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International Journal of Obesity (2005) Jun 2021Childhood obesity is a complex multifaceted condition, which is influenced by genetics, environmental factors, and their interaction. However, these interactions have...
BACKGROUND
Childhood obesity is a complex multifaceted condition, which is influenced by genetics, environmental factors, and their interaction. However, these interactions have mainly been studied in twin studies and evidence from population-based cohorts is limited. Here, we analyze the interaction of an obesity-related genome-wide polygenic risk score (PRS) with sociodemographic and lifestyle factors for BMI and waist circumference (WC) in European children and adolescents.
METHODS
The analyses are based on 8609 repeated observations from 3098 participants aged 2-16 years from the IDEFICS/I.Family cohort. A genome-wide polygenic risk score (PRS) was calculated using summary statistics from independent genome-wide association studies of BMI. Associations were estimated using generalized linear mixed models adjusted for sex, age, region of residence, parental education, dietary intake, relatedness, and population stratification.
RESULTS
The PRS was associated with BMI (beta estimate [95% confidence interval (95%-CI)] = 0.33 [0.30, 0.37], r = 0.11, p value = 7.9 × 10) and WC (beta [95%-CI] = 0.36 [0.32, 0.40], r = 0.09, p value = 1.8 × 10). We observed significant interactions with demographic and lifestyle factors for BMI as well as WC. Children from Southern Europe showed increased genetic liability to obesity (BMI: beta [95%-CI] = 0.40 [0.34, 0.45]) in comparison to children from central Europe (beta [95%-CI] = 0.29 [0.23, 0.34]), p-interaction = 0.0066). Children of parents with a low level of education showed an increased genetic liability to obesity (BMI: beta [95%-CI] = 0.48 [0.38, 0.59]) in comparison to children of parents with a high level of education (beta [95%-CI] = 0.30 [0.26, 0.34]), p-interaction = 0.0012). Furthermore, the genetic liability to obesity was attenuated by a higher intake of fiber (BMI: beta [95%-CI] interaction = -0.02 [-0.04,-0.01]) and shorter screen times (beta [95%-CI] interaction = 0.02 [0.00, 0.03]).
CONCLUSIONS
Our results highlight that a healthy childhood environment might partly offset a genetic predisposition to obesity during childhood and adolescence.
Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Europe; Female; Genome-Wide Association Study; Humans; Life Style; Male; Pediatric Obesity; Social Factors
PubMed: 33753884
DOI: 10.1038/s41366-021-00795-5 -
American Journal of Preventive... Jun 2024Triglycerides play a crucial role in the efficient storage of energy in the body. Mild and moderate hypertriglyceridemia (HTG) is a heterogeneous disorder with...
Triglycerides play a crucial role in the efficient storage of energy in the body. Mild and moderate hypertriglyceridemia (HTG) is a heterogeneous disorder with significant association with atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction, ischemic stroke, and peripheral artery disease and represents an important component of the residual ASCVD risk in statin treated patients despite optimal low-density lipoprotein cholesterol reduction. Individuals with severe HTG (>1,000 mg/dL) rarely develop atherosclerosis but have an incremental incidence of acute pancreatitis with significant morbidity and mortality. HTG can occur from a combination of genetic (both mono and polygenic) and environmental factors including poor diet, low physical activity, obesity, medications, and diseases like insulin resistance and other endocrine pathologies. HTG represents a potential target for ASCVD risk and pancreatitis risk reduction, however data on ASCVD reduction by treating HTG is still lacking and HTG-associated acute pancreatitis occurs too rarely to effectively demonstrate treatment benefit. In this review, we address the key aspects of HTG pathophysiology and examine the mechanisms and background of current and emerging therapies in the management of HTG.
PubMed: 38584606
DOI: 10.1016/j.ajpc.2024.100648 -
Nutrients Aug 2022Diabetes has reached epidemic proportions worldwide. Currently, approximately 537 million adults (20-79 years) have diabetes, and the total number of people with... (Review)
Review
Diabetes has reached epidemic proportions worldwide. Currently, approximately 537 million adults (20-79 years) have diabetes, and the total number of people with diabetes is continuously increasing. Diabetes includes several subtypes. About 80% of all cases of diabetes are type 2 diabetes (T2D). T2D is a polygenic disease with an inheritance ranging from 30 to 70%. Genetic and environment/lifestyle factors, especially obesity and sedentary lifestyle, increase the risk of T2D. In this review, we discuss how studies on the genetics of diabetes started, how they expanded when genome-wide association studies and exome and whole-genome sequencing became available, and the current challenges in genetic studies of diabetes. T2D is heterogeneous with respect to clinical presentation, disease course, and response to treatment, and has several subgroups which differ in pathophysiology and risk of micro- and macrovascular complications. Currently, genetic studies of T2D focus on these subgroups to find the best diagnoses and treatments for these patients according to the principles of .
