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EBioMedicine Jun 2024Birth weight (BW) is associated with risk of cardiometabolic disease (CMD) in adulthood, which may depend on the state of obesity, in particular if developed at a young...
BACKGROUND
Birth weight (BW) is associated with risk of cardiometabolic disease (CMD) in adulthood, which may depend on the state of obesity, in particular if developed at a young age. We hypothesised that BW and a polygenic score (PGS) for BW were associated with cardiometabolic risk and related plasma protein levels in children and adolescents. We aimed to determine the modifying effect of childhood obesity on these associations.
METHODS
We used data from The cross-sectional HOLBAEK Study with 4263 participants (median [IQR] age, 11.7 [9.2, 14.3] years; 57.1% girls and 42.9% boys; 48.6% from an obesity clinic and 51.4% from a population-based group). We gathered information on BW and gestational age, anthropometrics, cardiometabolic risk factors, calculated a PGS for BW, and measured plasma proteins using Olink Inflammation and Cardiovascular II panels. We employed multiple linear regression to examine the associations with BW as a continuous variable and performed interaction analyses to assess the effect of childhood obesity on cardiometabolic risk and plasma protein levels.
FINDINGS
BW and a PGS for BW associated with cardiometabolic risk and plasma protein levels in childhood and adolescence. Childhood obesity modified the associations between BW and measures of insulin resistance, including HOMA-IR (βadj [95% CI per SD] for obesity: -0.12 [-0.15, -0.08]; normal weight: -0.04 [-0.08, 0.00]; Pinteraction = 0.004), c-peptide (obesity: -0.11 [-0.14, -0.08]; normal weight: -0.02 [-0.06, 0.02]; Pinteraction = 5.05E-04), and SBP SDS (obesity: -0.12 [-0.16, -0.08]; normal weight: -0.06 [-0.11, -0.01]; Pinteraction = 0.0479). Childhood obesity also modified the associations between BW and plasma levels of 14 proteins (e.g., IL15RA, MCP1, and XCL1; Pinteraction < 0.05).
INTERPRETATION
We identified associations between lower BW and adverse metabolic phenotypes, particularly insulin resistance, blood pressure, and altered plasma protein levels, which were more pronounced in children with obesity. Developing effective prevention and treatment strategies for this group is needed to reduce the risk of future CMD.
FUNDING
Novo Nordisk Foundation (NNF15OC0016544, NNF0064142 to T.H., NNF15OC0016692 to T.H. and A.K., NNF18CC0033668 to S.E.S, NNF18SA0034956 to C.E.F., NNF20SA0067242 to DCA, NNF18CC0034900 to NNF CBMR), The Innovation Fund Denmark (0603-00484B to T.H.), The Danish Cardiovascular Academy (DCA) and the Danish Heart Foundation (HF) (PhD2021007-DCA to P.K.R, 18-R125-A8447-22088 (HF) and 21-R149-A10071-22193 (HF) to M.A.V.L., PhD2023009-HF to L.A.H), EU Horizon (668031, 847989, 825694, 964590 to A.K.), Innovative Health Initiative (101132901 for A.K.), A.P. Møller Foundation (19-L-0366 to T.H.), The Danish National Research Foundation, Steno Diabetes Center Sjælland, and The Region Zealand and Southern Denmark Health Scientific Research Foundation.
PubMed: 38918147
DOI: 10.1016/j.ebiom.2024.105205 -
Med (New York, N.Y.) Jun 2024Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant...
BACKGROUND
Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.
METHODS
We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1 individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan.
FINDINGS
We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure.
CONCLUSION
This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.
FUNDING
This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.
PubMed: 38906141
DOI: 10.1016/j.medj.2024.05.015 -
Expert Review of Endocrinology &... Jun 2024Obesity is a growing public health concern affecting both children and adults. Since it involves both genetic and environmental components, the management of obesity... (Review)
Review
INTRODUCTION
Obesity is a growing public health concern affecting both children and adults. Since it involves both genetic and environmental components, the management of obesity requires both, an understanding of the underlying genetics and changes in lifestyle. The knowledge of obesity genetics will enable the possibility of precision medicine in anti-obesity medications.
