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Saudi Journal of Biological Sciences Oct 2023Obesity is a polygenic disorder which has become a global epidemic in recent years. Aim of the present study was to assess the theranostic potential of probiotics ( and...
Obesity is a polygenic disorder which has become a global epidemic in recent years. Aim of the present study was to assess the theranostic potential of probiotics ( and local herbs (fenugreek seeds, aloe vera) on the body weight, biochemical (liver and kidney functions) and histology of some internal organs (liver, kidney, ovary, small intestine) in obese rats. In present study, nanoemulsions of probiotics and local herbs were formulated by high energy method and characterized by FTIR and UV analysis. One hundred and sixty (1 6 0) female wistar rats were divided into sixteen groups. A high-fat diet was given to induce obesity in them. Obese rats were treated with different doses of probiotics, local herbs and their combination. Weekly body weight was monitored. Rats were dissected after fifteen weeks; blood and organs were harvested for biochemical analysis and histology. Results demonstrated a protective effect of nanoemulsion of probiotics and local herbs on the central vein, glomerulus, villi and normal ovulatory function of obese rats. Rats treated with a combination of probiotics and local herbs (fenugreek seeds, aloe vera) exhibited improved levels of bilirubin (4 mg/dl to15 mg/dl), AST from (110 U/L to 18 U/L) and ALT from (52 U/L to 10U/L). Similar renoprotective effects were recorded on the overall renal function tests (RFT). A combination of probiotics and local herbs in post treatment rats improved urea (63 mg/dl to 22 mg/dl) and creatinine (0.2 mg/dl to 0.8 mg/dl) levels. It was therefore evident that a combination of probiotics and local herbs has the potential to reverse the effects of obesity on the biochemical parameters and histological architecture of liver, kidney, small intestine and ovary. The overall results indicated that probiotics have positive effects of their own, but when combined with local herbs, they produced highly effective results in obese rats and therefore can be used as a complementary option in obese individuals.
PubMed: 37680978
DOI: 10.1016/j.sjbs.2023.103790 -
BMC Cancer Jun 2020Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using Mendelian randomization (MR), we assessed whether associations of 36 reported glioma risk factors showed evidence of a causal relationship.
METHODS
We performed a systematic search of MEDLINE from inception to October 2018 to identify candidate risk factors and conducted a meta-analysis of two glioma genome-wide association studies (5739 cases and 5501 controls) to form our exposure and outcome datasets. MR analyses were performed using genetic variants to proxy for candidate risk factors. We investigated whether risk factors differed by subtype diagnosis (either glioblastoma (n = 3112) or non-glioblastoma (n = 2411)). MR estimates for each risk factor were determined using multiplicative random effects inverse-variance weighting (IVW). Sensitivity analyses investigated potential pleiotropy using MR-Egger regression, the weighted median estimator, and the mode-based estimator. To increase power, trait-specific polygenic risk scores were used to test the association of a genetically predicated increase in each risk factor with glioma onset.
RESULTS
Our systematic search identified 36 risk factors that could be proxied using genetic variants. Using MR, we found evidence that four genetically predicted traits increased risk of glioma, glioblastoma or non-glioblastoma: longer leukocyte telomere length, liability to allergic disease, increased alcohol consumption and liability to childhood extreme obesity (> 3 standard deviations from the mean). Two traits decreased risk of non-glioblastoma cancers: increased low-density lipoprotein cholesterol (LDLc) and triglyceride levels. Our findings were similar across sensitivity analyses that made allowance for pleiotropy (genetic confounding).
CONCLUSIONS
Our comprehensive investigation provides evidence of a causal link between both genetically predicted leukocyte telomere length, allergic disease, alcohol consumption, childhood extreme obesity, and LDLc and triglyceride levels, and glioma. The findings from our study warrant further research to uncover mechanisms that implicate these traits in glioma onset.
Topics: Cholesterol, LDL; Genetic Predisposition to Disease; Genome-Wide Association Study; Glioma; Humans; Hypersensitivity; Mendelian Randomization Analysis; Obesity; Polymorphism, Single Nucleotide; Risk Factors; Telomere Homeostasis; Triglycerides
PubMed: 32493226
DOI: 10.1186/s12885-020-06967-2 -
Diabetologia Sep 2023Iterative advances in understanding of the genetics of type 1 diabetes have identified >70 genetic regions associated with risk of the disease, including strong... (Review)
Review
Iterative advances in understanding of the genetics of type 1 diabetes have identified >70 genetic regions associated with risk of the disease, including strong associations across the HLA class II region that account for >50% of heritability. The increased availability of genetic data combined with the decreased costs of generating these data, have facilitated the development of polygenic scores that aggregate risk variants from associated loci into a single number: either a genetic risk score (GRS) or a polygenic risk score (PRS). PRSs incorporate the risk of many possibly correlated variants from across the genome, even if they do not reach genome-wide significance, whereas GRSs estimate the cumulative contribution of a smaller subset of genetic variants that reach genome-wide significance. Type 1 diabetes GRSs have utility in diabetes classification, aiding discrimination between type 1 diabetes, type 2 diabetes and MODY. Type 1 diabetes GRSs are also being used in newborn screening studies to identify infants at risk of future presentation of the disease. Most early studies of type 1 diabetes genetics have been conducted in European ancestry populations, but, to develop accurate GRSs across diverse ancestries, large case-control cohorts from non-European populations are still needed. The current barriers to GRS implementation within healthcare are mainly related to a lack of guidance and knowledge on integration with other biomarkers and clinical variables. Once these limitations are addressed, there is huge potential for 'test and treat' approaches to be used to tailor care for individuals with type 1 diabetes.