Topics: Adult; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Obesity; Sedentary Behavior
PubMed: 35956377
DOI: 10.3390/nu14153201 -
Diabetes, Metabolic Syndrome and... 2023Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases in Western countries, and its incidence is constantly increasing. Epidemiological studies have... (Review)
Review
Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases in Western countries, and its incidence is constantly increasing. Epidemiological studies have shown that in the next 20 years. The number of subjects affected by T2DM will double. In recent years, owing to the development and improvement in methods for studying the genome, several authors have evaluated the association between monogenic or polygenic genetic alterations and the development of metabolic diseases and complications. In addition, sedentary lifestyle and socio-economic and pandemic factors have a great impact on the habits of the population and have significantly contributed to the increase in the incidence of metabolic disorders, obesity, T2DM, metabolic syndrome, and liver steatosis. Moreover, patients with type 2 diabetes appear to respond to antihyperglycemic drugs. Only a minority of patients could be considered true non-responders. Thus, it appears clear that the main aim of precision medicine in T2DM is to identify patients who can benefit most from a specific drug class more than from the others. Precision medicine is a discipline that evaluates the applicability of genetic, lifestyle, and environmental factors to disease development. In particular, it evaluated whether these factors could affect the development of diseases and their complications, response to diet, lifestyle, and use of drugs. Thus, the objective is to find prevention models aimed at reducing the incidence of pathology and mortality and therapeutic personalized approaches, to obtain a greater probability of response and efficacy. This review aims to evaluate the applicability of precision medicine for T2DM, a healthcare burden in many countries.
PubMed: 38028995
DOI: 10.2147/DMSO.S390752 -
Biological Psychiatry Global Open... Jan 2024Maternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy...
BACKGROUND
Maternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy increase the likelihood of autism spectrum disorder (ASD) or other neurodevelopmental disorders (DDs) is not well understood.
METHODS
We conducted a case-control study among children born in California from 2011 to 2016 to investigate maternal immune-mediated and cardiometabolic conditions during pregnancy and risk of ASD ( = 311) and DDs ( = 1291) compared with children from the general population ( = 967). Data on maternal conditions and covariates were retrieved from electronic health records. Maternal genetic data were used to assess a causal relationship.
RESULTS
Using multivariable logistic regression, we found that mothers with asthma were more likely to deliver infants later diagnosed with ASD (odds ratio [OR] = 1.62, 95% CI: 1.15-2.29) or DDs (OR = 1.30, 95% CI: 1.02-1.64). Maternal obesity was also associated with child ASD (OR = 1.51, 95% CI: 1.07-2.13). Mothers with both asthma and extreme obesity had the greatest odds of delivering an infant later diagnosed with ASD (OR = 16.9, 95% CI: 5.13-55.71). These increased ASD odds were observed among female children only. Polygenic risk scores for obesity, asthma, and their combination showed no association with ASD risk. Mendelian randomization did not support a causal relationship between maternal conditions and ASD.
CONCLUSIONS
Inflammatory conditions during pregnancy are associated with risk for neurodevelopmental disorders in children. These risks do not seem to be due to shared genetic risk; rather, inflammatory conditions may share nongenetic risk factors with neurodevelopmental disorders. Children whose mothers have both asthma and obesity during pregnancy may benefit from earlier screening and intervention.
PubMed: 38045769
DOI: 10.1016/j.bpsgos.2023.09.008 -
BMJ Open Respiratory Research Dec 2022Obesity and asthma impose a heavy health and economic burden on millions of people around the world. The complex interaction between genetic traits and phenotypes caused...
BACKGROUND AND OBJECTIVE
Obesity and asthma impose a heavy health and economic burden on millions of people around the world. The complex interaction between genetic traits and phenotypes caused the mechanism between obesity and asthma is still vague. This study investigates the relationship among obesity-related polygenic risk score (PRS), obesity phenotypes and the risk of having asthma.
METHODS
This is a matched case-control study, with 4 controls (8288 non-asthmatic) for each case (2072 asthmatic). Data were obtained from the 2008-2015 Taiwan Biobank Database and linked to the 2000-2016 National Health Insurance Research Database. All participants were ≥30 years old with no history of cancer and had a complete questionnaire, as well as physical examination, genome-wide single nucleotide polymorphisms and clinical diagnosis data. Environmental exposure, PM, was also considered. Multivariate adjusted ORs and 95% CIs were calculated using conditional logistic regression stratified by age and sex. Mediation analysis was also assessed, using a generalised linear model.
