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Nutrients Apr 2024Obesity's variability is significantly influenced by the interplay between genetic and environmental factors. We aimed to integrate the combined impact of genetic risk...
Obesity's variability is significantly influenced by the interplay between genetic and environmental factors. We aimed to integrate the combined impact of genetic risk score (GRS) with physical activity (PA), sugar-sweetened beverages (SSB), wine intake, and eating habits score (EHS) on obesity predisposition risk. Adults' ( = 5824) data were analyzed for common obesity-related single nucleotide polymorphisms and lifestyle habits. The weighted GRS was constructed and categorized into quartiles (Qs), and the adjusted multivariate logistic regression models examined the association of GRS with obesity (BMI ≥ 30) and lifestyle factors. GRS was significantly associated with obesity risk. Each GRS unit was associated with an increase of 3.06 BMI units ( ≤ 0.0001). PA markedly reduced obesity risk across GRS Qs. Inactive participants' (≥90 min/week) mean BMI was higher in GRS Q3-Q4 compared to Q1 ( = 0.003 and < 0.001, respectively). Scoring EHS ≥ median, SSBs (≥1 cup/day), and non-wine drinking were associated with higher BMI within all GRS Qs compared to EHS < median, non-SSBs, and non-wine drinkers. Mean BMI was higher in GRS Q4 compared to other quartiles ( < 0.0001) in non-wine drinkers and compared to Q1 for SSB's consumers ( = 0.07). A higher GRS augmented the impact of lifestyle factors on obesity. The interplay between GRS and modifiable lifestyle factors provides a tailored personalized prevention and treatment for obesity management.
Topics: Humans; Male; Obesity; Female; Life Style; Genetic Predisposition to Disease; Adult; Middle Aged; Polymorphism, Single Nucleotide; Exercise; Body Mass Index; Risk Factors; Feeding Behavior; Sugar-Sweetened Beverages; Alcohol Drinking; Genetic Risk Score
PubMed: 38732542
DOI: 10.3390/nu16091296 -
Kidney International Reports May 2024Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite... (Review)
Review
Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite an established genotype-phenotype correlation in cystic kidney diseases, incomplete penetrance and variable disease expressivity are present as is the case in all monogenic diseases. In family members with autosomal dominant polycystic kidney disease (ADPKD), the same causal variant is responsible in all affected family members; however, there can still be striking discordance in phenotype severity. This narrative review explores contributors to within-family discordance in ADPKD severity. Cases of biallelic and digenic inheritance, where 2 rare pathogenic variants in cystogenic genes are coexistent in one family, account for a small proportion of within-family discordance. Genetic background, including cis and trans factors and the polygenic propensity for comorbid disease, also plays a role but has not yet been exhaustively quantified. Environmental exposures, including diet; smoking; alcohol, salt, and protein intake, and comorbid diseases, including obesity, diabetes, hypertension, kidney stones, dyslipidemia, and additional coexistent kidney diseases all contribute to ADPKD phenotypic variability among family members. Given that many of the factors contributing to phenotype variability are preventable, modifiable, or treatable, health care providers and patients need to be aware of these factors and address them in the treatment of ADPKD.
PubMed: 38707833
DOI: 10.1016/j.ekir.2024.01.053 -
Calcified Tissue International Jun 2024Type 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from:...
Type 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from: https://www.jax.org/strain/002468 ). While numerous mouse models for T2D exist, few effectively stimulate persistent hyperglycemia in both sexes, and even fewer are suitable for bone studies. Commonly used models like db/db and ob/ob have altered leptin pathways, confounding bone-related findings since leptin regulates bone properties (Fajardo et al. in Journal of Bone and Mineral Research 29(5): 1025-1040, 2014). The Yellow Kuo Kondo (KK/A) mouse, a polygenic mutation model of T2D, is able to produce a consistent diabetic state in both sexes and addresses the lack of a suitable model of T2D for bone studies. The diabetic state of KK/A stems from a mutation in the agouti gene, responsible for coat color in mice. This mutation induces ectopic gene expression across various tissue types, resulting in diabetic mice with yellow fur coats (Moussa and Claycombe in Obesity Research 7(5): 506-514, 1999). Male and female KK/A mice exhibited persistent hyperglycemia, defining them as diabetic with blood glucose (BG) levels consistently exceeding 300 mg/dL. Notably, male control mice in this study were also diabetic, presenting a significant limitation. Nevertheless, male and female KK/A mice showed significantly elevated BG levels, HbA1c, and serum insulin concentration when compared to the non-diabetic female control mice. Early stages of T2D are characterized by hyperglycemia and hyperinsulinemia resulting from cellular insulin resistance, whereas later stages may feature hypoinsulinemia due to β-cell apoptosis (Banday et al. Avicenna Journal of Medicine 10(04): 174-188, 2020 and Klein et al. Cell Metabolism 34(1): 11-20, 2022). The observed hyperglycemia, hyperinsulinemia, and the absence of differences in β-cell mass suggest that KK/A mice in this study are modeling the earlier stages of T2D. While compromised bone microarchitecture was observed in this study, older KK/A mice, representing more advanced stages of T2D, might exhibit more pronounced skeletal manifestations. Compared to the control group, the femora of KK/A mice had higher cortical area and cortical thickness, and improved trabecular properties which would typically be indicative of greater bone strength. However, KK/A mice displayed lower cortical tissue mineral density in both sexes and increased cortical porosity in females. Fracture instability toughness of the femora was lower in KK/A mice overall compared to controls. These findings indicate that decreased mechanical integrity noted in the femora of KK/A mice was likely due to overall bone quality being compromised.
