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1.
Ann Nutr Metab ; 80(2): 57-73, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38052180

RESUMEN

INTRODUCTION: Interventions promoting exclusive breastfeeding (EBF) may benefit infant health outcomes, but evidence is inconsistent. The objective of this review was to assess the effect of interventions promoting EBF on health outcomes in infants and children under 7 years of age. METHODS: A literature search was conducted using EMBASE, MEDLINE, CINAHL, Cochrane Central, Cochrane Database of Systematic Reviews, and WHO International Clinical Trials Registry Platform from inception to April 2022. Inclusion criteria were randomized or cluster-randomized controlled trials aiming to increase EBF that reported effects on offspring growth, morbidity, and/or mortality up to age 7 years. The primary outcome was infant/child growth. Secondary outcomes were infant morbidity and mortality and EBF rates. Data were pooled using a random-effects model. RESULTS: Thirty-two studies (40 papers) were identified. No effect on infant/child growth was observed. EBF promotion interventions significantly improved EBF rates up to 6 months (n = 25; OR 3.15; 95% CI: 2.36, 4.19) and significantly reduced the odds of respiratory illness at 0-3 months by 59% (n = 2; OR 0.41; 95% CI: 0.20, 0.84) but not at later time-points. A borderline significant effect was observed for diarrhea (n = 12; OR 0.84; 95% CI: 0.70, 1.00). Effects on hospitalizations or mortality were not significant. DISCUSSION/CONCLUSION: EBF promotion interventions improve EBF rates and might yield modest reductions in infant morbidity without affecting infant/child growth. Future studies should investigate the cost-effectiveness of these interventions and examine potential benefits on other health outcomes.


Asunto(s)
Lactancia Materna , Diarrea , Lactante , Femenino , Niño , Humanos , Factores de Tiempo , Morbilidad
2.
Nutrients ; 15(21)2023 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-37960169

RESUMEN

To understand the extent to which different sources of diet and nutrition information are sought, trusted, and relied upon for making dietary changes, the present international web-based survey study gauged participants' (n = 3419) diet-nutrition information-seeking behaviors from 22 interpersonal and general sources with varying quality, trust levels in these sources, and reliance on each source for making dietary changes. Qualitative insights were also captured regarding trustworthiness formation. The results revealed a disconnect between source popularity and perceived trustworthiness. While nutrition-health websites, Google-Internet searches, and diet-health books were most commonly consulted, participants placed the highest level of trust in nutrition scientists, nutrition professionals, and scientific journals, suggesting that frequent information seeking from a subpar source may not be a reliable predictor of the level of trust assigned to it. Although the frequency of source-seeking behaviors and source trustworthiness both contributed to dietary changes, the latter appeared to have a more pronounced influence. When a source was less trusted, there was a reduced likelihood of relying on it for changing diet. Additionally, source seeking may not always translate into effective dietary change, as shown by the less strong correlation between the two. These associations significantly differed depending on the source.


Asunto(s)
Dieta , Conducta en la Búsqueda de Información , Humanos , Encuestas y Cuestionarios , Estado Nutricional , Conducta Alimentaria , Internet
4.
Curr Obes Rep ; 12(3): 223-230, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37335395

RESUMEN

PURPOSE OF REVIEW: There is a large variability between individuals in the weight loss response to any given diet treatment, which fuels interest into personalized or precision nutrition. Although most efforts are directed toward identifying biological or metabolic factors, several behavioral and psychological factors can also be responsible for some of this interindividual variability. RECENT FINDINGS: There are many factors that can influence the response to dietary weight loss interventions, including factors related to eating behavior (emotional eating, disinhibition, restraint, perceived stress), behaviors and societal norms related to age and sex, psychological and personal factors (motivation, self-efficacy, locus of control, self-concept), and major life events. The success of a weight loss intervention can be influenced by many psychological and behavioral constructs and not merely by physiological factors such as biology and genetics. These factors are difficult to capture accurately and are often overlooked. Future weight loss studies should consider assessing such factors to better understand the underlying reasons for the large interindividual variability to weight loss therapy.


