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1.
Gene ; 825: 146442, 2022 May 30.
Article in English | MEDLINE | ID: covidwho-1783331

ABSTRACT

BACKGROUND: Our previous bivariate genome-wide association study in dizygotic twins suggested that the olfactory transduction pathway genes were associated with obesity in Northern Han Chinese adults. In this study, we attempted to verify the associations of the olfactory transduction pathway genes score with obesity in population with the same genetic background, and to estimate the interaction between gene variants and potential environment factors. METHODS: A case-control study was conducted in Qingdao, China in 2019-2021, which enrolled 301 obesity cases and 307 controls. Based on the candidate gene selection method, 29 single nucleotide polymorphisms (SNPs) in 7 olfactory pathway genes were selected. Genomic deoxyribonucleic acid (DNA) was isolated and purified from the peripheral blood leukocytes by using DNA extraction kits and was genotyped by the MassArray system. The weighted genetic score of each gene was calculated to analyze the effect of whole gene. The effect of gene scores on obesity and the gene-environment interaction were estimated by logistic regression. RESULTS: After adjusting for age, sex, smoking, alcohol drinking, physical activity, we observed positive associations of OR4D1 (OR = 1.531, 95% CI = 1.083-2.164, P = 0.016) and OR52K1 (OR = 1.437, 95% CI = 1.055-1.957, P = 0.022) gene scores with obesity, as well as negative associations of OR2L8 (OR = 0.708, 95% CI = 0.504-0.995, P = 0.046) and CALML3 (OR = 0.601, 95% CI = 0.410-0.881, P = 0.009) gene scores with obesity. Significant multiplicative model interaction between OR4D1 and smoking (Pinteraction = 0.041) as well as CALML3 and smoking (Pinteraction = 0.026) on obesity were identified. Stratified analysis showed that in smokers, OR4D1 gene score was positively associated with obesity (OR = 2.673, 95% CI = 1.348-5.299, P = 0.005) and CALML3 gene score was negatively correlated with obesity (OR = 0.252, 95% CI = 0.103-0.618, P = 0.003). The relationships were not statistically significant in non-smokers (OR4D1: OR = 1.216, 95% CI = 0.806-1.836, P = 0.351; CALML3: OR = 0.764, 95% CI = 0.492-1.188, P = 0.232). CONCLUSIONS: Genetic variations in the olfactory pathway were associated with obesity in Northern Han Chinese adults. Smoking modified the effect of OR4D1 and CALML3 gene variants on obesity.


Subject(s)
Genome-Wide Association Study , Olfactory Pathways , Adult , Case-Control Studies , China/epidemiology , DNA , Genetic Predisposition to Disease , Humans , Obesity/genetics , Polymorphism, Single Nucleotide , Risk Factors
3.
Biosci Rep ; 42(3)2022 03 31.
Article in English | MEDLINE | ID: covidwho-1713232

ABSTRACT

The adipose tissue (AT) has a major role in contributing to obesity-related pathologies through regulating systemic immunometabolism. The pathogenicity of the AT is underpinned by its remarkable plasticity to be reprogrammed during obesity, in the perspectives of tissue morphology, extracellular matrix (ECM) composition, angiogenesis, immunometabolic homoeostasis and circadian rhythmicity. Dysregulation in these features escalates the pathogenesis conferred by this endometabolic organ. Intriguingly, the potential to be reprogrammed appears to be an Achilles' heel of the obese AT that can be targeted for the management of obesity and its associated comorbidities. Here, we provide an overview of the reprogramming processes of white AT (WAT), with a focus on their dynamics and pleiotropic actions over local and systemic homoeostases, followed by a discussion of potential strategies favouring therapeutic reprogramming. The potential involvement of AT remodelling in the pathogenesis of COVID-19 is also discussed.