AREAS COVERED
Here, we explore health complications and the prevalence of obesity. We discuss disruptions in energy balance as a symptom of obesity, examining evolutionary theories, its multi-factorial origins, and heritability. Additionally, we discuss monogenic and polygenic obesity, the converging biological pathways, potential pharmacogenomics applications, and existing anti-obesity medications - specifically focussing on the leptin-melanocortin and incretin pathways. Comparisons between childhood and adult obesity genetics are made, along with insights into structural variants, epigenetic changes, and environmental influences on epigenetic signatures.
EXPERT OPINION
With recent advancements in anti-obesity drugs, genetic studies pinpoint new targets and allow for repurposing existing drugs. This creates opportunities for genotype-informed treatment options. Also, lifestyle interventions can help in the prevention and treatment of obesity by altering the epigenetic signatures. The comparison of genetic architecture in adults and children revealed a significant overlap. However, more robust studies with diverse ethnic representation is required in childhood obesity.
PubMed: 38869356
DOI: 10.1080/17446651.2024.2365785 -
Cureus Jun 2024Type 2 diabetes mellitus (T2DM) is a consequence of insulin resistance, insulin deficiency, or both. It is usually seen in adults and is a consequence of genetic...
Metformin Monotherapy With and Without Lifestyle Changes Affects Anthropometric Parameters, Blood Pressure, Blood Glucose, and Lipid Profile in Indian Patients With Newly Diagnosed Type 2 Diabetes.
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a consequence of insulin resistance, insulin deficiency, or both. It is usually seen in adults and is a consequence of genetic (polygenic inheritance), endogenous (obesity and or hormonal factors), and environmental factors (e.g., obesogenic environment, endocrine disrupting chemicals, stress, and medicines). The prevalence of T2DM has increased over the past few decades. South Asians, including Indians, are more prone to central adiposity and develop lifestyle diseases like T2DM at body mass index values lower than those considered normal for the Western population. Generally, the first line of treatment is metformin monotherapy with lifestyle changes in patients with T2DM. Most of the research conducted on this drug is on Western subjects. Since the Indian population has genetic differences in the site of deposition of adipose and is more prone to develop lifestyle diseases, the effect of metformin may be different in Indians.
METHODS
Seventy-one (34 female, non-pregnant, non-lactating) adults with newly diagnosed T2DM were recruited in this short-duration pilot study after obtaining written informed consent. Patients regularly taking any drug were excluded, as were patients with chronic comorbidities. Treatment was initiated with metformin 500 mg OD. Lifestyle changes were recommended according to the age and physical condition of the patients. Anthropometric parameters (age, weight, height, BMI, waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR)), blood pressure, glycemic status (fasting and 2 h PP glucose and HbA1c), and lipid profile of the subjects were recorded before initiating and six months after initiating metformin monotherapy with lifestyle changes.
RESULTS
Small but statistically significant improvements were observed in the WHR,WHtR, blood pressure, blood glucose, and glycated hemoglobin. Although improvement was also observed in weight and lipid profile, these changes were not statistically significant.
CONCLUSION
This study shows that metformin monotherapy with lifestyle changes is suitable for patients of Indian origin and results in improvement in the WHR, WHtR, blood pressure, plasma glucose, and glycated hemoglobin.
PubMed: 38868550
DOI: 10.7759/cureus.62131 -
Neuropsychopharmacology : Official... Jun 2024Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants...
Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N = 130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across hundreds of biomarkers, health, and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from the UK Biobank (UKB; N = 334,659). We observed consistent positive genetic correlations with substance use and obesity in both cohorts. Other genetic correlations were discrepant, including positive genetic correlations between coffee intake and psychiatric illnesses, pain, and gastrointestinal traits in 23andMe that were absent or negative in the UKB, and genetic correlations with cognition that were negative in 23andMe but positive in the UKB. Phenome-wide association study using polygenic scores of coffee intake derived from 23andMe or UKB summary statistics also revealed consistent associations with increased odds of obesity- and red blood cell-related traits, but all other associations were cohort-specific. Our study shows that the genetics of coffee intake associate with substance use and obesity across cohorts, but also that GWAS performed in different populations could capture cultural differences in the relationship between behavior and genetics.