Asunto(s)
Dieta Reductora , Obesidad , Humanos , Obesidad/psicología , Pérdida de Peso/fisiología , Conducta Alimentaria/psicología , Motivación
5.
J Hum Nutr Diet ; 36(3): 1011-1018, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36428232

RESUMEN

BACKGROUND: The COVID-19 pandemic has negatively impacted people living with obesity. The aim was to examine the continued impact of the COVID-19 pandemic on the mental health of people living with obesity and associations with food insecurity, loneliness and health-related behaviours. METHODS: The study recruited 1187 UK adults living with obesity who completed an online survey, which examined mental health and associations with food insecurity, loneliness and health-related behaviours from July 2020 (end of the first lockdown in the United Kingdom) to the point they completed the survey in 2021. Regression analyses were used to examine relationships between outcome variables and demographic factors, and hierarchical linear regression models were used to assess levels of loneliness, depression and well-being. RESULTS: Participants reported worse loneliness, depression, well-being and food insecurity compared to pre-COVID. However, participants reported attempting to lose weight, healthier food shopping, diet and increased physical activity. Quality and quantity of sleep deteriorated compared to prior to COVID-19. CONCLUSIONS: Adults living with obesity in the United Kingdom report a continued negative impact of the COVID-19 pandemic upon their mental health together with increased loneliness and food insecurity. However, our findings suggest that UK adults living with obesity have increased their engagement in positive health behaviours and were attempting to lose weight.


Asunto(s)
COVID-19 , Adulto , Humanos , COVID-19/epidemiología , Salud Mental , Soledad , Pandemias , Control de Enfermedades Transmisibles , Obesidad/epidemiología , Conductas Relacionadas con la Salud , Inseguridad Alimentaria , Pérdida de Peso
6.
Artículo en Inglés | MEDLINE | ID: mdl-36231195

RESUMEN

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterised by immune dysregulation affecting multiple organs. Current anti-inflammatory treatments used in SLE are associated with unwanted side-effects. Dietary supplementation has been suggested as a safe and effective addition to conventional treatment, but evidence of efficacy in SLE or preventing associated comorbidities is uncertain. METHODS: We identified literature on clinical trials focused on nutritional interventions in SLE aiming to improve inflammation and comorbidities. A systematic-type search on Embase, Medline, and the Cochrane Library, was conducted to identify nutritional interventions among SLE patients in the past 15 years that met our inclusion criteria. RESULTS: We identified 2754 articles, of which 14 were eligible for inclusion based on our set criteria and were subsequently quality assessed. Vitamin D or E supplementation was associated with respective improvement of inflammatory markers or antibody production, but not disease activity scores in most studies. Despite their expected synergistic actions, the addition of curcumin on vitamin D supplementation had no additional effects on disease activity or inflammatory markers. Trials of omega-3 fatty acid supplementation presented significant reductions in ESR, CRP, disease activity, inflammatory markers, and oxidative stress, and improved lipid levels and endothelial function, while a low glycaemic index (GI) diet showed evidence of reduced weight and improved fatigue in patients. CONCLUSIONS: Different dietary guidelines can therefore be implicated to target specific SLE symptoms or therapeutic side-effects. This systematic review highlights the scarcity of larger and longer in duration trials with homogenous methodologies and verifiable outcomes to assess disease progression.


Asunto(s)
Curcumina , Ácidos Grasos Omega-3 , Lupus Eritematoso Sistémico , Biomarcadores , Curcumina/uso terapéutico , Dieta , Suplementos Dietéticos , Ácidos Grasos Omega-3/uso terapéutico , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Vitamina D/uso terapéutico
7.
Obes Rev ; 23(10): e13494, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35934011