Subject(s)
COVID-19 , Adipose Tissue/pathology , Adipose Tissue, White/pathology , Humans , Obesity/genetics , Obesity/pathology , SARS-CoV-2
4.
Metabolism ; 129: 155156, 2022 04.
Article in English | MEDLINE | ID: covidwho-1654927

ABSTRACT

BACKGROUND: Both obesity and type 2 diabetes (T2D) are reported to be highly enriched in hospitalized COVID-19 patients. Due to the close correlation between obesity and T2D, it is important to examine whether obesity and T2D are independently related to COVID-19 hospitalization. OBJECTIVE: To examine the causal effect of obesity and T2D in hospitalized COVID-19 patients using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS: This two-sample MR analysis applied genetic markers of obesity identified in the genome wide association study (GWAS) by the GIANT Consortium as instrumental variables (IVs) of obesity; and genetic markers of T2D identified by the DIAGRAM Consortium as IVs of T2D. The MR analysis was performed in hospitalized COVID-19 patient by the COVID-19 Host Genetics Initiative using the MR-Base platform. RESULTS: All 3 classes of obesity (Class 1/2/3) were shown as the causal risk factors of COVID-19 hospitalization; however, T2D doesn't increase the risk of hospitalization or critically ill COVID-19 as an independent factor. CONCLUSIONS: Obesity, but not T2D, is a primary risk factor of COVID-19 hospitalization.


Subject(s)
COVID-19/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Hospitalization/statistics & numerical data , Mendelian Randomization Analysis , Obesity/epidemiology , SARS-CoV-2 , Body Mass Index , COVID-19/genetics , COVID-19/therapy , Causality , Comorbidity , Diabetes Mellitus, Type 2/genetics , Genome-Wide Association Study , Humans , Obesity/classification , Obesity/genetics , Polymorphism, Single Nucleotide/genetics , Risk Factors , Severity of Illness Index
5.
Obesity (Silver Spring) ; 30(4): 869-873, 2022 04.
Article in English | MEDLINE | ID: covidwho-1633996

ABSTRACT

OBJECTIVE: The triad of obesity, a high-protein diet from animal sources, and disturbed gut microbiota have been linked to poor clinical outcomes in patients with COVID-19. In this report, the effect of oxidative stress resulting from the Na+ /K+ -ATPase transporter signaling cascade is explored as a driver of this poor clinical outcome. METHODS: Protein-protein interactions with the SARS-CoV-2 proteome were identified from the interactome data for Na+ /K+ -transporting ATPase subunit α-1 (ATP1A1), epidermal growth factor receptor, and ERB-B2 receptor tyrosine kinase 2, using the curated data from the BioGRID Database of Protein Interactions. Data for the gene expression pattern of inflammatory response were from the Gene Expression Omnibus database for cardiomyocytes post SARS-CoV-2 infection (number GSE151879). RESULTS: The ATP1A1 subunit of the Na+ /K+ -ATPase transporter is targeted by multiple SARS-CoV-2 proteins. Furthermore, receptor proteins associated with inflammatory response, including epidermal growth factor receptor and ERB-B2 receptor tyrosine kinase 2 (which interact with ATP1A1), are also targeted by some SARS-CoV-2 proteins. This heightened interaction likely triggers a cytokine release that increases the severity of the viral infection in individuals with obesity. CONCLUSIONS: The similarities between the effects of SARS-CoV-2 proteins and indoxyl sulphate on the Na+ /K+ -ATPase transporter signaling cascade suggest the possibility of an augmentation of gene changes seen with COVID-19 infection that can result in a hyperinduction of cytokine release in individuals with obesity.


Subject(s)
COVID-19 , Gastrointestinal Microbiome , Animals , Diet , Humans , Obesity/genetics , SARS-CoV-2 , Sodium-Potassium-Exchanging ATPase/genetics , Sodium-Potassium-Exchanging ATPase/metabolism
6.
Obes Facts ; 15(1): 90-98, 2022.
Article in English | MEDLINE | ID: covidwho-1571513

