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Genes Jan 2024Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute... (Review)
Review
Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in , , , and triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism. Hypertriglyceridemia resulting from such genetic abnormalities can be categorized as monogenic or polygenic. Monogenic hypertriglyceridemia, also known as familial chylomicronemia syndrome, is caused by homozygous or compound heterozygous pathogenic variants in the five canonical genes. Polygenic hypertriglyceridemia, also known as multifactorial chylomicronemia syndrome in extreme cases of hypertriglyceridemia, is caused by heterozygous pathogenic genetic variants with variable penetrance affecting the canonical genes, and a set of common non-pathogenic genetic variants (polymorphisms, using the former nomenclature) with well-established association with elevated triglyceride levels. We further address recent progress in triglyceride-lowering treatments. Understanding the genetic basis of hypertriglyceridemia opens new translational opportunities in the scope of genetic screening and the development of novel therapies.
Topics: Humans; Lipoprotein Lipase; Acute Disease; Pancreatitis; Hypertriglyceridemia; Triglycerides
PubMed: 38397180
DOI: 10.3390/genes15020190 -
Orphanet Journal of Rare Diseases Feb 2024The determinants of early-onset obesity (< 6 years) are not completely elucidated, however eating behavior has a central role. To date no study has explored eating...
Hyperphagia and impulsivity: use of self-administered Dykens' and in-house impulsivity questionnaires to characterize eating behaviors in children with severe and early-onset obesity.
BACKGROUND
The determinants of early-onset obesity (< 6 years) are not completely elucidated, however eating behavior has a central role. To date no study has explored eating behavior in children with severe, early-onset obesity. Self-administered questionnaire data from these children were examined to evaluate eating behavior and the etiology of early-onset obesity.
METHODS
Children with severe, early-onset obesity (body mass index [BMI] > International Obesity Task Force [IOTF] 30) of different etiologies (hypothalamic obesity [HO], intellectual disability with obesity [IDO], common polygenic obesity [CO]) were prospectively included. BMI history and responses from the Dykens' Hyperphagia Questionnaire and an in-house Impulsivity Questionnaire at first visit were compared between groups.
RESULTS
This cohort of 75 children (39 girls; mean age ± standard deviation [SD] 10.8 ± 4.4 years) had severe, early-onset obesity at an age of 3.8 ± 2.7 years, with a BMI Z-score of 4.9 ± 1.5. BMI history varied between the 3 groups, with earlier severe obesity in the HO group versus 2 other groups (BMI > IOTF40 at 3.4 ± 1.6 vs. 4.6 ± 1.6 and 8.4 ± 4.1 years for the IDO and CO groups, respectively [P < 0.01]). Absence of adiposity rebound was more prevalent in the HO group (87% vs. 63% and 33% for the IDO and CO groups, respectively [P < 0.01]). The Dykens' mean total score for the cohort was 22.1 ± 7.2 with no significant between-group differences. Hyperphagia (Dykens' score > 19) and impulsivity (score > 7) were found in 50 (67%) and 11 children (15%), respectively, with no difference between the HO, IDO and CO groups regarding the number of patients with hyperphagia (10 [67%], 14 [74%], and 26 [63%] children, respectively) or impulsivity (2 [13%], 1 [7%], and 8 [19%] children, respectively). Children with food impulsivity had significantly higher total and severity scores on the Dykens' Questionnaire versus those without impulsivity.
CONCLUSION
The Dykens' and Impulsivity questionnaires can help diagnose severe hyperphagia with/without food impulsivity in children with early-onset obesity, regardless of disease origin. Their systematic use can allow more targeted management of food access control in clinical practice and monitor the evolution of eating behavior in the case of innovative therapeutic targeting hyperphagia.
Topics: Child; Female; Humans; Infant; Child, Preschool; Hyperphagia; Obesity; Body Mass Index; Feeding Behavior; Impulsive Behavior; Surveys and Questionnaires
PubMed: 38395939
DOI: 10.1186/s13023-024-03085-1 -
PloS One 2024A striking global health development over the past few decades has been the increasing prevalence of overweight and obesity. At the same time, depression has become...
A striking global health development over the past few decades has been the increasing prevalence of overweight and obesity. At the same time, depression has become increasingly common in almost all high-income countries. We investigated whether body weight, measured by body mass index (BMI), has a causal effect on depression symptoms in Finland. Using data drawn from the Cardiovascular Risk in Young Finns Study (N = 1,523, mean age 41.9, SD 5), we used linear regression to establish the relationship between BMI and depression symptoms measured by 21-item Beck's Depression Inventory. To identify causal relationships, we used the Mendelian randomization (MR) method with weighted sums of genetic markers (single nucleotide polymorphisms, SNPs) as instruments for BMI. We employ instruments (polygenic risk scores, PGSs) with varying number of SNPs that are associated with BMI to evaluate the sensitivity of our results to instrument strength. Based on linear regressions, higher BMI was associated with a higher prevalence of depression symptoms among females (b = 0.238, p = 0.000) and males (b = 0.117, p = 0.019). However, the MR results imply that the positive link applies only to females (b = 0.302, p = 0.007) but not to males (b = -0.070, p = 0.520). Poor instrument strength may explain why many previous studies that have utilized genetic instruments have been unable to identify a statistically significant link between BMI and depression-related traits. Although the number of genetic markers in the instrument had only a minor effect on the point estimates, the standard errors were much smaller when more powerful instruments were employed.