RESULTS
We found that the obese phenotype was associated with significantly increased odds of asthma by approximately 26%. Four obesity-related PRS, including body mass index (OR=1.07 (1.01-1.13)), waist circumference (OR=1.10 (1.04-1.17)), central obesity as defined by waist-to-height ratio (OR=1.09 (1.03-1.15)) and general-central obesity (OR=1.06 (1.00-1.12)), were associated with increased odds of asthma. Additional independent risk factors for asthma included lower educational level, family history of asthma, certain chronic diseases and increased PM exposure. Obesity-related PRS is an indirect risk factor for asthma, the link being fully mediated by the trait of obesity.
CONCLUSIONS
Obese phenotypes and obesity-related PRS are independent risk factors for having asthma in adults in the Taiwan Biobank. Overall, genetic risk for obesity increases the risk of asthma by affecting the obese phenotype.
Topics: Humans; Obesity, Abdominal; Taiwan; Case-Control Studies; Biological Specimen Banks; Obesity; Asthma; Phenotype; Particulate Matter
PubMed: 36600406
DOI: 10.1136/bmjresp-2022-001355 -
Chest Jan 2021There is an unclear relationship of obesity to the pathogenesis and severity of pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH).
BACKGROUND
There is an unclear relationship of obesity to the pathogenesis and severity of pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH).
RESEARCH QUESTION
Is BMI casually associated with pulmonary artery pressure (PAP) and/or markers of pulmonary vascular remodeling?
STUDY DESIGN AND METHODS
The study design was a two-sample inverse-variance weighted Mendelian randomization. We constructed two BMI genetic risk scores from genome-wide association study summary data and deployed them in nonoverlapping cohorts of subjects referred for right heart catheterization (RHC) or echocardiography. A BMI highly polygenic risk score (hpGRS) optimally powered to detect shared genetic architecture of obesity with other traits was tested for association with RHC parameters including markers of pulmonary vascular remodeling. A BMI strict genetic risk score (sGRS) composed of high-confidence genetic variants was used for Mendelian randomization analyses to assess if higher BMI causes higher PAP.
RESULTS
Among all subjects, both directly measured BMI and hpGRS were positively associated with pulmonary arterial pressures but not markers of pulmonary vascular remodeling. Categorical analyses revealed BMI and hpGRS were associated with PVH but not PAH. Mendelian randomization of the sGRS supported that higher BMI is causal of higher systolic pulmonary artery pressure (sPAP). Sensitivity analyses showed sPAP-BMI sGRS relationship was preserved when either individuals with PAH or PVH were excluded. In the echocardiographic cohort, BMI and hpGRS were positively associated with estimated PAP and markers of left heart remodeling.
INTERPRETATION
BMI is a modifier of pulmonary hypertension severity in both PAH and PVH but is only involved in the pathogenesis of PVH.
Topics: Aged; Body Mass Index; Causality; Cohort Studies; Female; Genome-Wide Association Study; Humans; Male; Mendelian Randomization Analysis; Middle Aged; Obesity; Pulmonary Arterial Hypertension; Pulmonary Artery; Risk Factors; Vascular Remodeling
PubMed: 32712226
DOI: 10.1016/j.chest.2020.07.038 -
Frontiers in Oncology 2023Pancreatic ductal adenocarcinoma (PDAC) is lethal due to its late diagnosis and lack of successful treatments. A possible strategy to reduce its death burden is...
INTRODUCTION
Pancreatic ductal adenocarcinoma (PDAC) is lethal due to its late diagnosis and lack of successful treatments. A possible strategy to reduce its death burden is prevention. Intraductal papillary mucinous neoplasms (IPMNs) are precursors of PDAC. It is difficult to estimate the incidence of IPMNs because they are asymptomatic. Two recent studies reported pancreatic cysts in 3% and 13% of scanned subjects. The possibility of identifying a subgroup of IPMN patients with a higher probability of progression into cancer could be instrumental in increasing the survival rate. In this study, genetic and non-genetic PDAC risk factors were tested in a group of IPMN patients under surveillance.
METHODS
A retrospective study was conducted on 354 IPMN patients enrolled in two Italian centres with an average follow-up of 64 months. With the use of DNA extracted from blood, collected at IPMN diagnosis, all patients were genotyped for 30 known PDAC risk loci. The polymorphisms were analysed individually and grouped in an unweighted polygenic score (PGS) in relation to IPMN progression. The ABO blood group and non-genetic PDAC risk factors were also analysed. IPMN progression was defined based on the development of worrisome features and/or high-risk stigmata during follow-up.