ABSTRACT

INTRODUCTION: Neuropilin 1 (NRP-1) is a novel co-receptor promoting SARS-CoV-2 infectivity. Animal data indicate a role in trans-endothelial lipid transport and storage. As human data are sparse, we aimed to assess the role of NRP-1 in 2 metabolic active tissues in human obesity and in the context of weight loss-induced short- and long-term metabolic changes. METHODS: After a standardized 12-week weight reduction program, 143 subjects (age >18; body mass index ≥27 kg/m2, 78% female) were randomized to a 12-month lifestyle intervention or a control group using a stratified randomization scheme. This was followed by 6-month follow-up without any intervention. Phenotyping was performed before and after weight loss, after 12-month intervention and after subsequent 6 months of follow-up. Tissue-specific insulin sensitivity was estimated by HOMA-IR (whole body and mostly driven by liver), insulin sensitivity index (ISI)Clamp (predominantly skeletal muscle), and free fatty acid (FFA) suppression during hyperinsulinemic-euglycemic clamp (FFASupp) (predominantly adipose tissue). NRP-1 mRNA expression was measured in subcutaneous adipose tissue (NRP-1AT) and skeletal muscle (NRP-1SM) before and after weight loss. RESULTS: NRP-1 was highly expressed in adipose tissue (7,893 [7,303-8,536] counts), but neither NRP-1AT nor NRP-1SM were related to estimates of obesity. Higher NRP-1AT was associated with stronger FFASupp (r = -0.343, p = 0.003) and a tendency to higher ISIClamp (r = 0.202, p = 0.085). Weight loss induced a decline of NRP-1AT but not NRP-1SM. This was more pronounced in subjects with stronger reduction of adipose ACE-2 mRNA expression (r = 0.250; p = 0.032) but was not associated with short- and long-term improvement of FFASupp and ISIClamp. CONCLUSION: NRP-1AT is related to adipose insulin sensitivity in obesity. Weight loss-induced decline of NRP-1AT seems not to be involved in metabolic short- and long-term improvements after weight loss. However, weight loss-induced reduction of both NRP-1AT and ACE-2AT indicates a lower susceptibility of adipose tissue for SARS-CoV-2 after body weight reduction.


Subject(s)
COVID-19 , Insulin Resistance , Adipose Tissue , Female , Humans , Male , Neuropilin-1/genetics , Obesity/genetics , RNA, Messenger , SARS-CoV-2 , Weight Loss
7.
Genes (Basel) ; 12(10)2021 09 26.
Article in English | MEDLINE | ID: covidwho-1480689

ABSTRACT

Trefoil Factor Family Member 2 (TFF2) belongs to TFF family peptides that includes TFF1, TFF2, TFF3. TFF2 is mainly known for its roles in the mucosal protection. In the context of obesity and high fat diet (HFD), Tff2 has been characterized as a HFD-induced gene. The knock-out of Tff2 in mice lead to the protection from HFD-induced obesity with a metabolic profile towards a negative energy balance. Such HFD-specific expression gives Tff2 a pattern worth exploring in biomedical research. Indeed, measuring TFF2/TFF2/Tff2 expression in biological samples following the ingestion of high-fat diet reflects the biological "responsiveness" to the lipids ingestion and would reflect the severity of obesity establishment afterwards. Such property could be explored for instance to screen animal models, evaluate the predisposition to HFD-induced obesity as well as in biomedical and clinical applications. Results might advance obesity research especially in terms of understanding lipid-induced signals, appetite control and adiposity storage.


Subject(s)
Obesity/metabolism , Trefoil Factor-2/genetics , Animals , Diet, High-Fat/adverse effects , Humans , Obesity/etiology , Obesity/genetics , Obesity/pathology , Trefoil Factor-2/metabolism
8.
Surg Obes Relat Dis ; 16(12): 1910-1918, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1454528