Topics: Adult; Female; Humans; Male; Body Mass Index; Depression; Genetic Markers; Genome-Wide Association Study; Mendelian Randomization Analysis; Obesity; Overweight; Polymorphism, Single Nucleotide; Middle Aged
PubMed: 38394117
DOI: 10.1371/journal.pone.0297594 -
The British Journal of Nutrition May 2024We aimed to investigate the intricate interplay between genetic predisposition and lifestyle factors on stroke. We conducted a comprehensive genome-wide association...
We aimed to investigate the intricate interplay between genetic predisposition and lifestyle factors on stroke. We conducted a comprehensive genome-wide association study to identify the genetic variants linked to stroke in the participants who experienced a stroke event (cases; 672) and those with no stroke history (non-stroke; 58 029) in a large hospital-based cohort. Using generalised multifactor dimensionality reduction, we identified genetic variants with interactive effects and constructed polygenic risk scores (PRS) by summing up the risk alleles from the genetic variants. Food intake was measured with a validated semi-quantitative FFQ. No significant differences in stroke incidence were seen in demographic variables between the two groups. Among the metabolic indicators, only serum TAG levels were higher in males with stroke than those without stroke. The daily nutrient intake, dietary inflammation index, glycaemic index, dietary patterns, alcohol consumption, exercise and smoking did not display associations with the OR for stroke. The stroke-linked genetic variants were related to the - pathway. After accounting for covariates, the PRS derived from the 5-, 6- and 7-SNP models were positively associated with stroke chance with 2·5-, 2·9- and 2·8-fold. Furthermore, interactions between genetic predisposition and dietary components, including energy, carbohydrates, -3 fatty acids and branched-chain amino acids (BCAA), that affected OR for stroke were observed. A high intake of energy, carbohydrates and BCAA and a low intake of -3 fatty acids were positively associated with the chances of stroke occurrence. In conclusion, understanding the interaction between genetic variants and lifestyle factors can assist in developing stroke prevention and management strategies.
Topics: Humans; Male; Genome-Wide Association Study; Life Style; Stroke; Middle Aged; Female; Genetic Predisposition to Disease; Aged; Polymorphism, Single Nucleotide; Diet; Multifactorial Inheritance; Risk Factors; Cohort Studies
PubMed: 38374659
DOI: 10.1017/S0007114524000394 -
Nature Mar 2024Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell...
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
Topics: Humans; Adipocytes; Chromatin; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endothelial Cells; Enteroendocrine Cells; Epigenomics; Genetic Predisposition to Disease; Genome-Wide Association Study; Islets of Langerhans; Multifactorial Inheritance; Peripheral Arterial Disease; Single-Cell Analysis
PubMed: 38374256
DOI: 10.1038/s41586-024-07019-6 -
Nature Communications Feb 2024Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide...
Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identify eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supports novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homoeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggests that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and serum creatinine. Finally, we demonstrate how a retinol polygenic score could identify individuals more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further investigation with respect to retinol related therapies or nutritional intervention.
Topics: Humans; Vitamin A; Genome-Wide Association Study; Phenotype; Obesity; Adiposity; Mendelian Randomization Analysis; Retinol-Binding Proteins, Plasma
PubMed: 38374065
DOI: 10.1038/s41467-024-45779-x -
MedRxiv : the Preprint Server For... Feb 2024Sleep is a complex behavior regulated by genetic and environmental factors, and is known to influence health outcomes. However, the effect of multidimensional sleep...
Sleep is a complex behavior regulated by genetic and environmental factors, and is known to influence health outcomes. However, the effect of multidimensional sleep encompassing several sleep dimensions on diseases has yet to be fully elucidated. Using the Mass General Brigham Biobank, we aimed to examine the association of multidimensional sleep with health outcomes and investigate whether sleep behaviors modulate genetic predisposition to unfavorable sleep on mental health outcomes. First, we generated a Polygenic Sleep Health Score using previously identified single nucleotide polymorphisms for sleep health and constructed a Sleep Lifestyle Index using data from self-reported sleep questions and electronic health records; second, we performed phenome-wide association analyses between these indexes and clinical phenotypes; and third, we analyzed the interaction between the indexes on prevalent mental health outcomes. Fifteen thousand eight hundred and eighty-four participants were included in the analysis (mean age 54.4; 58.6% female). The Polygenic Sleep Health Score was associated with the Sleep Lifestyle Index (β=0.050, 95%CI=0.032, 0.068) and with 114 disease outcomes spanning 12 disease groups, including obesity, sleep, and substance use disease outcomes (p<3.3×10). The Sleep Lifestyle Index was associated with 458 disease outcomes spanning 17 groups, including sleep, mood, and anxiety disease outcomes (p<5.1×10). No interactions were found between the indexes on prevalent mental health outcomes. These findings suggest that favorable sleep behaviors and genetic predisposition to healthy sleep may independently be protective of disease outcomes. This work provides novel insights into the role of multidimensional sleep on population health and highlights the need to develop prevention strategies focused on healthy sleep habits.
