlation across Europe and the North Atlantic. We discuss the advantages of such an approach, and the key challenges for the further integration of terrestrial palaeoenvironmental records with those from ice cores and the marine realm.

Diversity and abundance of soil arthropods in urban and suburban holm oak stands

We investigated the soil arthropod communities of urban and suburban holm oak (Quercus ilex L.) stands in a small (Siena) and a large Italian city (Naples) and tested whether the abundance and diversity of higher arthropod taxa are affected by the biotic and abiotic conditions of urban forest soils, including pollution. Acarina and Collembola were the dominant taxa in both cities. In Siena the total number of arthropod individuals collected in the samples was over 1/3 greater than in Naples, but all diversity indices scored higher in Naples than in Siena, probably in response to the higher heterogeneity of microclimatic and pedological conditions found in Naples study area. Oribatids resulted twice more abundant in Siena and so were the total mites with respect to Collembola. While “taxonomic richness” per site increased with distance from road traffic, entropy and evenness indices scored higher at the two ends of the impact gradient in both cities. The overall variation in basic pedological and microbiological soil parameters positively correlated with the total abundance of arthropods, and negatively correlated with their taxonomic richness. At the resolution employed, no significant relation emerged between anthropogenic factors, such as traffic load and soil pollution, and the arthropod fauna density and variety. These results are consistent with conclusions drawn from a previous study on the enchytraeid fauna examined at species level, which is remarkable considering the different taxonomic resolutions of the two studies. CCA results suggest that the higher abundance of Oribatid mites, Protura and Thysanura and the lower abundance of Diplopoda and Symphyla in Siena could depend on a higher fungi/bacteria ratio. This observation can be interpreted in terms of differences in fungi and bacteria between the two cities: Siena is shifted towards the fungal decomposition channel, which supports taxa such as oribatid mites, while Naples is shifted towards the bacterial channel, which supports chiefly detritivorous groups, such as diplopods.

Repeated measures of body mass index and C-reactive protein in relation to all-cause mortality and cardiovascular disease: Results from the consortium on health and ageing network of cohorts in Europe and the United States (CHANCES)

Obesity has been linked with elevated levels of C-reactive protein (CRP), and both have been associated with increased risk of mortality and cardiovascular disease (CVD). Previous studies have used a single ‘baseline’ measurement and such analyses cannot account for possible changes in these which may lead to a biased estimation of risk. Using four cohorts from CHANCES which had repeated measures in participants 50 years and older, multivariate time-dependent Cox proportional hazards was used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) to examine the relationship between body mass index (BMI) and CRP with all-cause mortality and CVD. Being overweight (≥25–<30 kg/m2) or moderately obese (≥30–<35) tended to be associated with a lower risk of mortality compared to normal (≥18.5–<25): ESTHER, HR (95 % CI) 0.69 (0.58–0.82) and 0.78 (0.63–0.97); Rotterdam, 0.86 (0.79–0.94) and 0.80 (0.72–0.89). A similar relationship was found, but only for overweight in Glostrup, HR (95 % CI) 0.88 (0.76–1.02); and moderately obese in Tromsø, HR (95 % CI) 0.79 (0.62–1.01). Associations were not evident between repeated measures of BMI and CVD. Conversely, increasing CRP concentrations, measured on more than one occasion, were associated with an increasing risk of mortality and CVD. Being overweight or moderately obese is associated with a lower risk of mortality, while CRP, independent of BMI, is positively associated with mortality and CVD risk. If inflammation links CRP and BMI, they may participate in distinct/independent pathways. Accounting for independent changes in risk factors over time may be crucial for unveiling their effects on mortality and disease morbidity.

Assessing Climate Effects on Railway Earthworks Using MASW

Many parts of the UK’s rail network were constructed in the mid-19th century long before the advent of modern construction standards. Historic levels of low investment, poor maintenance strategies and the deleterious effects of climate change have resulted in critical elements of the rail network being at significant risk of failure. The majority of failures which have occurred over recent years have been triggered by extreme weather events. Advance assessment and remediation of earthworks is, however, significantly less costly than dealing with failures reactively. It is therefore crucial that appropriate approaches for assessment of the stability of earthworks are developed, so that repair work can be better targeted and failures avoided wherever possible. This extended abstract briefly discusses some preliminary results from an ongoing geophysical research project being carried out in order to study the impact of climate or seasonal weather variations on the stability of a century old railway embankment on the Gloucestershire Warwickshire steam railway line in Southern England.