RESULTS
Two genetic variants (rs1517037 and rs10094872) showed suggestive associations with an increment of IPMN progression. After correction for multiple testing, using the Bonferroni correction, none of the variants showed a statistically significant association. However, associations were observed for the non-genetic variables, such as smoking status, comparing heavy smokers with light smokers (HR = 3.81, 95% 1.43-10.09, = 0.007), and obesity (HR = 2.46, 95% CI 1.22-4.95, = 0.012).
CONCLUSION
In conclusion, this study is the first attempt to investigate the presence of shared genetic background between PDAC risk and IPMN progression; however, the results suggest that the 30 established PDAC susceptibility polymorphisms are not associated with clinical IPMN progression in a sample of 354 patients. However, we observed indications of cigarette smoking and body mass index (BMI) involvement in IPMN progression. The biological mechanism that could link these two risk factors to progression could be chronic inflammation, of which both smoking and obesity are strong promoters.
PubMed: 37346070
DOI: 10.3389/fonc.2023.1172606 -
Methodist DeBakey Cardiovascular Journal 2021Familial hypercholesterolemia (FH) is a monogenic form of severe hypercholesterolemia that, if left untreated, is associated with early onset of atherosclerosis. FH... (Review)
Review
Familial hypercholesterolemia (FH) is a monogenic form of severe hypercholesterolemia that, if left untreated, is associated with early onset of atherosclerosis. FH derives from genetic variants that lead to inefficient hepatic clearance of low-density lipoprotein (LDL) particles from the circulation. The FH phenotype is encountered in approximately 1 of every 300 people. The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in those with FH than in normolipidemic individuals and in those with polygenic hypercholesterolemia. FH is usually diagnosed by clinical scores that consider hypercholesterolemia, family history of early ASCVD and hypercholesterolemia, and cutaneous stigmata. Genetic diagnosis is important and should be offered to individuals suspected of FH. Family cascade screening is important to identify asymptomatic hypercholesterolemic individuals. Despite the high risk of ASCVD, this risk is heterogenous in heterozygous FH and depends not only on high LDL cholesterol (LDL-C) but also on other risk biomarkers. Risk can be evaluated by considering biomarkers such as male sex, late-onset therapy (> age 40), LDL-C > 310 mg/dL, low high-density lipoprotein cholesterol, elevated lipoprotein(a), obesity, diabetes, and hypertension by using specific risk equations and by detecting subclinical coronary atherosclerosis. Statins are the main therapy for FH and change the natural history of ASCVD; however, most individuals persist with elevated LDL-C. PCSK9 inhibitors provide robust and safe LDL-C lowering in FH, although elevated costs preclude their widespread use. Newer therapies such as ANGPTL3 inhibitors add intensive LDL-C lowering for refractory forms of FH. Finally, while it is possible to normalize LDL-C in people with FH, the disease unfortunately is still severely underdiagnosed and undertreated.
Topics: Adult; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Cholesterol, LDL; Humans; Hyperlipoproteinemia Type II; Male; Proprotein Convertase 9; Risk Factors
PubMed: 34824679
DOI: 10.14797/mdcvj.887 -
The European Respiratory Journal Oct 2021Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most...
BACKGROUND
Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWASs in other populations are lacking.
METHODS
We included 100 285 subjects from the China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS analyses were performed on forced expiratory volume in 1 s (FEV), forced vital capacity (FVC) and FEV/FVC in the CKB. We then performed genome-wide cross-trait analysis between lung function and obesity traits (body mass index (BMI), BMI-adjusted waist-to-hip ratio and BMI-adjusted waist circumference) to investigate the shared genetic effects in the CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in the CKB and their interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with the CKB using up to 457 756 subjects from the UK Biobank (UKB) for replication and investigation of ancestry-specific effects.
RESULTS
We identified nine genome-wide significant novel loci for FEV, six for FVC and three for FEV/FVC in the CKB. FEV and FVC showed significant negative genetic correlation with obesity traits in both the CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important biological pathways, including cell proliferation, embryo, skeletal and tissue development, and regulation of gene expression. Mendelian randomisation analysis suggested significant negative causal effects of BMI on FEV and on FVC in both the CKB and UKB. Lung function PRSs significantly modified the effect of change in BMI on change in lung function during an average follow-up of 8 years.
CONCLUSION
This large-scale GWAS of lung function identified novel loci and shared genetic aetiology between lung function and obesity. Change in BMI might affect change in lung function differently according to a subject's polygenic background. These findings may open new avenues for the development of molecular-targeted therapies for obesity and lung function improvement.
Topics: Body Mass Index; China; Forced Expiratory Volume; Genome-Wide Association Study; Humans; Lung; Obesity; Polymorphism, Single Nucleotide
PubMed: 33766948
DOI: 10.1183/13993003.00199-2021