Topics: Animals; Diabetes Mellitus, Type 2; Mice; Female; Disease Models, Animal; Male; Mutation; Obesity; Bone and Bones; Mice, Obese; Bone Density
PubMed: 38642089
DOI: 10.1007/s00223-024-01216-1 -
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 -
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 -
Nature Genetics Apr 2024Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence...
Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.
Topics: Adult; Humans; Adaptor Proteins, Signal Transducing; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Induced Pluripotent Stem Cells; Liver Diseases; Nerve Tissue Proteins; Obesity; Proteomics
PubMed: 38575728
DOI: 10.1038/s41588-024-01694-x -
Journal of Clinical Medicine Feb 2024Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can... (Review)
Review
Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity.
PubMed: 38546831
DOI: 10.3390/jcm13051347 -
Nutrients Mar 2024Both genetics and vitamin D deficiency are associated with childhood obesity. However, the role of vitamin D status between polygenic and childhood obesity has been...
BACKGROUND
Both genetics and vitamin D deficiency are associated with childhood obesity. However, the role of vitamin D status between polygenic and childhood obesity has been unknown. The current study aimed to determine the relation between genetic factors, vitamin D status, and BMI-for-age score (zBMI) in Chinese preschool children.
METHODS
A total of 1046 participants aged 3.7 to 6.6 years old from the Long-term Health Effects Assessment Project of Infants and Toddlers Nutritional Pack (LHEAPITNP) were included in this study. The polygenic risk score (PRS) was established based on 55 BMI-related single nucleotide polymorphisms (SNPs) derived from a published genome-wide association study (GWAS) for BMI. Serum 25(OH)D was used as an index of vitamin D status and measured with liquid chromatography-tandem mass spectrometry (LC/MS-MS) assay. The Wilcoxon test or Kruskal-Wallis test was used to compare the differences of variables between different groups and Spearman correlation analysis was used for analyzing the correlations between the PRS, 25(OH)D levels, and zBMI.
RESULTS
The PRS showed a positive relation to zBMI ( = 0.0953, = 0.0022) and 25(OH)D showed a negative relation to zBMI ( = -0.1082, = 0.0005) in the full-adjustment model. In addition, the differences in zBMI at different vitamin D statuses in the low-risk PRS group and the intermediate-risk PRS group were both statistically significant ( = 0.0308, = 0.0121), the median zBMI was both higher at vitamin D insufficiency status. And the difference in zBMI between different genetic risk groups was also statistically significant at vitamin D sufficiency status ( = 0.0077). Furthermore, genetic risk showed a positive relation to zBMI at vitamin D sufficiency status, and the for trend was 0.0028.
CONCLUSIONS
Our findings suggested that vitamin D was related to zBMI negatively in Chinese preschoolers and maintaining adequate vitamin D levels may only contribute to lower the zBMI in preschoolers with low and intermediate genetic susceptibility.
Topics: Child; Infant; Humans; Child, Preschool; Vitamin D; Pediatric Obesity; Body Mass Index; Genetic Risk Score; Genome-Wide Association Study; Vitamin D Deficiency; China
PubMed: 38542703
DOI: 10.3390/nu16060792 -
JAMA Network Open Mar 2024Despite consistent public health recommendations, obesity rates in the US continue to increase. Physical activity recommendations do not account for individual genetic...
IMPORTANCE
Despite consistent public health recommendations, obesity rates in the US continue to increase. Physical activity recommendations do not account for individual genetic variability, increasing risk of obesity.
OBJECTIVE
To use activity, clinical, and genetic data from the All of Us Research Program (AoURP) to explore the association of genetic risk of higher body mass index (BMI) with the level of physical activity needed to reduce incident obesity.