PubMed: 38370718
DOI: 10.1101/2024.02.06.24302416 -
MedRxiv : the Preprint Server For... Jan 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for...
Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ≈7000 proteins in ≈5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk. The MASLD proteome was encoded by genes that demonstrated transcriptional enrichment in liver, with spatial transcriptional activity in areas of steatosis in human liver biopsy and dynamicity for select targets in human liver across stages of steatosis. We replicated several top relations from proteomics and spatial tissue transcriptomics in a humanized "liver-on-a-chip" model of MASLD, highlighting the power of a full translational approach to discovery in MASLD. Collectively, these results underscore utility of blood-based proteomics as a dynamic "liquid biopsy" of human liver relevant to clinical biomarker and mechanistic applications.
PubMed: 38352394
DOI: 10.1101/2024.01.26.24301828 -
Preventive Medicine Mar 2024We aimed to evaluate potential modifying effects of genetic susceptibility to obesity on the association of lifestyle factors with coronary artery disease (CAD) risk.
OBJECTIVE
We aimed to evaluate potential modifying effects of genetic susceptibility to obesity on the association of lifestyle factors with coronary artery disease (CAD) risk.
METHODS
A total of 328,606 participants (54% women) were included using data from the UK Biobank. We evaluated the risk of developing CAD associated with obesity-related polygenic scores (PGSs) and healthy lifestyle scores (HLSs). HLSs were constructed using six lifestyle factors. Obesity PGSs were created using genetic variants identified by genome-wide association studies, including 941 variants for body mass index (BMI) and 457 for waist-to-hip ratio (WHR). Both HLSs and PGSs were categorized into three groups.
RESULTS
During a 9-year median follow-up, 14,541 participants developed CAD. An unhealthy lifestyle was significantly associated with an increased CAD risk (hazard ratio [HR] = 2.24, 95% confidence interval [CI] = 2.09-2.40). High BMI and WHR PGSs were each significantly associated with an increased CAD risk (HR = 1.23, 1.17-1.29; HR = 1.15, 1.09-1.21). Lifestyle factors explained 41% (95% CI = 38%-45%) of CAD, while genetic variants for BMI explained only 10% (7%-14%). Risks of CAD were increased with poorer HLS independent of obesity-related PGSs. Individuals with the most unhealthy lifestyle and highest BMI PGS had the highest risk of CAD risk (HR = 2.59, 95% CI = 2.26-2.97), compared with participants with the healthiest lifestyle and lowest BMI PGS.
CONCLUSIONS
While the observational nature of the study precludes the establishment of causality, our study provides supports for a causal association between obesity and CAD risk and the importance of lifestyle modification in the prevention of CAD.
Topics: Humans; Female; Male; Coronary Artery Disease; Risk Factors; Cohort Studies; Genome-Wide Association Study; Biological Specimen Banks; UK Biobank; Obesity; Life Style; Genetic Predisposition to Disease
PubMed: 38316272
DOI: 10.1016/j.ypmed.2024.107886 -
The Journals of Gerontology. Series A,... Apr 2024Longevity and disease-free survival are influenced by a combination of genetics and lifestyle. Biological age (BioAge), a measure of aging based on composite biomarkers,...
Longevity and disease-free survival are influenced by a combination of genetics and lifestyle. Biological age (BioAge), a measure of aging based on composite biomarkers, may outperform chronological age in predicting health and longevity. This study investigated the relationship between genetic risks, lifestyle factors, and delta age (Δage), estimated as the difference between biological and chronological age. BioAge and Δage were calculated for 52 418 participants from the population-based Lifelines cohort. We computed 2 independent polygenic risk scores (PRS) for health span and DNA methylation-based aging clock to characterize genetic risks. The capacity of BioAge to predict all-cause mortality when adjusted for chronological age and genetic risks for aging, was assessed. Obesity, lifestyle, socioeconomic status, sex, and genetic variations in a population contributed to the differences in the rates of accelerated aging. The overall risk of death for a 1-year increase in BioAge for a given chronological age and sex among the genotyped participants was 11% (HR = 1.11; 95% CI: 1.09, 1.13). After adjusting for genetic factors, BioAge maintained its sensitivity for predicting mortality. Findings from this study ascertain that BioAge can be a useful tool for risk stratification in research and aging interventions.
Topics: Humans; Aging; Longevity; DNA Methylation; Risk Factors; Biomarkers; Epigenesis, Genetic
PubMed: 38305578
DOI: 10.1093/gerona/glae024