ABSTRACT

BACKGROUND: Bariatric surgery is well established as a treatment for obesity and associated complications. This procedure improves metabolic homeostasis through changes in energy expenditure. We hypothesized that sleeve gastrectomy (SG) improves metabolic homeostasis by modulating energy expenditure and enhancing thermogenesis through increasing the expression level of meteorin-like protein (METRNL) and fibronectin type III domain-containing protein 5 (FNDC5/Irisin) through uncoupling proteins 1/2/3 (UCP1, UCP2, and UCP3). OBJECTIVES: To study the effect of SG on the levels of proteins involved in thermogenesis process. SETTING: Laboratory rats at Kuwait University. METHODS: Male Sprague-Dawley rats, aged 4 to 5 weeks, were divided into 2 groups, control (n = 11) and diet-induced obesity (DIO) (n = 22). The control group was fed regular rat chow ad libitum, whereas the DIO group was fed cafeteria diet "high-fat/carbohydrate diet" ad libitum. At 21 weeks, rats in the DIO group that weighed 20% more than the control group animals underwent surgery. These rats were randomly subdivided into Sham and SG operation groups. Gene expression was evaluated, and enzyme-linked immunosorbent assays were employed to assess the changes in gene and protein levels in tissue and circulation. RESULTS: The protein expression data revealed an increase in METRNL levels in the muscles and white adipose tissue of SG animals. METRNL level in circulation in SG animals was reduced compared with control and Sham rats. The level of Irisin increased in the muscle of SG animals compared with the control and Sham group animals; however, a decrease in Irisin level was observed in the white adipose tissue and brown adipose tissue of SG animals compared with controls. Gene expression analysis revealed decreased METRNL levels in muscle tissues in the SG group compared with the control group animals. Increased expression of FNDC5 (Irisin), UCP2, and UCP3 in the muscle tissue of SG animals was also observed. Furthermore, the levels of UCP1, UCP2, UCP3, and METRNL in the brown adipose tissue of SG animals were upregulated. No significant alteration in the gene expression of Irisin was observed in brown adipose tissue. CONCLUSIONS: Sleeve gastrectomy induces weight loss through complex mechanisms that may include browning of fat.


Subject(s)
Adipose Tissue, Brown , Obesity , Adipose Tissue/metabolism , Animals , Diet , Fibronectins/genetics , Fibronectins/metabolism , Gastrectomy , Kuwait , Male , Mitochondrial Uncoupling Proteins , Muscles/metabolism , Obesity/genetics , Obesity/surgery , Rats , Rats, Sprague-Dawley
9.
Eur J Clin Invest ; 52(2): e13685, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1440744

ABSTRACT

BACKGROUND: Obesity was consistently associated with a poor prognosis in patients with COVID-19. Epigenetic mechanisms were proposed as the link between obesity and comorbidities risk. AIM: To evaluate the methylation levels of angiotensin-converting enzyme 2 (ACE2) gene, the main entry receptor of SARS-CoV-2, in different depots of adipose tissue (AT) and leukocytes (PBMCs) in obesity and after weight loss therapy based on a very-low-calorie ketogenic diet (VLCKD), a balanced hypocaloric diet (HCD) or bariatric surgery (BS). MATERIALS AND METHODS: DNA methylation levels of ACE2 were extracted from our data sets generated by the hybridization of subcutaneous (SAT) (n = 32) or visceral (VAT; n = 32) adipose tissue, and PBMCs (n = 34) samples in Infinium HumanMethylation450 BeadChips. Data were compared based on the degree of obesity and after 4-6 months of weight loss either by following a nutritional or surgical treatment and correlated with ACE2 transcript levels. RESULTS: As compared with normal weight, VAT from patients with obesity showed higher ACE2 methylation levels. These differences were mirrored in PBMCs but not in SAT. The observed obesity-associated methylation of ACE2 was reversed after VLCKD and HCD but not after BS. Among the studied CpG sites, cg16734967 and cg21598868, located at the promoter, were the most affected and correlated with BMI. The observed DNA methylation pattern was inversely correlated with ACE2 expression. CONCLUSION: Obesity-related VAT shows hypermethylation and downregulation of the ACE2 gene that is mirrored in PBMCs and is restored after nutritional weight reduction therapy. The results warrant the necessity to further evaluate its implication for COVID-19 pathogenesis.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Intra-Abdominal Fat/metabolism , Leukocytes, Mononuclear/metabolism , Obesity/genetics , Receptors, Coronavirus/genetics , Subcutaneous Fat/metabolism , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Bariatric Surgery , COVID-19 , DNA Methylation , Diet, Ketogenic , Diet, Reducing , Female , Gene Expression Regulation , Humans , Male , Middle Aged , Obesity/metabolism , Obesity/therapy , Obesity, Morbid/genetics , Obesity, Morbid/metabolism , Obesity, Morbid/therapy , Receptors, Coronavirus/metabolism , SARS-CoV-2 , Weight Loss
10.
Hum Mol Genet ; 31(3): 471-480, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1434399