PubMed: 38858598
DOI: 10.1038/s41386-024-01870-x -
Mammalian Genome : Official Journal of... Jun 2024Hypercholesterolemia raises the risk for cardiovascular complications and overall health. Hypercholesterolemia is common, affecting 10% of the general population of the...
Hypercholesterolemia raises the risk for cardiovascular complications and overall health. Hypercholesterolemia is common, affecting 10% of the general population of the US, and heritable. Most individuals with hypercholesterolemia have a polygenic predisposition to the condition. Previously we identified a quantitative trait locus, Tachol1, linked to hypercholesterolemia on mouse chromosome 1 (Chr1) in a cross between C57BL/6J (B6) and TALLYHO/JngJ (TH) mice, a polygenic model for human obesity, type 2 diabetes and hyperlipidemia. Subsequently, using congenic mice that carry a TH-derived genomic segment of Chr1 on a B6 background, we demonstrated that the distal segment of Chr1, where Tachol1 maps, is necessary to cause hypercholesterolemia, as well as diet-induced obesity. In this study, we generated overlapping subcongenic lines to the distal segment of congenic region and characterized subcongenic mice carrying the smallest TH region of Tachol1, ~ 16.2 Mb in size (B6.TH-Chr1-16.2 Mb). Both male and female B6.TH-Chr1-16.2 Mb mice showed a significantly increased plasma total cholesterol levels compared to B6 on both chow and high fat (HF) diet. B6.TH-Chr1-16.2 Mb mice also had greater fat mass than B6 on HF diet, without increasing food intake. The gene and protein expression levels of absent in melanoma 2 (Aim2) gene were significantly upregulated in B6.TH-Chr1-16.2 Mb mice compared to B6. In summary, we confirmed the effect of Tachol1 on hypercholesterolemia and diet-induced obesity using subcongenic analysis.
PubMed: 38837040
DOI: 10.1007/s00335-024-10045-4 -
Diabetes Care Jun 2024While most genetic variants of type 2 diabetes (T2D) are suggested to be associated with β-cell dysfunction cross sectionally, their association with the longitudinal...
OBJECTIVE
While most genetic variants of type 2 diabetes (T2D) are suggested to be associated with β-cell dysfunction cross sectionally, their association with the longitudinal change of β-cell function remains largely unknown.
RESEARCH DESIGN AND METHODS
We analyzed data from 6,311 participants without T2D at baseline (mean [SD] age 51.6 [8.7] years) from a community-based prospective cohort in Korea. Participants underwent biennial 2-h 75-g oral glucose tolerance tests (OGTTs) during 14 years of follow-up, and the OGTT-derived disposition index (DI) was used as a marker for β-cell function. Genetic risk was quantified using the genome-wide polygenic risk score (PRS) and was stratified into low (1st quintile), intermediate (2nd-4th quintiles), and high (5th quintile) genetic risk. Lifestyle was assessed according to Life's Essential 8.
RESULTS
During a mean follow-up of 10.9 years, 374 (29.6%), 851 (22.5%), and 188 (14.9%) participants developed T2D in the high, intermediate, and low genetic risk groups, respectively. Compared with the low genetic risk group, participants in the high genetic risk group had a 25% lower DI at baseline. Furthermore, in longitudinal analysis, we observed a 1.83-fold faster decline in log2-transformed DI per year (-0.034 vs. -0.019, P = 2.1 × 10-3; per 1-SD increase in T2D PRS, P = 1.2 × 10-4). Healthy lifestyle attenuated the rate of decline in DI across all genetic risk groups.
CONCLUSIONS
Individuals with a higher genetic risk for T2D exhibited not only a lower OGTT-derived β-cell function at baseline but also a notably more rapid decline during follow-up. This information could be used to enable a focused precision prevention with lifestyle intervention.
