ABSTRACT
Obesity and anxiety are morbidities notable for their increased impact on society during the recent COVID-19 pandemic. Understanding the mechanisms governing susceptibility to these conditions will increase quality of life and our resilience to future pandemics. In the current study we explored the function of a highly conserved regulatory region (BE5.1) within the BDNF gene that harbours a polymorphism strongly associated with obesity (rs10767664; p = 4.69x10− 26). Analysis in primary cells suggested that the major T-allele of BE5.1 was an enhancer whereas the obesity associated A-allele was not. However, CRISPR/CAS9 deletion of BE5.1 from the mouse genome (BE5.1KO) produced no significant effect on the expression of BDNF transcripts in the hypothalamus, no change in weight gain after 28 days and only a marginally significant increase in food intake. Nevertheless, transcripts were significantly increased in the amygdala of female mice and elevated zero maze and marble burying tests demonstrated a significant increase in anxiety-like behaviour that could be reversed by diazepam. Consistent with these observations, human GWAS cohort analysis demonstrated a significant association between rs10767664 and anxiousness in human populations. Intriguingly, interrogation of the human GTEx eQTL database demonstrated no effect on BDNF mRNA levels associated with rs10767664 but a highly significant effect on BDNF-antisense (BDNF-AS) gene expression and splicing. The subsequent observation that deletion of BE5.1 also significantly reduced BDNF-AS expression in mice suggests a novel mechanism in the regulation of BDNF expression common to mice and humans which contributes to the modulation of mood and anxiety in both species.
Subject(s)
Anxiety Disorders , Weight Gain , Hypothalamic Neoplasms , Obesity , COVID-19ABSTRACT
Background: To date, COVID-19 has claimed 4.9 million lives. Diabetes has been identified as an independent risk factor of serious outcomes in people with COVID-19 infection. Whether that holds true across world regions uniformly has not been previously assessed.Methods: This study offers the first ONTOP systematic review and meta-analysis to analyse the collective and geographically stratified mortality, ICU admission, ventilation requirement, illness severity and discharge rate among patients with diabetes. Five databases were searched from inception to 30 th of August 2021. Prospective and retrospective cohort studies, reporting the association between diabetes and one or more COVID-19 hospitalization outcomes, were included. This meta-analysis was registered on PROSPERO, CRD42021278579.Findings: Overall, 158 observational studies were included, with a total of 270212 of participants, median age 59 [53-65 IQR] of who 56.5 % were male. A total of 22 studies originated from EU, 90 from Far East, 16 from Middle East, and 30 from America. Data were synthesised with mixed heterogeneity across outcomes. Pooled results highlighted that patients with diabetes were at a higher risk of COVID-19-related mortality, OR 1.87 [95%CI 1.61, 2.17]. ICU admissions were increased across all studies for patients with diabetes, OR 1.59 [95%CI 1.15, 2.18], a result that was mainly skewed by Far East-originating studies, OR 1.94 [95%CI 1.51, 2.49]. Ventilation requirements were also increased amongst patients with diabetes worldwide, OR 1.44 [95%CI 1.20, 1.73] as well as their presentation with severe or critical condition, OR 2.88 [95%CI 2.29, 3.63]. HbA1C levels under < 70 mmol and metformin use constituted protective factors in view of COVID-19 mortality, while the inverse was true for concurrent insulin use.Interpretation: Whilst diabetes constitutes a poor prognosticator for various COVID-19 infection outcomes, variability across world regions is significant and may skew overall trends.Registration Details: This meta-analysis was registered on PROSPERO, CRD42021278579.Funding Information: No funding was received for the presented work.Declaration of Interests: The authors have no conflict of interest to declare.
Subject(s)
COVID-19 , Diabetes MellitusABSTRACT
Obesity and anxiety are morbidities notable for their increased impact on society during the recent COVID-19 pandemic. Understanding the mechanisms governing susceptibility to these conditions will increase quality of life and our resilience to future pandemics. In the current study we explored the function of a highly conserved regulatory region (BE5.1) within the BDNF gene that harbours a polymorphism strongly associated with obesity (rs10767664; p=4.69×10 −26 ). Analysis in primary cells suggested that the major T-allele of BE5.1 was an enhancer whereas the obesity associated A-allele was not. However, CRISPR/CAS9 deletion of BE5.1 from the mouse genome (BE5.1KO) produced no significant effect on the expression of BDNF transcripts in the hypothalamus, no change in weight gain after 28 days and only a marginally significant increase in food intake. Nevertheless, transcripts were significantly increased in the amygdala of female mice and elevated zero maze and marble burying tests demonstrated a significant increase in anxiety-like behaviour that could be reversed by diazepam. Consistent with these observations, human GWAS cohort analysis demonstrated a significant association between rs10767664 and anxiousness in human populations. Intriguingly, interrogation of the human GTEx eQTL database demonstrated no effect on BDNF mRNA levels associated with rs10767664 but a highly significant effect on BDNF-antisense (BDNF-AS) gene expression and splicing suggesting a possible mechanism. We discuss our findings within the context of the known function and regulation of BDNF in obesity and anxiety whilst exploring the validity of interrogating GWAS data using comparative genomics and functional analysis using CRISPR genome editing in mice.