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Biomedicines Jan 2023Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the liver. NAFLD is epidemiologically associated with obesity, type 2 diabetes, and dyslipidemia. Environmental factors, such as physical inactivity and an unbalanced diet, interact with genetic factors, such as epigenetic mechanisms and polymorphisms for the genesis and development of the condition. Different genetic polymorphisms seem to be involved in this context, including variants in PNPLA3, TM6SF2, PEMT, and CHDH genes, playing a role in the disease's susceptibility, development, and severity. From carbohydrate intake and weight loss to omega-3 supplementation and caloric restriction, different dietary and nutritional factors appear to be involved in controlling the onset and progression of NAFLD conditions influencing metabolism, gene, and protein expression. The polygenic risk score represents a sum of trait-associated alleles carried by an individual and seems to be associated with NAFLD outcomes depending on the dietary context. Understanding the exact extent to which lifestyle interventions and genetic predispositions can play a role in the prevention and management of NAFLD can be crucial for the establishment of a personalized and integrative approach to patients.
PubMed: 36830856
DOI: 10.3390/biomedicines11020319 -
Best Practice & Research. Clinical... Oct 2014Heritability of obesity and body weight variation is high. Molecular genetic studies have led to the identification of mutations in a few genes, with a major effect on... (Review)
Review
Heritability of obesity and body weight variation is high. Molecular genetic studies have led to the identification of mutations in a few genes, with a major effect on obesity (major genes and monogenic forms). Analyses of these genes have helped to unravel important pathways and have created a more profound understanding of body weight regulation. For most individuals, a polygenic basis is relevant for the genetic predisposition to obesity. Small effect sizes are conveyed by the polygenic variants. Hence, only if a number of these variants is harboured, a sizeable phenotypic effect is detectable. Most, if not all, of the genes relevant to weight regulation are expressed in the hypothalamus. This underscores the major role of this region of the brain in body weight regulation.
Topics: Body Weight; Energy Metabolism; Genetic Predisposition to Disease; Genetic Variation; Humans; Hypothalamus; Obesity; Phenotype
PubMed: 25256760
DOI: 10.1016/j.beem.2014.04.007 -
Circulation. Genomic and Precision... Jun 2018Type 2 diabetes mellitus (T2D) and obesity already represent 2 of the most prominent risk factors for cardiovascular disease, and are destined to increase in importance... (Review)
Review
Type 2 diabetes mellitus (T2D) and obesity already represent 2 of the most prominent risk factors for cardiovascular disease, and are destined to increase in importance given the global changes in lifestyle. Ten years have passed since the first round of genome-wide association studies for T2D and obesity. During this decade, we have witnessed remarkable developments in human genetics. We have graduated from the despair of candidate gene-based studies that generated few consistently replicated genotype-phenotype associations, to the excitement of an exponential harvest of loci robustly associated with medical outcomes through ever larger genome-wide association study meta-analyses. As well as discovering hundreds of loci, genome-wide association studies have provided transformative insights into the genetic architecture of T2D and other complex traits, highlighting the extent of polygenicity and the tiny effect sizes of many common risk alleles. Genome-wide association studies have also provided a critical starting point for discovering new biology relevant to these traits. Expectations are high that these discoveries will foster development of more effective strategies for intervention, through optimization of precision medicine approaches. In this article, we review current knowledge and provide suggestions for the next steps in genetic research for T2D and obesity. We focus on four areas relevant to precision medicine: genetic architecture, pharmacogenetics and other gene-environment interactions, mechanistic inference, and drug development. As we describe, the genetic architecture of complex traits has major implications for the prospects of precision medicine, rendering some anticipated approaches decidedly unrealistic. We highlight obstacles to the translation of human genetic findings into mechanism inference but are optimistic that, as these are overcome, there is untapped potential for novel drugs and more effective strategies for treating and preventing T2D and obesity.