PubMed: 38829722
DOI: 10.2337/dc24-0058 -
Research Square May 2024Satiation is the physiologic process that regulates meal size and termination, and it is quantified by the calories consumed to reach satiation. Given its role in energy...
Satiation is the physiologic process that regulates meal size and termination, and it is quantified by the calories consumed to reach satiation. Given its role in energy intake, changes in satiation contribute to obesity's pathogenesis. Our study employed a protocolized approach to study the components of food intake regulation including a standardized breakfast, a gastric emptying study, appetite sensation testing, and a satiation measurement by an test. These studies revealed that satiation is highly variable among individuals, and while baseline characteristics, anthropometrics, body composition and hormones, contribute to this variability, these factors do not fully account for it. To address this gap, we explored the role of a germline polygenic risk score, which demonstrated a robust association with satiation. Furthermore, we developed a machine-learning-assisted gene risk score to predict satiation and leveraged this prediction to anticipate responses to anti-obesity medications. Our findings underscore the significance of satiation, its inherent variability, and the potential of a genetic risk score to forecast it, ultimately allowing us to predict responses to different anti-obesity interventions.
PubMed: 38826309
DOI: 10.21203/rs.3.rs-4402499/v1 -
Journal of Gastrointestinal Surgery :... May 2024Bariatric surgery (BS) is currently the most effective long-term treatment of severe obesity. However, the interindividual variability observed in surgical outcomes...
BACKGROUND
Bariatric surgery (BS) is currently the most effective long-term treatment of severe obesity. However, the interindividual variability observed in surgical outcomes suggests a moderating effect of several factors, including individual genetic background. This study aimed to investigate the contribution of the genetic architecture of body mass index (BMI) to the variability in weight loss outcomes after BS.
METHODS
A total of 106 patients with severe obesity who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy were followed up for 5 years. Changes in BMI (BMIchange) and percentage of total weight loss (%TWL) were evaluated during the postoperative period. Polygenic risk scores (PRSs), including 50 genetic variants, were calculated for each participant to determine their genetic risk of high BMI based on a previous genome-wide association study. Generalized estimating equation models were used to study the role of the individual's polygenic score and other factors on BMIchange and %TWL in the long term after surgery.
RESULTS
This study found an effect of the polygenic score on %TWL and BMIchange, in which patients with lower scores had better outcomes after surgery than those with higher scores. Furthermore, when analyzing only patients who underwent RYGB, the results were replicated, showing greater weight loss after surgery for patients with lower polygenic scores.
DISCUSSION
Our results indicate that genetic background assessed with PRSs, along with other individual factors, such as biological sex, age, and preoperative BMI, has an effect on BS outcomes and could represent a useful tool for estimating surgical outcomes in advance.
PubMed: 38821212
DOI: 10.1016/j.gassur.2024.05.029 -
Genes Apr 2024Statistical genetic models of genotype-by-environment (G×E) interaction can be divided into two general classes, one on G×E interaction in response to dichotomous... (Review)
Review
Statistical genetic models of genotype-by-environment (G×E) interaction can be divided into two general classes, one on G×E interaction in response to dichotomous environments (e.g., sex, disease-affection status, or presence/absence of an exposure) and the other in response to continuous environments (e.g., physical activity, nutritional measurements, or continuous socioeconomic measures). Here we develop a novel model to jointly account for dichotomous and continuous environments. We develop the model in terms of a joint genotype-by-sex (for the dichotomous environment) and genotype-by-social determinants of health (SDoH; for the continuous environment). Using this model, we show how a depression variable, as measured by the Beck Depression Inventory-II survey instrument, is not only underlain by genetic effects (as has been reported elsewhere) but is also significantly determined by joint G×Sex and G×SDoH interaction effects. This model has numerous applications leading to potentially transformative research on the genetic and environmental determinants underlying complex diseases.
Topics: Gene-Environment Interaction; Humans; Models, Genetic; Genotype; Depression; Models, Statistical; Male
PubMed: 38790175
DOI: 10.3390/genes15050547