Topics: Infant, Newborn; Humans; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Risk Factors; Biomarkers; Genome-Wide Association Study
PubMed: 37439792
DOI: 10.1007/s00125-023-05955-y -
Nature Genetics May 2024We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl...
We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.
Topics: Humans; Liver Cirrhosis; Genome-Wide Association Study; Genetic Predisposition to Disease; Liver Neoplasms; Carcinoma, Hepatocellular; Alanine Transaminase; Polymorphism, Single Nucleotide; Male; Lipase; Female; gamma-Glutamyltransferase; Membrane Proteins; Cohort Studies; Case-Control Studies; Multifactorial Inheritance; Risk Factors; Genetic Variation
PubMed: 38632349
DOI: 10.1038/s41588-024-01720-y -
Current Obesity Reports Dec 2020Eating behaviours are hypothesised to be the behavioural expression of genetic risk of obesity. In this review, we summarise findings from behavioural genetic research... (Review)
Review
PURPOSE OF REVIEW
Eating behaviours are hypothesised to be the behavioural expression of genetic risk of obesity. In this review, we summarise findings from behavioural genetic research on the association between genetic risk for obesity and validated psychometrics measures of eating behaviours in children and adults (published in the past 10 years).
RECENT FINDINGS
Twin studies have produced some evidence for a shared genetic aetiology underlying body mass index and eating behaviours. Studies using measured genetic susceptibility to obesity have suggested that increased genetic liability for obesity is associated with variation in obesogenic eating behaviours such as emotional and uncontrolled eating. More research on this topic is needed. Especially longitudinal studies using genetically sensitive designs to investigate the direction of genetic pathways between genetic liability of eating behaviours to weight and vice versa, as well as the potential subsequent link to eating disorders.
Topics: Body Mass Index; Feeding Behavior; Feeding and Eating Disorders; Genetic Predisposition to Disease; Humans; Obesity; Psychometrics; Risk Factors
PubMed: 32880821
DOI: 10.1007/s13679-020-00402-0 -
Circulation. Genomic and Precision... Apr 2020Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD...
BACKGROUND
Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk.
METHODS
We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK Biobank-based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen).
RESULTS
In FINRISK, median LDL-C was 3.39 (95% CI, 3.38-3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82-2.94) to 3.78 (95% CI, 3.71-3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18-1.20) mmol/L, ranging from 0.97 (95% CI, 0.94-1.00) to 1.55 (95% CI, 1.48-1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24-1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19-1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16-1.38] for LDL-C and 1.24 [95% CI, 1.13-1.36] for TG PRS).
CONCLUSIONS
The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.
Topics: Cholesterol, LDL; Cohort Studies; Coronary Artery Disease; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Hyperlipidemias; Male; Middle Aged; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Prognosis; Risk Factors; Triglycerides
PubMed: 32154731
DOI: 10.1161/CIRCGEN.119.002725 -
Lifestyle Genomics 2023Exposure to discrimination has emerged as a risk factor for obesity. It remains unclear, however, whether the genotype of the individual can modulate the sensitivity or... (Observational Study)
Observational Study
INTRODUCTION
Exposure to discrimination has emerged as a risk factor for obesity. It remains unclear, however, whether the genotype of the individual can modulate the sensitivity or response to discrimination exposure (gene × environment interaction) or increase the likelihood of experiencing discrimination (gene-environment correlation).
METHODS
This was an observational study of 4,102 white/European Americans in the Health and Retirement Study with self-reported, biological assessments, and genotyped data from 2006 to 2014. Discrimination was operationalized using the average of nine Everyday Discrimination Scale items. Polygenic risk scores (PRSs) for body mass index (BMI) and waist circumference (WC) were calculated using the weighted sum of risk alleles based on studies conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium.
RESULTS
We found that greater PRS-BMI was significantly associated with more reports of discrimination (β = 0.04 ± 0.02; p = 0.037). Further analysis showed that measured BMI partially mediated the association between PRS-BMI and discrimination. There was no evidence that the association between discrimination and BMI, or the association between discrimination and WC, differed by PRS-BMI or PRS-WC, respectively.
CONCLUSION
Our findings suggest that individuals with genetic liability for obesity may experience greater discrimination in their lifetime, consistent with a gene-environment correlation hypothesis. There was no evidence of a gene-environment interaction. More genome-wide association studies in diverse populations are needed to improve generalizability of study findings. In the meantime, prevention and clinical intervention efforts that seek to reduce exposure to all forms of discrimination may help reduce obesity at the population level.