RESUMEN

Weight stigma impacts negatively healthcare quality and hinders public health goals. The aim of this review was to identify strategies for minimizing weight bias among healthcare professionals and explore future research directions. An electronic search was performed in PubMed, PsycINFO and Scopus (until June 2020). Studies on weight stigma reduction in healthcare students, trainees and professionals were assessed based on specific inclusion and exclusion criteria. A narrative synthesis was undertaken to analyze emerging themes. We identified five stigma reduction strategies in healthcare: (i) increased education, (ii) causal information and controllability, (iii) empathy evoking, (iv) weight-inclusive approach, and (v) mixed methodology. Weight stigma needs to be addressed early on and continuously throughout healthcare education and practice, by teaching the genetic and socioenvironmental determinants of weight, and explicitly discussing the sources, impact and implications of stigma. There is a need to move away from a solely weight-centric approach to healthcare to a health-focused weight-inclusive one. Assessing the effects of weight stigma in epidemiological research is equally important. The ethical argument and evidence base for the need to reduce weight stigma in healthcare and beyond is strong. Although evidence on long-term stigma reduction is emerging, precautionary action is needed.


Asunto(s)
Prejuicio de Peso , Atención a la Salud , Personal de Salud/educación , Humanos , Estigma Social , Estudiantes
9.
Lupus ; 31(1): 65-76, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34978516

RESUMEN

INTRODUCTION: Previous studies have reported that patients affected by systemic lupus erythematosus (SLE) are interested in using diet to treat fatigue, cardiovascular disease and other symptoms. However, to date, there is insufficient information regarding the ways for patients to modify their diet to improve SLE symptoms. We investigated the relationship between the eating patterns of SLE patients and their self-reported disease symptoms and general aspects of health. METHODS: A UK-based, online survey was developed, in which patients with SLE were asked about their attitudes and experiences regarding their SLE symptoms and diet. RESULTS: The majority (>80%) of respondents that undertook new eating patterns with increased vegetable intake and/or decreased intake of processed food, sugar, gluten, dairy and carbohydrates reported benefiting from their dietary change. Symptom severity ratings after these dietary changes were significantly lower than before (21.3% decrease, p<0.0001). The greatest decreases in symptom severity were provided by low/no dairy (27.1% decrease), low/no processed foods (26.6% decrease) and vegan (26% decrease) eating patterns (p<0.0001). Weight loss, fatigue, joint/muscle pain and mood were the most cited symptoms that improved with dietary change. CONCLUSION: SLE patients who changed their eating patterns to incorporate more plant-based foods while limiting processed foods and animal products reported improvements in their disease symptoms. Thus, our findings show promises in using nutrition interventions for the management of SLE symptoms, setting the scene for future clinical trials in this area. Randomised studies are needed to further test whether certain dietary changes are effective for improving specific symptoms of SLE.


Asunto(s)
Enfermedades Cardiovasculares , Lupus Eritematoso Sistémico , Dieta , Fatiga , Conducta Alimentaria , Humanos
10.
J Cachexia Sarcopenia Muscle ; 13(1): 23-41, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34881518

RESUMEN

Cancer-associated cachexia (CAC) is a wasting syndrome characterized by involuntary weight loss and anorexia. Clear definition and diagnostic criteria for CAC are lacking, which makes it difficult to estimate its prevalence, to interpret research and to compare studies. There is no standard treatment to manage CAC, but previous studies support the use of cannabinoids for cachexia in other chronic diseases including HIV and multiple sclerosis. However, only a few randomized controlled trials (RCTs) and one meta-analysis of this intervention in cancer populations are available. Non-randomized studies of interventions (NRSIs) are often excluded from reviews due to variable methodology and potential for biases. This review aimed to consider NRSIs alongside RCTs to provide a complete summary of the available evidence that clinical decision makers could use in future investigations. Literature searches were conducted using three databases for relevant RCTs or NRSIs according to Cochrane methodology. Abstract and full texts of retrieved manuscripts were selected and retrieved by two investigators based on the PRISMA-A guidelines, and risk of bias and quality of evidence assessments were performed. Outcome data on weight, appetite, quality of life, performance status, adverse effects, and mortality were combined by narrative synthesis and meta-analysis where possible. Ten studies were included, four of which were RCTs and six NRSIs matching the eligibility criteria. Very low-quality evidence from meta-analysis suggested no significant benefits of cannabinoids for appetite compared with control (standardized mean difference: -0.02; 95% confidence interval: -0.51, 0.46; P = 0.93). Patient-reported observations from NRSIs suggested improvements in appetite. Another meta-analysis of moderate quality evidence showed that cannabinoids were significantly less efficient than active or inactive control on quality of life (standardized mean difference: -0.25; 95% confidence interval: -0.43, -0.07; P = 0.007). The effectiveness of cannabinoids alone to improve outcomes of CAC remains unclear. Low-quality evidence from both RCTs and NRSIs shows no significant benefits of cannabinoids for weight gain, appetite stimulation, and better quality of life, three important outcomes of cachexia. Higher quality research integrating cannabinoids into multi-modal therapies may offer better opportunities for developing CAC-specific treatments. This review also highlights that findings from non-randomized studies of interventions (NRSIs) can provide evidence of the effects of an intervention and advocate for the feasibility of larger RCTs.


