Recent developments in genetics and genomics are providing a detailed and systematic characterization of the genetic underpinnings of common metabolic diseases and traits, highlighting the inherent ...complexity within systems for homeostatic control and the many ways in which that control can fail. The genetic architecture underlying these common metabolic phenotypes is complex, with each trait influenced by hundreds of loci spanning a range of allele frequencies and effect sizes. Here, we review the growing appreciation of this complexity and how this has fostered the implementation of genome-scale approaches that deliver robust mechanistic inference and unveil new strategies for translational exploitation.
The genetic architecture of metabolic traits and diseases is complex, but recent advances are enabling the characterization of loci and mechanisms that control metabolic phenotypes and opening new avenues for translational strategies
In 2007, an association of single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated ( FTO ) gene region with body mass index (BMI) and risk of obesity was identified in multiple ...populations, making FTO the first locus unequivocally associated with adiposity. At the time, FTO was a gene of unknown function and it was not known whether these SNPs exerted their effect on adiposity by affecting FTO or neighboring genes. Therefore, this breakthrough association inspired a wealth of in silico , in vitro , and in vivo analyses in model organisms and humans to improve knowledge of FTO function. These studies suggested that FTO plays a role in controlling feeding behavior and energy expenditure. Here, we review the approaches taken that provide a blueprint for the study of other obesity-associated genes in the hope that this strategy will result in increased understanding of the biological mechanisms underlying body weight regulation.
Extracellular vesicles (EVs) have garnered growing attention as promising acellular tools for bone repair. Although EVs' potential for bone regeneration has been shown, issues associated with their ...therapeutic potency and short half-life in vivo hinders their clinical utility. Epigenetic reprogramming with the histone deacetylase inhibitor Trichostatin A (TSA) has been reported to promote the osteoinductive potency of osteoblast-derived EVs. Gelatin methacryloyl (GelMA) hydrogels functionalised with the synthetic nanoclay laponite (LAP) have been shown to effectively bind, stabilise, and improve the retention of bioactive factors. This study investigated the potential of utilising a GelMA-LAP hydrogel to improve local retention and control delivery of epigenetically enhanced osteoblast-derived EVs as a novel bone repair strategy. LAP was found to elicit a dose-dependent increase in GelMA compressive modulus and shear-thinning properties. Incorporation of the nanoclay was also found to enhance shape fidelity when 3D printed compared to LAP-free gels. Interestingly, GelMA hydrogels containing LAP displayed increased mineralisation capacity (1.41-fold) (
≤ 0.01) over 14 days. EV release kinetics from these nanocomposite systems were also strongly influenced by LAP concentration with significantly more vesicles being released from GelMA constructs as detected by a CD63 ELISA (
≤ 0.001). EVs derived from TSA-treated osteoblasts (TSA-EVs) enhanced proliferation (1.09-fold), migration (1.83-fold), histone acetylation (1.32-fold) and mineralisation (1.87-fold) of human bone marrow stromal cells (hBMSCs) when released from the GelMA-LAP hydrogel compared to the untreated EV gels (
≤ 0.01). Importantly, the TSA-EV functionalised GelMA-LAP hydrogel significantly promoted encapsulated hBMSCs extracellular matrix collagen production (≥1.3-fold) and mineralisation (≥1.78-fold) in a dose-dependent manner compared to untreated EV constructs (
≤ 0.001). Taken together, these findings demonstrate the potential of combining epigenetically enhanced osteoblast-derived EVs with a nanocomposite photocurable hydrogel to promote the therapeutic efficacy of acellular vesicle approaches for bone regeneration.
...the project demonstrates that non-coding regions must be considered when interpreting GWAS results, and it provides a strong motivation for reinterpreting previous GWAS findings.
The consumption of sugar-sweetened beverages (SSBs), which has increased substantially during the last decades, has been associated with obesity and weight gain.
Common genetic susceptibility to ...obesity has been shown to modify the association between SSB intake and obesity risk in 3 prospective cohorts from the United States. We aimed to replicate these findings in 2 large Swedish cohorts.
Data were available for 21,824 healthy participants from the Malmö Diet and Cancer study and 4902 healthy participants from the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk Study. Self-reported SSB intake was categorized into 4 levels (seldom, low, medium, and high). Unweighted and weighted genetic risk scores (GRSs) were constructed based on 30 body mass index (BMI) in kg/m(2)-associated loci, and effect modification was assessed in linear regression equations by modeling the product and marginal effects of the GRS and SSB intake adjusted for age-, sex-, and cohort-specific covariates, with BMI as the outcome. In a secondary analysis, models were additionally adjusted for putative confounders (total energy intake, alcohol consumption, smoking status, and physical activity).