ABSTRACT

Symptoms related with gastro-esophageal reflux disease (GERD) were previously shown to be linked with increased risk for the 2019 coronavirus disease (COVID-19). We aim to interrogate the possibility of a shared genetic basis between GERD and COVID-19 outcomes. Using published GWAS data for GERD (78 707 cases; 288 734 controls) and COVID-19 susceptibility (up to 32 494 cases; 1.5 million controls), we examined the genetic relationship between GERD and three COVID-19 outcomes: risk of developing severe COVID-19, COVID-19 hospitalization and overall COVID-19 risk. We estimated the genetic correlation between GERD and COVID-19 outcomes followed by Mendelian randomization (MR) analyses to assess genetic causality. Conditional analyses were conducted to examine whether known COVID-19 risk factors (obesity, smoking, type-II diabetes, coronary artery disease) can explain the relationship between GERD and COVID-19. We found small to moderate genetic correlations between GERD and COVID-19 outcomes (rg between 0.06 and 0.24). MR analyses revealed a OR of 1.15 (95% CI: 0.96-1.39) for severe COVID-19; 1.16 (1.01-1.34) for risk of COVID-19 hospitalization; 1.05 (0.97-1.13) for overall risk of COVID-19 per doubling of odds in developing GERD. The genetic correlation/associations between GERD and COVID-19 showed mild attenuation towards the null when obesity and smoking was adjusted for. Susceptibility for GERD and risk of COVID-19 hospitalization were genetically correlated, with MR findings supporting a potential causal role between the two. The genetic association between GERD and COVID-19 was partially attenuated when obesity is accounted for, consistent with obesity being a major risk factor for both diseases.


Subject(s)
COVID-19/genetics , Diabetes Mellitus, Type 2/genetics , Gastroesophageal Reflux/genetics , Genetic Predisposition to Disease , Body Mass Index , COVID-19/complications , COVID-19/virology , Coronary Artery Disease/complications , Coronary Artery Disease/genetics , Coronary Artery Disease/virology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/virology , Female , Gastroesophageal Reflux/complications , Gastroesophageal Reflux/virology , Genome-Wide Association Study , Hospitalization , Humans , Male , Mendelian Randomization Analysis , Obesity/complications , Obesity/genetics , Obesity/virology , Polymorphism, Single Nucleotide , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index , Smoking/adverse effects
11.
PLoS One ; 16(9): e0256988, 2021.
Article in English | MEDLINE | ID: covidwho-1394552

ABSTRACT

Epidemiological studies suggest that individuals with comorbid conditions including diabetes, chronic lung, inflammatory and vascular disease, are at higher risk of adverse COVID-19 outcomes. Genome-wide association studies have identified several loci associated with increased susceptibility and severity for COVID-19. However, it is not clear whether these associations are genetically determined or not. We used a Phenome-Wide Association (PheWAS) approach to investigate the role of genetically determined COVID-19 susceptibility on disease related outcomes. PheWAS analyses were performed in order to identify traits and diseases related to COVID-19 susceptibility and severity, evaluated through a predictive COVID-19 risk score. We utilised phenotypic data in up to 400,000 individuals from the UK Biobank, including Hospital Episode Statistics and General Practice data. We identified a spectrum of associations between both genetically determined COVID-19 susceptibility and severity with a number of traits. COVID-19 risk was associated with increased risk for phlebitis and thrombophlebitis (OR = 1.11, p = 5.36e-08). We also identified significant signals between COVID-19 susceptibility with blood clots in the leg (OR = 1.1, p = 1.66e-16) and with increased risk for blood clots in the lung (OR = 1.12, p = 1.45 e-10). Our study identifies significant association of genetically determined COVID-19 with increased blood clot events in leg and lungs. The reported associations between both COVID-19 susceptibility and severity and other diseases adds to the identification and stratification of individuals at increased risk, adverse outcomes and long-term effects.