Asunto(s)
Cannabinoides , Neoplasias , Sesgo , Caquexia/tratamiento farmacológico , Caquexia/etiología , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Humanos , Neoplasias/complicaciones , Calidad de Vida
11.
Artículo en Inglés | MEDLINE | ID: mdl-34682637

RESUMEN

Adult cancer survivors have an increased prevalence of mental health comorbidities and other adverse late-effects interdependent with mental illness outcomes compared with the general population. Coronavirus Disease 2019 (COVID-19) heralds an era of renewed call for actions to identify sustainable modalities to facilitate the constructs of cancer survivorship care and health care delivery through physiological supportive domestic spaces. Building on the concept of therapeutic architecture, psychoneuroimmunology (PNI) indicators-with the central role in low-grade systemic inflammation-are associated with major psychiatric disorders and late effects of post-cancer treatment. Immune disturbances might mediate the effects of environmental determinants on behaviour and mental disorders. Whilst attention is paid to the non-objective measurements for examining the home environmental domains and mental health outcomes, little is gathered about the multidimensional effects on physiological responses. This exploratory review presents a first analysis of how addressing the PNI outcomes serves as a catalyst for therapeutic housing research. We argue the crucial component of housing in supporting the sustainable primary care and public health-based cancer survivorship care model, particularly in the psychopathology context. Ultimately, we illustrate a series of interventions aiming at how housing environmental attributes can trigger PNI profile changes and discuss the potential implications in the non-pharmacological treatment of cancer survivors and patients with mental morbidities.


Asunto(s)
COVID-19 , Supervivientes de Cáncer , Neoplasias , Adulto , Vivienda , Humanos , Salud Mental , Morbilidad , Neoplasias/epidemiología , Psiconeuroinmunología , SARS-CoV-2
13.
Nutrients ; 13(4)2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33808403

RESUMEN

INTRODUCTION: In most sub-Saharan African countries iron deficiency anaemia remains highly prevalent in children and this has not changed in the last 25 years. Supplementation with iron hydroxide adipate tartrate (IHAT) was being investigated in anaemic children in a phase two clinical trial (termed IHAT-GUT), conducted at the Medical Research Council Unit the Gambia at the London School of Hygiene and Tropical Medicine (LSHTM) (abbreviated as MRCG hereof). This qualitative study aimed to explore the personal perceptions of the trial staff in relation to conducting a clinical trial in such settings in order to highlight the health system specific needs and strengths in the rural, resource-poor setting of the Upper River Region in the Gambia. METHODS: Individual interviews (n = 17) were conducted with local trial staff of the IHAT-GUT trial. Data were analysed using inductive thematic analysis. RESULTS: Potential barriers and facilitators to conducting this clinical trial were identified at the patient, staff, and trial management levels. Several challenges, such as the rural location and cultural context, were identified but noted as not being long-term inhibitors. Participants believed the facilitators and benefits outnumbered the barriers, and included the impact on education and healthcare, the ambitious and knowledgeable locally recruited staff, and the local partnership. CONCLUSIONS: While facilitators and barriers were identified to conducting this clinical trial in a rural, resource-poor setting, the overall impact was perceived as beneficial, and this study is a useful example of community involvement and partnership for further health improvement programs. To effectively implement a nutrition intervention, the local health systems and context must be carefully considered through qualitative research beforehand.


Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Compuestos Férricos/administración & dosificación , Población Rural , Anemia Ferropénica/epidemiología , Niño , Atención a la Salud/economía , Atención a la Salud/métodos , Suplementos Dietéticos , Método Doble Ciego , Grupos Focales , Gambia/epidemiología , Humanos , Hierro de la Dieta , Pobreza , Investigación Cualitativa
14.
EClinicalMedicine ; 34: 100796, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33754138

RESUMEN

BACKGROUND: Coronavirus disease 2019 (COVID-19) has led to unprecedented changes in the way we live, particularly for people at higher risk of severe illness from COVID-19. People with pre-existing health conditions have been markedly impacted and, in some instances, left unsupported due to reduced provision of routine healthcare services. People living with obesity (PLWO) are identified as at higher risk of severe illness from COVID-19 infection. Currently, there is a paucity of evidence about the impact of the first COVID-19 lockdown on PLWO, including those accessing weight management and bariatric surgery services (WMS). METHODS: 543 adults (16-80 years) with obesity (BMI ≥ 30 kg/m2) were recruited between 14th May and 9th July 2020 through social media advertisements, professional and patient obesity organisations and WMS. Participants completed an online survey regarding the impact of the first COVID-19 lockdown upon, mental health, well-being, health-related behaviours, risk mitigating behaviours, access to WMS and weight stigma. FINDINGS: During the first COVID-19 lockdown, the majority of PLWO reported deterioration of their mental health and health-related behaviours such as diet, physical activity (PA) and sleep. With 55% reporting an unhealthier diet, 61% reduced PA and 80% worsening of their sleep. Higher depression and lower wellbeing scores were found to associate with the greatest adverse impact upon health-related behaviours. PLWO who were attending WMS prior to the first lockdown reported a greater deterioration of their diet, with nearly 50% reporting worsening of their diet and PA worsening compared to PLWO who were not attending WMS. Most participants took two or more risk mitigating actions (73%). PLWO attending WMS reported reduced access (44%) with insufficient information (49%) from their clinical service providers. The majority of participants reported no change in perceived weight stigma. INTERPRETATION: This study shows the detrimental impact of the first COVID-19 lockdown on PLWO in relation to health-related behaviours, mental health and access to WMS. Our findings show that PLWO with poor mental health and those attending WMS were most adversely impacted and highlights the need for greater mental health support and continued provision of support from WMS for PLWO during future lockdowns. FUNDING: This research was funded through National Institute for Health Research University College London Hospitals Biomedical Research Centre funding.

16.
Proc Nutr Soc ; 78(1): 19-26, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-29986781

RESUMEN

Iron deficiency remains the largest nutritional deficiency worldwide and the main cause of anaemia. Severe iron deficiency leads to anaemia known as iron deficiency anaemia (IDA), which affects a total of 1·24 billion people, the majority of whom are children and women from resource-poor countries. In sub-Saharan Africa, iron deficiency is frequently exacerbated by concomitant parasitic and bacterial infections and contributes to over 120 000 maternal deaths a year, while it irreparably limits the cognitive development of children and leads to poor outcomes in pregnancy.Currently available iron compounds are cheap and readily available, but constitute a non-physiological approach to providing iron that leads to significant side effects. Consequently, iron deficiency and IDA remain without an effective treatment, particularly in populations with high burden of infectious diseases. So far, despite considerable investment in the past 25 years in nutrition interventions with iron supplementation and fortification, we have been unable to significantly decrease the burden of this disease in resource-poor countries.If we are to eliminate this condition in the future, it is imperative to look beyond the strategies used until now and we should make an effort to combine community engagement and social science approaches to optimise supplementation and fortification programmes.