DESIGN, SETTING, AND PARTICIPANTS
In this US population-based retrospective cohort study, participants were enrolled in the AoURP between May 1, 2018, and July 1, 2022. Enrollees in the AoURP who were of European ancestry, owned a personal activity tracking device, and did not have obesity up to 6 months into activity tracking were included in the analysis.
EXPOSURE
Physical activity expressed as daily step counts and a polygenic risk score (PRS) for BMI, calculated as weight in kilograms divided by height in meters squared.
MAIN OUTCOME AND MEASURES
Incident obesity (BMI ≥30).
RESULTS
A total of 3124 participants met inclusion criteria. Among 3051 participants with available data, 2216 (73%) were women, and the median age was 52.7 (IQR, 36.4-62.8) years. The total cohort of 3124 participants walked a median of 8326 (IQR, 6499-10 389) steps/d over a median of 5.4 (IQR, 3.4-7.0) years of personal activity tracking. The incidence of obesity over the study period increased from 13% (101 of 781) to 43% (335 of 781) in the lowest and highest PRS quartiles, respectively (P = 1.0 × 10-20). The BMI PRS demonstrated an 81% increase in obesity risk (P = 3.57 × 10-20) while mean step count demonstrated a 43% reduction (P = 5.30 × 10-12) when comparing the 75th and 25th percentiles, respectively. Individuals with a PRS in the 75th percentile would need to walk a mean of 2280 (95% CI, 1680-3310) more steps per day (11 020 total) than those at the 50th percentile to have a comparable risk of obesity. To have a comparable risk of obesity to individuals at the 25th percentile of PRS, those at the 75th percentile with a baseline BMI of 22 would need to walk an additional 3460 steps/d; with a baseline BMI of 24, an additional 4430 steps/d; with a baseline BMI of 26, an additional 5380 steps/d; and with a baseline BMI of 28, an additional 6350 steps/d.
CONCLUSIONS AND RELEVANCE
In this cohort study, the association between daily step count and obesity risk across genetic background and baseline BMI were quantified. Population-based recommendations may underestimate physical activity needed to prevent obesity among those at high genetic risk.
Topics: Female; Humans; Middle Aged; Male; Cohort Studies; Retrospective Studies; Population Health; Obesity; Exercise; Genetic Risk Score
PubMed: 38536175
DOI: 10.1001/jamanetworkopen.2024.3821 -
Therapeutic Advances in Respiratory... 2024Prior pulmonary tuberculosis (PTB) might be associated with the development of chronic obstructive pulmonary disease (COPD). However, the impact of prior PTB on the risk...
BACKGROUND
Prior pulmonary tuberculosis (PTB) might be associated with the development of chronic obstructive pulmonary disease (COPD). However, the impact of prior PTB on the risk of incident COPD has not been studied in a large prospective cohort study of the European population.
OBJECTIVES
This study aimed to investigate the association of prior PTB with the risk of COPD.
DESIGN
Prospective cohort study.
METHODS
A multivariable Cox proportional model was used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) for the association of prior PTB with COPD. Subgroup analyses were further conducted among individuals stratified by age, sex, body mass index, smoking status, drinking status, physical activity, and polygenic risk score (PRS).
RESULTS
The study involved a total of 216,130 participants, with a median follow-up period of 12.6 years and 2788 incident cases of COPD. Individuals with a prior history of PTB at baseline had an 87% higher risk of developing incident COPD compared to those without such history [adjusted hazard ratio (aHR) = 1.87; 95% confidence interval (CI): 1.26-2.77; = 0.002]. Subgroup analysis revealed that individuals having prior PTB history presented a higher risk of incident COPD among individuals who were aged from 50 to 59 years with aHR of 2.47 (1.02-5.95, = 0.044), older than 59 years with aHR of 1.81 (1.16-2.81, = 0.008), male with aHR of 2.37 (1.47-3.83, < 0.001), obesity with aHR of 3.35 (2.16-5.82, < 0.001), previous smoking with aHR of 2.27 (1.39-3.72, < 0.001), current drinking with aHR of 1.98 (1.47-3.83, < 0.001), low physical activity with aHR of 2.62 (1.30-5.26, = 0.007), and low PRS with aHR of 3.24 (1.61-6.53, < 0.001), as well as high PRS with aHR of 2.43 (1.15-5.14, = 0.019).
CONCLUSION
A history of PTB is an important independent risk factor for COPD. Clinical staff should be aware of this risk factor in patients with prior PTB, particularly in countries or regions with high burdens of PTB.
Topics: Humans; Male; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Tuberculosis, Pulmonary; Risk Factors; Smoking
PubMed: 38529640
DOI: 10.1177/17534666241239455