Subject(s)
COVID-19/genetics , Obesity/genetics , Thrombophlebitis/genetics , Thrombosis/genetics , COVID-19/epidemiology , COVID-19/virology , Cardiovascular Diseases/genetics , Cardiovascular Diseases/pathology , Cardiovascular Diseases/virology , Female , Genetic Predisposition to Disease , Humans , Male , Mendelian Randomization Analysis , Obesity/epidemiology , Obesity/virology , Phenomics , Phenotype , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2/pathogenicity , Thrombophlebitis/epidemiology , Thrombophlebitis/virology , Thrombosis/epidemiology , Thrombosis/virology
13.
Clin Nutr ESPEN ; 44: 475-478, 2021 08.
Article in English | MEDLINE | ID: covidwho-1242904

ABSTRACT

BACKGROUND & AIMS: Obesity is associated with low grade systemic inflammation and insulin resistance. Although metabolic and immunological changes may contribute to the increased risk for COVID-19 mortality in obese, little is known about the impact of obesity in the lungs of patients with COVID-19. METHODS: We analyzed gene expression profiles of autopsy lungs of a cohort of 14 COVID-19 patients and 4 control individuals. Patients were divided into 3 groups according to their comorbidities: hypertension, type 2 diabetes (T2D) and obesity. We then identified the molecular alterations associated with these comorbidities in COVID-19 patients. RESULTS: Patients with only hypertension showed higher levels of inflammatory genes and B-cell related genes when compared to those with T2D and obesity. However, the levels of IFN-gamma, IL22, and CD274 (a ligand that binds to receptor PD1) were higher in COVID-19 patients with T2D and obesity. Several metabolic- and immune-associated genes such as G6PD, LCK and IL10 were significantly induced in the lungs of the obese group. CONCLUSION: Our findings suggest that SARS-CoV-2 infection in the lungs may exacerbate the immune response and chronic condition in obese COVID-19 patients.


Subject(s)
COVID-19/complications , COVID-19/genetics , Gene Expression/genetics , Lung/immunology , Obesity/complications , Obesity/genetics , Autopsy , COVID-19/immunology , Cohort Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/immunology , Humans , Hypertension/complications , Hypertension/genetics , Hypertension/immunology , Obesity/immunology , SARS-CoV-2
14.
Int J Mol Sci ; 22(10)2021 May 17.
Article in English | MEDLINE | ID: covidwho-1234744