Topics: Humans; Gene-Environment Interaction; Genome-Wide Association Study; Genetic Predisposition to Disease; Obesity; Social Discrimination
PubMed: 36750036
DOI: 10.1159/000529527 -
The Journal of Nutritional Biochemistry Mar 2022Although obesity has been a longstanding health crisis, the genetic architecture of the disease remains poorly understood. Genome-wide association studies have... (Review)
Review
Although obesity has been a longstanding health crisis, the genetic architecture of the disease remains poorly understood. Genome-wide association studies have identified many genomic loci associated with obesity, with genes being enriched in the brain, particularly in the hypothalamus. This points to the role of the central nervous system (CNS) in predisposition to obesity, and we emphasize here several key genes along the satiety signaling pathway involved in genetic susceptibility. Interest has also risen regarding the chronic, low-grade obesity-associated inflammation, with a growing concern toward inflammation in the hypothalamus as a precursor to obesity. Recent studies have found that genetic variation in inflammatory genes play a role in obesity susceptibility, and we highlight here several key genes. Despite the interest in the genetic variants of these pathways individually, there is a lack of research that investigates the relationship between the two. Understanding the interplay between genetic variation in obesity genes enriched in the CNS and inflammation genes will advance our understanding of obesity etiology and heterogeneity, improve genetic risk prediction analyses, and highlight new drug targets for the treatment of obesity. Additionally, this increased knowledge will assist in physician's ability to develop personalized nutrition and medication strategies for combating the obesity epidemic. Though it often seems to present universally, obesity is a highly individual disease, and there remains a need in the field to develop methods to treat at the individual level.
Topics: Animals; Appetite Regulation; Brain; Genetic Predisposition to Disease; Genetic Variation; Humans; Hypothalamus; Inflammation; Multifactorial Inheritance; Obesity; Satiation; Signal Transduction
PubMed: 34936921
DOI: 10.1016/j.jnutbio.2021.108928 -
PLoS Genetics Jun 2023The 16p11.2 and 22q11.2 copy number variants (CNVs) are associated with neurobehavioral traits including autism spectrum disorder (ASD), schizophrenia, bipolar disorder,...
The 16p11.2 and 22q11.2 copy number variants (CNVs) are associated with neurobehavioral traits including autism spectrum disorder (ASD), schizophrenia, bipolar disorder, obesity, and intellectual disability. Identifying specific genes contributing to each disorder and dissecting the architecture of CNV-trait association has been difficult, inspiring hypotheses of more complex models, such as multiple genes acting together. Using multi-tissue data from the GTEx consortium, we generated pairwise expression imputation models for CNV genes and then applied these elastic net models to GWAS for: ASD, bipolar disorder, schizophrenia, BMI (obesity), and IQ (intellectual disability). We compared the variance in these five traits explained by gene pairs with the variance explained by single genes and by traditional interaction models. We also modeled polygene region-wide effects using summed predicted expression ranks across many genes to create a regionwide score. We found that in all CNV-trait pairs except for bipolar disorder at 22q11.2, pairwise effects explain more variance than single genes. Pairwise model superiority was specific to the CNV region for all 16p11.2 traits and ASD at 22q11.2. We identified novel individual genes over-represented in top pairs that did not show single-gene signal. We also found that BMI and IQ have significant regionwide association with both CNV regions. Overall, we observe that genetic architecture differs by trait and region, but 9/10 CNV-trait combinations demonstrate evidence for multigene contribution, and for most of these, the importance of combinatorial models appears unique to CNV regions. Our results suggest that mechanistic insights for CNV pathology may require combinational models.
Topics: Humans; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 22; DNA Copy Number Variations; Behavior; Nervous System Diseases
PubMed: 37267418
DOI: 10.1371/journal.pgen.1010780 -
South African Medical Journal =... Apr 2022Acute pancreatitis is an often-overlooked cause of acute abdominal pain in children and adolescents. Severe hypertriglyceridaemia is an important cause of recurrent...
Acute pancreatitis is an often-overlooked cause of acute abdominal pain in children and adolescents. Severe hypertriglyceridaemia is an important cause of recurrent acute pancreatitis. Monogenic causes of hypertriglyceridaemia, such as familial chylomicronaemia caused by lipoprotein lipase deficiency, are more frequently encountered in children and adolescents, but remain rare. Polygenic hypertriglyceridaemia is more common, but may require a precipitant before manifesting. With the global increase in obesity and type 2 diabetes, secondary causes of hypertriglyceridaemia in children and adolescents are increasing. We report two cases of severe hypertriglyceridaemia and pancreatitis in adolescent females. Hypertriglyceridaemia improved markedly with restriction of dietary fat. An inhibitor to lipoprotein lipase was found to be the cause in one patient, while in the other limited genetic investigation excluded chylomicronaemia owing to deficiency of lipoprotein lipase, its activators and processing proteins.
Topics: Acute Disease; Adolescent; Diabetes Mellitus, Type 2; Female; Humans; Hyperlipoproteinemia Type I; Hypertriglyceridemia; Lipoprotein Lipase; Pancreatitis; South Africa
PubMed: 35587241
DOI: No ID Found