Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10−5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10−8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10−6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. Funding: Innovative Medicines Initiative and the Wellcome Trus

Reducing depression in older home care clients: design of a prospective study of a nurse-led interprofessional mental health promotion intervention

Abstract Background Very little research has been conducted in the area of depression among older home care clients using personal support services. These older adults are particularly vulnerable to depression because of decreased cognition, comorbid chronic conditions, functional limitations, lack of social support, and reduced access to health services. To date, research has focused on collaborative, nurse-led depression care programs among older adults in primary care settings. Optimal management of depression among older home care clients is not currently known. The objective of this study is to evaluate the feasibility, acceptability and effectiveness of a 6-month nurse-led, interprofessional mental health promotion intervention aimed at older home care clients with depressive symptoms using personal support services. Methods/Design This one-group pre-test post-test study aims to recruit a total of 250 long-stay (> 60 days) home care clients, 70 years or older, with depressive symptoms who are receiving personal support services through a home care program in Ontario, Canada. The nurse-led intervention is a multi-faceted 6-month program led by a Registered Nurse that involves regular home visits, monthly case conferences, and evidence-based assessment and management of depression using an interprofessional approach. The primary outcome is the change in severity of depressive symptoms from baseline to 6 months using the Centre for Epidemiological Studies in Depression Scale. Secondary outcomes include changes in the prevalence of depressive symptoms and anxiety, health-related quality of life, cognitive function, and the rate and appropriateness of depression treatment from baseline to 12 months. Changes in the costs of use of health services will be assessed from a societal perspective. Descriptive and qualitative data will be collected to examine the feasibility and acceptability of the intervention and identify barriers and facilitators to implementation. Discussion Data collection began in May 2010 and is expected to be completed by July 2012. A collaborative nurse-led strategy may provide a feasible, acceptable and effective means for improving the health of older home care clients by improving the prevention, recognition, and management of depression in this vulnerable population. The challenges involved in designing a practical, transferable and sustainable nurse-led intervention in home care are also discussed. Trial Registration ClinicalTrials.gov: NCT0140792

ARENA - Evaluation de la régulation naturelle des ravageurs en grandes cultures par les auxiliaires de cultures : réseau d’observations et construction de ressources pour intégrer ce service dans le raisonnement de la protectionintégrée

Promoting pest biological control within agrosystems is a way to reduce the use of pesticides. The lack of quantification tools of this ecosystem service is a major obstacle to the changes in crop protection strategies. ARENA's ambition was to build methods to observe natural pest control directly on fields, provide tools to quantify and predict natural pest control potential. An important monitoring campaign of pests (slugs and aphids) and natural enemies monitoring took place in 171 fields (wheat, barley, corn, rape). On the basis of the monitoring carried out, tools for quantifying the regulation service were developed along three lines: (1) identification of agro-environmental contexts favourable to the expression of a high level of biological control, (2) development of a statistical model for the early evaluation of pest risk taking into account the level of local biological control and (3) development of an indicator of the potential for regulation by communities of beneficials in the field.Favoriser le contrôle biologique des ravageurs dans les agrosystèmes est un levier pour réduire l’usage des produits phytosanitaires. Le manque d’outils de quantification de ce service écosystémique est un frein à sa prise en compte dans les stratégies de protection des plantes. Les objectifs du projet ARENA (Anticiper les REgulations Naturelles) étaient de proposer des méthodes d’observation des égulations naturelles en parcelles agricoles ainsi que le développement des outils de quantification et de prévisiondu potentiel de contrôle biologique. Une importante campagne de suivi de ravageurs (limaces et pucerons) et de leurs ennemis naturels a eu lieu sur 171 parcelles de grandes cultures (blé, orge, colza, maïs) pendant 3 ans (printemps et automne). Sur la base des suivis réalisés, des outils de quantification du service de régulation ont été développés suivant trois axes : (1) identification de contextes agroenvironnementaux favorables à l’expression d’un niveau élevé de contrôle biologique, (2) élaboration d’un modèle statistique pour l’évaluation précoce du risque ravageur prenant en compte le potentiel de régulation biologique et (3) élaboration d’un indicateur du potentiel de régulation par les communautés d’auxiliaires au champ

ARENA -Evaluation de la régulation naturelle des ravageurs en grandes cultures par les auxiliaires de cultures : réseau d'observations et construction de ressources pour intégrer ce service dans le raisonnement de la protection intégrée

National audienceARENA: Assessment of pest biocontrol in arable crops by naturally ocuring pest enemies: sampling network and tools to integrate this ecosystem service into integrated crop management Promoting pest biological control within agrosystems is a way to reduce the use of pesticides. The lack of quantification tools of this ecosystem service is a major obstacle to the changes in crop protection strategies. ARENA's ambition was to build methods to observe natural pest control directly on fields, provide tools to quantify and predict natural pest control potential. An important monitoring campaign of pests (slugs and aphids) and natural enemies monitoring took place in 171 fields (wheat, barley, corn, rape). On the basis of the monitoring carried out, tools for quantifying the regulation service were developed along three lines: (1) identification of agro-environmental contexts favourable to the expression of a high level of biological control, (2) development of a statistical model for the early evaluation of pest risk taking into account the level of local biological control and (3) development of an indicator of the potential for regulation by communities of beneficials in the field.Favoriser le contrôle biologique des ravageurs dans les agrosystèmes est un levier pour réduire l’usage des produits phytosanitaires. Le manque d’outils de quantification de ce service écosystémique est un frein à sa prise en compte dans les stratégies de protection des plantes. Les objectifs du projet ARENA (Anticiper les REgulations Naturelles) étaient de proposer des méthodes d’observation des égulations naturelles en parcelles agricoles ainsi que le développement des outils de quantification et de prévisiondu potentiel de contrôle biologique. Une importante campagne de suivi de ravageurs (limaces et pucerons) et de leurs ennemis naturels a eu lieu sur 171 parcelles de grandes cultures (blé, orge, colza, maïs) pendant 3 ans (printemps et automne). Sur la base des suivis réalisés, des outils de quantification du service de régulation ont été développés suivant trois axes : (1) identification de contextes agroenvironnementaux favorables à l’expression d’un niveau élevé de contrôle biologique, (2) élaboration d’un modèle statistique pour l’évaluation précoce du risque ravageur prenant en compte le potentiel de régulation biologique et (3) élaboration d’un indicateur du potentiel de régulation par les communautés d’auxiliaires au champ

Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice

Hsp27 belongs to the small heat shock protein family, which are ATP-independent chaperones. The most important function of Hsp27 is based on its ability to bind non-native proteins and inhibit the aggregation of incorrectly folded proteins maintaining them in a refolding-competent state. Additionally, it has anti-apoptotic and antioxidant activities. To study the effect of Hsp27 on memory and synaptic functions, amyloid-β (Aβ) accumulation, and neurodegeneration, we generated transgenic mice overexpressing human Hsp27 protein and crossed with APPswe/PS1dE9 mouse strain, a mouse model of Alzheimer's disease (AD). Using different behavioral tests, we found that spatial learning was impaired in AD model mice and was rescued by Hsp27 overexpression. Electrophysiological recordings have revealed that excitability of neurons was significantly increased, and long-term potentiation (LTP) was impaired in AD model mice, whereas they were normalized in Hsp27 overexpressing AD model mice. Using anti-amyloid antibody, we counted significantly less amyloid plaques in the brain of APPswe/PS1dE9/Hsp27 animals compared to AD model mice. These results suggest that overexpression of Hsp27 protein might ameliorate certain symptoms of AD. © 2013 Cell Stress Society International