ABSTRACT

The global coronavirus disease 2019 (COVID-19) pandemic was associated with multiple organ failure and comorbidities, such as type 2 diabetes mellitus (T2DM). Risk factors, such as age, gender, and obesity, were associated with COVID-19 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to use several host receptors for viral entry, such as angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the lung and other organs. However, ACE2 could be shed from the surface to be soluble ACE2 (sACE2) in the circulation. The epigenetic factors affecting ACE2 expression include a type of small non-coding RNAs called microRNAs (miRNAs). In this study, we aimed at exploring the status of the sACE2 as well as serum levels of several upstream novel miRNAs as non-invasive biomarkers that might have a potential role in T2DM patients. Serum samples were collected from 50 T2DM patients and 50 healthy controls, and sACE2 levels were quantified using enzyme-linked immunosorbent assay (ELISA). Also, RNA was extracted, and TaqMan miRNA reverse transcription quantitative PCR (RT-qPCR) was performed to measure serum miRNA levels. Our results revealed that sACE2 is decreased in the T2DM patients and is affected by age, gender, and obesity level. Additionally, 4 miRNAs, which are revealed by in silico analysis to be potentially upstream of ACE2 were detectable in the serum. Among them, miR-421 level was found to be decreased in the serum of diabetic patients, regardless of the presence or absence of diabetic complications, as well as being differential in various body mass index (BMI) groups. The other 3 miRNAs (miR-3909, miR-212-5p, and miR-4677-3p) showed associations with multiple factors including age, gender, BMI, and serum markers, in addition to being correlated to each other. In conclusion, our study reveals a decline in the circulating serum levels of sACE2 in T2DM patients and identified 4 novel miRNAs that were associated with T2DM, which are influenced by different clinical and demographic factors.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , Diabetes Complications/blood , Diabetes Mellitus, Type 2/blood , MicroRNAs/blood , Adult , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Biomarkers/blood , Body Mass Index , COVID-19/blood , COVID-19/complications , COVID-19/genetics , Diabetes Complications/genetics , Diabetes Complications/virology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/virology , Down-Regulation , Female , Gene Expression Regulation/genetics , Humans , Male , MicroRNAs/genetics , Middle Aged , Obesity/blood , Obesity/genetics
15.
Nutrients ; 13(5)2021 May 10.
Article in English | MEDLINE | ID: covidwho-1224082

ABSTRACT

BACKGROUND: Acute and chronic alcohol abuse has adverse impacts on both the innate and adaptive immune response, which may result in reduced resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and promote the progression of coronavirus disease 2019 (COVID-19). However, there are no large population-based data evaluating potential causal associations between alcohol consumption and COVID-19. METHODS: We conducted a Mendelian randomization study using data from UK Biobank to explore the association between alcohol consumption and risk of SARS-CoV-2 infection and serious clinical outcomes in patients with COVID-19. A total of 12,937 participants aged 50-83 who tested for SARS-CoV-2 between 16 March to 27 July 2020 (12.1% tested positive) were included in the analysis. The exposure factor was alcohol consumption. Main outcomes were SARS-CoV-2 positivity and death in COVID-19 patients. We generated allele scores using three genetic variants (rs1229984 (Alcohol Dehydrogenase 1B, ADH1B), rs1260326 (Glucokinase Regulator, GCKR), and rs13107325 (Solute Carrier Family 39 Member 8, SLC39A8)) and applied the allele scores as the instrumental variables to assess the effect of alcohol consumption on outcomes. Analyses were conducted separately for white participants with and without obesity. RESULTS: Of the 12,937 participants, 4496 were never or infrequent drinkers and 8441 were frequent drinkers. Both logistic regression and Mendelian randomization analyses found no evidence that alcohol consumption was associated with risk of SARS-CoV-2 infection in participants either with or without obesity (All q > 0.10). However, frequent drinking, especially heavy drinking (HR = 2.07, 95%CI 1.24-3.47; q = 0.054), was associated with higher risk of death in patients with obesity and COVID-19, but not in patients without obesity. Notably, the risk of death in frequent drinkers with obesity increased slightly with the average amount of alcohol consumed weekly (All q < 0.10). CONCLUSIONS: Our findings suggest that alcohol consumption has adverse effects on the progression of COVID-19 in white participants with obesity, but was not associated with susceptibility to SARS-CoV-2 infection.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Alcohol Dehydrogenase/genetics , Alcohol Drinking , Biological Specimen Banks , COVID-19 , Cation Transport Proteins/genetics , Obesity , Polymorphism, Single Nucleotide , SARS Virus , Aged , Alcohol Drinking/genetics , Alcohol Drinking/mortality , COVID-19/genetics , COVID-19/mortality , Disease-Free Survival , Female , Humans , Male , Mendelian Randomization Analysis , Middle Aged , Obesity/genetics , Obesity/mortality , Survival Rate , United Kingdom/epidemiology
16.
Physiol Rev ; 101(4): 1745-1807, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1216831

ABSTRACT

The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical, and experimental evidence supports the existence of a unique disease entity termed "obesity cardiomyopathy," which develops independent of hypertension, coronary heart disease, and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.