Asunto(s)
Anemia Ferropénica , Deficiencias de Hierro , Adulto , Anemia Ferropénica/complicaciones , Niño , Enfermedades Transmisibles/etiología , Costo de Enfermedad , Países en Desarrollo , Suplementos Dietéticos , Femenino , Humanos , Masculino , Embarazo
17.
Physiol Rep ; 6(23): e13939, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30548130

RESUMEN

The bioactive peptides of the apelinergic system and its receptor APJ have been shown to play a protective role in experimental cardiovascular and diabetic kidney disease (DKD). Mechanisms of this renoprotective effect remain to be elucidated. In this study, we examined the localization of APJ within the normal kidney and its kidney expression in the db/db model of DKD. The effect of hyperglycemia and angiotensin II on APJ was examined in cultured podocytes. In the glomerulus, APJ colocalized with podocyte but not endothelial cell markers. In podocytes stimulated with Pyr1 Apelin-13, a change in the phosphorylation status of the signaling proteins, AKT, ERK, and p70S6K, was observed with an increase 15 min after stimulation. Apelin-13 decreased activity of Caspase-3 in podocytes after high glucose treatment reflecting an antiapoptotic effect of APJ stimulation. In podocytes, APJ mRNA was downregulated in high glucose, when compared to normal glucose conditions and exposure to angiotensin II led to a further significant decrease in APJ mRNA. APJ and preproapelin mRNA levels in kidneys from db/db mice were markedly decreased along with decreased tubular APJ protein by western blotting and immunostaining when compared to db/m controls. In conclusion, the apelinergic system is decreased in kidneys from db/db mice. Within the glomerulus, APJ is mainly localized in podocytes and in this cell type its activation by Apelin-13 abolishes the proapoptotic effect of high glucose, suggesting a potential therapeutic role of apelin and emerging agonists with extended half-life for therapy of DKD.


Asunto(s)
Apelina/metabolismo , Nefropatías Diabéticas/metabolismo , Riñón/metabolismo , Animales , Apelina/genética , Apoptosis , Caspasa 3/metabolismo , Línea Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Péptidos y Proteínas de Señalización Intercelular/farmacología , Riñón/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo
18.
Curr Opin Clin Nutr Metab Care ; 21(4): 252-259, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29847446

RESUMEN

PURPOSE OF REVIEW: We present a current perspective of epigenetic alterations that can lead to cardiovascular disease (CVD) and the potential of dietary factors to counteract their actions. In addition, we discuss the challenges and opportunities of dietary treatments as epigenetic modifiers for disease prevention and therapy. RECENT FINDINGS: Recent epigenome-wide association studies along with candidate gene approaches and functional studies in cell culture and animal models have delineated mechanisms through which nutrients, food compounds and dietary patterns may affect the epigenome. Several risk factors for CVD, including adiposity, inflammation and oxidative stress, have been associated with changes in histone acetylation, lower global DNA methylation levels and shorter telomere length. A surplus of macronutrients such as in a high-fat diet or deficiencies of specific nutrients such as folate and other B-vitamins can affect the activity of DNA methyltransferases and histone-modifying enzymes, affecting foetal growth, glucose/lipid metabolism, oxidative stress, inflammation and atherosclerosis. Bioactive compounds such as polyphenols (resveratrol, curcumin) or epigallocatechin may activate deacetylases Sirtuins (SIRTs), histone deacetylases or acetyltransferases and in turn the response of inflammatory mediators. Adherence to cardioprotective dietary patterns, such as the Mediterranean diet (MedDiet), has been associated with altered methylation and expression of genes related to inflammation and immuno-competence. SUMMARY: The mechanisms through which nutrients and dietary patterns may alter the cardiovascular epigenome remain elusive. The research challenge is to determine which of these nutriepigenetic effects are reversible, so that novel findings translate into effective dietary interventions to prevent CVD or its progression.