Topics: Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Obesity; Risk Factors
PubMed: 29899044
DOI: 10.1161/CIRCGEN.118.002090 -
Current Genomics Jul 2022Individuals with a phenotype of early-onset severe obesity associated with intellectual disability can have molecular diagnoses ranging from monogenic to complex... (Review)
Review
Individuals with a phenotype of early-onset severe obesity associated with intellectual disability can have molecular diagnoses ranging from monogenic to complex genetic traits. Severe overweight is the major sign of a syndromic physical appearance and predicting the influence of a single gene and/or polygenic risk profile is extremely complicated among the majority of the cases. At present, considering rare monogenic bases as the principal etiology for the majority of obesity cases associated with intellectual disability is scientifically poor. The diversity of the molecular bases responsible for the two entities makes the appliance of the current routinely powerful genomics diagnostic tools essential. Clinical investigation of these difficult-to-diagnose patients requires pediatricians and neurologists to use optimized descriptions of signs and symptoms to improve genotype correlations. The use of modern integrated bioinformatics strategies which are conducted by experienced multidisciplinary clinical teams. Evaluation of the phenotype of the patient's family is also of importance. The next step involves discarding the monogenic canonical obesity syndromes and considering infrequent unique molecular cases, and/or then polygenic bases. Adequate management of the application of the new technique and its diagnostic phases is essential for achieving good cost/efficiency balances. With the current clinical management, it is necessary to consider the potential coincidence of risk mutations for obesity in patients with genetic alterations that induce intellectual disability. In this review, we describe an updated algorithm for the molecular characterization and diagnosis of patients with a syndromic obesity phenotype.
PubMed: 36777005
DOI: 10.2174/1389202923666220426093436 -
JAMA Cardiology Jul 2022Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM...
IMPORTANCE
Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis.
OBJECTIVE
To assess the contributions of rare and common genetic variation to risk of HCM in the general population.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022.
EXPOSURES
Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors.
MAIN OUTCOMES AND MEASURES
Risk of HCM.
RESULTS
The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87).
CONCLUSIONS AND RELEVANCE
Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.
Topics: Adolescent; Biological Specimen Banks; Cardiomyopathy, Hypertrophic; Cohort Studies; Death, Sudden, Cardiac; Female; Humans; Male; Middle Aged; Mutation
PubMed: 35583889
DOI: 10.1001/jamacardio.2022.1061 -
Reviews in Endocrine & Metabolic... Oct 2023Obesity is a common complex trait that elevates the risk for various diseases, including type 2 diabetes and cardiovascular disease. A combination of environmental and... (Review)
Review
Obesity is a common complex trait that elevates the risk for various diseases, including type 2 diabetes and cardiovascular disease. A combination of environmental and genetic factors influences the pathogenesis of obesity. Advances in genomic technologies have driven the identification of multiple genetic loci associated with this disease, ranging from studying severe onset cases to investigating common multifactorial polygenic forms. Additionally, findings from epigenetic analyses of modifications to the genome that do not involve changes to the underlying DNA sequence have emerged as key signatures in the development of obesity. Such modifications can mediate the effects of environmental factors, including diet and lifestyle, on gene expression and clinical presentation. This review outlines what is known about the genetic and epigenetic contributors to obesity susceptibility, along with the albeit limited therapeutic options currently available. Furthermore, we delineate the potential mechanisms of actions through which epigenetic changes can mediate environmental influences and the related opportunities they present for future interventions in the management of obesity.
Topics: Humans; Diabetes Mellitus, Type 2; Obesity; Epigenesis, Genetic; Epigenomics; Genome-Wide Association Study
PubMed: 37032403
DOI: 10.1007/s11154-023-09804-6 -
Current Opinion in Clinical Nutrition... Jul 2022Intrahepatic triglyceride (IHTG) content is determined by substrate flux to, fatty acid synthesis and partitioning within, and triglyceride disposal from the liver.... (Review)
Review
PURPOSE OF REVIEW
Intrahepatic triglyceride (IHTG) content is determined by substrate flux to, fatty acid synthesis and partitioning within, and triglyceride disposal from the liver. Dysregulation of these processes may cause IHTG accumulation, potentially leading to nonalcoholic fatty liver disease. The aetiology of IHTG accumulation has not been fully elucidated; however, environmental factors and heritability are important. Here, we review recent evidence regarding the contribution of metabolic and genetic components of IHTG accumulation.