In an inverse variance-weighted fixed-effects meta-analysis, each SSB intake category increment was associated with a 0.18 higher BMI (SE = 0.02; P = 1.7 × 10(-20); n = 26,726). In the fully adjusted model, a nominal significant interaction between SSB intake category and the unweighted GRS was observed (P-interaction = 0.03). Comparing the participants within the top and bottom quartiles of the GRS to each increment in SSB intake was associated with 0.24 (SE = 0.04; P = 2.9 × 10(-8); n = 6766) and 0.15 (SE = 0.04; P = 1.3 × 10(-4); n = 6835) higher BMIs, respectively.
The interaction observed in the Swedish cohorts is similar in magnitude to the previous analysis in US cohorts and indicates that the relation of SSB intake and BMI is stronger in people genetically predisposed to obesity.
Mitigating conflicts associated with predation on livestock is essential for conserving large carnivores in human dominated landscapes. This is generally addressed by targeting at individual ...management practices affecting predation risk, often disregarding that different livestock husbandry systems (i.e., groups of farms sharing similar resource bases, production patterns and management practices) with different vulnerabilities to predation may coexist within predator ranges, each of which requiring tailored prescriptions to reduce predation. Here we evaluated the importance of considering both husbandry systems and individual management practices to mitigate conflicts due to cattle predation by wolves in Portugal, where attacks on cattle increased >3 times in 1999–2013. Government records from 2012 to 2013 indicated that only <2% of cattle farms suffered wolf attacks, of which <4% had >10attacks per year. We found that attacks were concentrated in the free-ranging husbandry system, which was characterized by multi-owner herds, largely grazing communal land far from shelter, and seldom confined. Protecting these herds at night in winter was the most important factor reducing wolf attacks, which could be achieved by changing practices of ≈25% of farmers in this system. Attacks were much lower in the semi-confined system, probably because herds grazed pastures closer to shelter, and they were often confined with fences or in barns. Farms bringing calves <3months old to pastures were associated with about 90% of attacks, but changing this practice would involve ≈50% of farmers in this system. Our results underline the importance of identifying livestock husbandry systems and to adjust mitigation strategies to each system.
•Wolf attacks on cattle greatly increased in Portugal in 1999–2013.•There were far more wolf attacks on free-ranging than on semi-confined herds.•Protecting free-ranging herds at night in winter would greatly decrease wolf predation risk.•Keeping calves <3months old indoor would decrease wolf predation in semi-confined herds.•Under adequate management both free-ranging and semi-confined herds may be compatible with wolf presence.
Predation on livestock is a source of human-wildlife conflicts and can undermine the conservation of large carnivores. To design effective mitigation strategies, it is important to understand the ...determinants of predation across livestock species, which often differ in husbandry practices, vulnerability to predators and economic value. Moreover, attention should be given to both predation occurrence and intensity, because these can have different spatial patterns and predictors. We used spatial risk modelling to quantify factors affecting wolf predation on five livestock species in Portugal. Within the 1619 parishes encompassing the entire wolf range in the country, the national wolf compensation scheme recorded 17,670 predation events in 2009–2015, each involving one or more livestock species: sheep (31.7%), cattle (27.7%), goats (26.8%), horses (14.8%) and donkeys (3.2%). Models built with 2009–2013 data and validated with 2014–2015 data, showed a shared general pattern of predation probability on each species increasing with its own density and proximity to wolf packs. For some species there were positive relations with the density of other livestock species, and with habitat variables such as altitude, and land cover by shrubland and natural pastures. There was also a general pattern for predation intensity on each species increasing with its own density, while proximity to wolf packs had no significant effects. Predation intensity on goats, cattle and horses increased with the use of communal versus private pastures. Our results suggest that although predation may occur wherever wolves coexist with livestock species, high predation intensity is mainly restricted to particular areas where husbandry practices increase the vulnerability of animals, and this is where mitigation efforts should concentrate.
•We analysed 17,670 wolf predation events on five livestock species in Portugal.•Predation probability was mainly related to wolf presence and livestock densities.•Predation intensity was mainly related to livestock densities and the use of communal pastures.•Patterns and determinants of predation risk varied across livestock species.•Mitigation should prioritise areas where husbandry practices favour high predation intensity.
Glycaemic traits such as fasting and post-challenge glucose and insulin measures, as well as glycated haemoglobin (HbA1c), are used to diagnose and monitor diabetes. These traits are risk factors for ...cardiovascular disease even below the diabetic threshold, and their study can additionally yield insights into the pathophysiology of type 2 diabetes. To date, a diverse set of genetic approaches have led to the discovery of over 97 loci influencing glycaemic traits. In this review, we will focus on recent advances in the genetic aetiology of glycaemic traits, and the resulting biological insights. We will provide a brief overview of results ranging from common, to low- and rare-frequency variant-trait association studies, studies leveraging the diversity across populations, and studies harnessing the power of genetic and genomic approaches to gain insights into the biological underpinnings of these traits.
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