Asunto(s)
Enfermedades Cardiovasculares , Metilación de ADN , Dieta , Epigénesis Genética , Histonas/metabolismo , Estado Nutricional , Acetilación , Animales , Enfermedades Cardiovasculares/dietoterapia , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Histona Desacetilasas del Grupo III/metabolismo , Humanos , Inflamación/genética , Polifenoles , Procesamiento Proteico-Postraduccional
19.
Atherosclerosis ; 261: 60-68, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28456096

RESUMEN

BACKGROUND AND AIMS: Annexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulate low-density lipoprotein cholesterol (LDL-C) levels. Here we identify variants in ANXA2 influencing LDL-C levels and we determine the molecular mechanisms of their effects. RESULTS: The ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (n∼2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (n∼14,600). The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C (p = 0.004), and higher risk of coronary heart disease (CHD) (p = 0.04). The SNP is in modest linkage disequilibrium (r2 > 0.5) with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression (≈18%, p < 0.001). In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression (p = 1.36 × 10-05). CONCLUSIONS: Both rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus increase LDL-C levels and risk of CHD. This supports, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering.


Asunto(s)
Anexina A2/genética , LDL-Colesterol/sangre , Enfermedad Coronaria/sangre , Enfermedad Coronaria/genética , Polimorfismo de Nucleótido Simple , Anexina A2/metabolismo , Biomarcadores/sangre , Biología Computacional , Enfermedad Coronaria/diagnóstico , Bases de Datos Genéticas , Femenino , Frecuencia de los Genes , Genes Reporteros , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Células Hep G2 , Heterocigoto , Homocigoto , Humanos , Células K562 , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Fenotipo , Proproteína Convertasa 9/metabolismo , Sitios de Carácter Cuantitativo , Transfección , Reino Unido
20.
PLoS One ; 11(12): e0167676, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27973560

RESUMEN

BACKGROUND: The Low-Density Lipoprotein Receptor (LDLR) SNP rs6511720 (G>T), located in intron-1 of the gene, has been identified in genome-wide association studies (GWAS) as being associated with lower plasma levels of LDL-C and a lower risk of coronary heart disease (CHD). Whether or not rs6511720 is itself functional or a marker for a functional variant elsewhere in the gene is not known. METHODS: The association of LDLR SNP rs6511720 with incidence of CHD and levels of LDL-C was determined by reference to CARDIoGRAM, C4D and Global lipids genetics consortium (GLGC) data. SNP annotation databases were used to identify possible SNP function and prioritization. Luciferase reporter assays in the liver cell line Huh7 were used to measure the effect of variant genotype on gene expression. Electrophoretic Mobility Shift Assays (EMSAs) were used to identify the Transcription Factors (TFs) involved in gene expression regulation. RESULTS: The phenotype-genotype analysis showed that the rs6511720 minor allele is associated with lower level of LDL-C [beta = -0.2209, p = 3.85 x10-262], and lower risk of CHD [log (OR) = 0.1155, p = 1.04 x10-7]. Rs6511720 is in complete linkage. Rs6511720 is in complete linkage disequilibrium (LD) with three intron-1 SNPs (rs141787760, rs60173709, rs57217136). Luciferase reporter assays in Huh7 cells showed that the rare alleles of both rs6511720 and rs57217136 caused a significant increase in LDLR expression compared to the common alleles (+29% and +24%, respectively). Multiplex Competitor-EMSAs (MC-EMSA) identified that the transcription factor serum response element (SRE) binds to rs6511720, while retinoic acid receptor (RAR) and signal transducer and activator of transcription 1 (STAT1) bind to rs57217136. CONCLUSION: Both LDLR rs6511720 and rs57217136 are functional variants. Both these minor alleles create enhancer-binding protein sites for TFs and may contribute to increased LDLR expression, which is consequently associated with reduced LDL-C levels and 12% lower CHD risk.


Asunto(s)
LDL-Colesterol/metabolismo , Enfermedad de la Arteria Coronaria/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Línea Celular , Ensayo de Cambio de Movilidad Electroforética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Intrones/genética , Desequilibrio de Ligamiento/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
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