Subject(s)
Cardiomyopathies/etiology , Cardiomyopathies/pathology , Obesity/complications , COVID-19/complications , COVID-19/mortality , Cardiomyopathies/mortality , Humans , Obesity/etiology , Obesity/genetics , SARS-CoV-2
17.
Genome Med ; 13(1): 66, 2021 04 21.
Article in English | MEDLINE | ID: covidwho-1197350

ABSTRACT

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.


Subject(s)
Bronchi , COVID-19/genetics , Respiratory Mucosa , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Asthma/genetics , COVID-19/immunology , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Gene Expression , Genetic Variation , Humans , Middle Aged , Obesity/genetics , Obesity/immunology , Pulmonary Disease, Chronic Obstructive/genetics , Quantitative Trait Loci , Risk Factors , Smoking/genetics
18.
J Mol Med (Berl) ; 99(7): 899-915, 2021 07.
Article in English | MEDLINE | ID: covidwho-1171990

ABSTRACT

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has proven a challenge to healthcare systems since its first appearance in late 2019. The global spread and devastating effects of coronavirus disease 2019 (COVID-19) on patients have resulted in countless studies on risk factors and disease progression. Overweight and obesity emerged as one of the major risk factors for developing severe COVID-19. Here we review the biology of coronavirus infections in relation to obesity. In particular, we review literature about the impact of adiposity-related systemic inflammation on the COVID-19 disease severity, involving cytokine, chemokine, leptin, and growth hormone signaling, and we discuss the involvement of hyperactivation of the renin-angiotensin-aldosterone system (RAAS). Due to the sheer number of publications on COVID-19, we cannot be completed, and therefore, we apologize for all the publications that we do not cite.


Subject(s)
COVID-19/genetics , Inflammation/genetics , Obesity/genetics , SARS-CoV-2/genetics , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Disease Progression , Humans , Inflammation/complications , Inflammation/pathology , Inflammation/virology , Obesity/complications , Obesity/pathology , Obesity/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Renin-Angiotensin System/genetics , Risk Factors , SARS-CoV-2/pathogenicity
19.
Cell ; 184(6): 1530-1544, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-1118348

ABSTRACT

The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.


Subject(s)
COVID-19/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/therapy , Obesity/epidemiology , Obesity/therapy , Pandemics , Precision Medicine/methods , SARS-CoV-2 , COVID-19/virology , Circadian Rhythm , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Epigenesis, Genetic , Genetic Predisposition to Disease , Humans , Inflammation/immunology , Inflammation/metabolism , Obesity/genetics , Obesity/metabolism , Prevalence , Risk Factors , Thermotolerance
20.
Wien Klin Wochenschr ; 133(7-8): 383-392, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1086590

ABSTRACT

The current review critically analyzes obesity as an important risk factor for increased predisposition towards coronavirus disease 2019 (COVID-19), its severity and causal death in current pandemic. Countries with higher prevalence of exposed obese individuals experienced the highest number of mortalities. The analysis also proved that individuals having more adipose tissue in body have a higher level of angiotensin-converting enzyme 2 (ACE2), which is identified as functional receptor for COVID-19. Therefore, obese individuals are worse in condition because of a higher presence of adiposity increases the number of ACE2 expressing cells. Furthermore, in silico interactions of ACE2 and different variants of coronavirus 2 (CoV-2) spike S1 protein suggest that mutant strains are more infectious than wildtype as they bind to host ACE2 protein with high binding affinities. Certain specific cancers including cervical cancer, pancreatic and rectal adenocarcinomas have more expression of such receptors and pose additional risk to already immunocompromised cancer patients. This review emphasizes obesity, as the covert risk factor of COVID-19 infection and sensitizes about of calorie restrictions, immunity building and preventive measures.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Obesity/epidemiology , Obesity/genetics , Protein Binding , Spike Glycoprotein, Coronavirus/metabolism
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