RECENT FINDINGS
Obesity and insulin resistance are the primary metabolic drivers for IHTG accumulation. These risk factors have pronounced and seemingly overlapping effects on all processes involved in determining IHTG content. The strong and interchangeable associations between obesity, insulin resistance and IHTG make it challenging to determine their relative contributions. Genome-wide association studies have identified a growing list of single nucleotide polymorphisms associated with IHTG content and recent work has begun to elucidate their mechanistic effects. The mechanisms underlying metabolic and genetic drivers of IHTG appear to be distinct.
SUMMARY
Both metabolic and genetic factors influence IHTG content by apparently distinct mechanisms. Further work is needed to determine metabolic and genetic interaction effects, which may lead to more personalized and potentially efficacious therapeutic interventions. The development of a comprehensive polygenic risk score for IHTG content may help facilitate this.
Topics: Genome-Wide Association Study; Glucose Clamp Technique; Humans; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Obesity; Triglycerides
PubMed: 35762159
DOI: 10.1097/MCO.0000000000000838 -
Clinical Genetics Jan 2019Obesity has become a major health problem worldwide. To date, more than 25 different syndromic forms of obesity are known in which one (monogenic) or multiple... (Review)
Review
Obesity has become a major health problem worldwide. To date, more than 25 different syndromic forms of obesity are known in which one (monogenic) or multiple (polygenic) genes are involved. This review gives an overview of these forms and focuses more in detail on 6 syndromes: Prader Willi Syndrome and Prader Willi like phenotype, Bardet Biedl Syndrome, Alström Syndrome, Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation syndrome and 16p11.2 (micro)deletions. Years of research provided plenty of information on the molecular genetics of these disorders and the obesity phenotype leading to a more individualized treatment of the symptoms, however, many questions still remain unanswered. As these obesity syndromes have different signs and symptoms in common, it makes it difficult to accurately diagnose patients which may result in inappropriate treatment of the disease. Therefore, the big challenge for clinicians and scientists is to more clearly differentiate all syndromic forms of obesity to provide conclusive genetic explanations and eventually deliver accurate genetic counseling and treatment. In addition, further delineation of the (functions of the) underlying genes with the use of array- or next-generation sequencing-based technology will be helpful to unravel the mechanisms of energy metabolism in the general population.
Topics: Alstrom Syndrome; Aniridia; Bardet-Biedl Syndrome; Genetic Counseling; High-Throughput Nucleotide Sequencing; Humans; Intellectual Disability; Obesity; Phenotype; Prader-Willi Syndrome; Wilms Tumor
PubMed: 29700824
DOI: 10.1111/cge.13367 -
Pediatric Obesity Apr 2019Both polygenic and unhealthy lifestyle factors contribute to individual-level risk of obesity during childhood. The extent to which increased polygenic risk can be...
BACKGROUND
Both polygenic and unhealthy lifestyle factors contribute to individual-level risk of obesity during childhood. The extent to which increased polygenic risk can be offset by healthy lifestyle is unknown.
OBJECTIVE
To examine whether increased polygenic risk of obesity is modified by a healthy lifestyle during childhood.
METHODS
A total of 997 children (418 boys and 579 girls) who had complete DNA genotyping and body mass index (BMI) were eligible for the study were analyzed from an established prospective puberty cohort. The polygenic risk score (PRS) was computed based on 11 BMI-increasing single nucleotide polymorphisms (SNPs) derived from a published genome-wide association study (GWAS) for child obesity. Seven lifestyle factors were selected to determine a composite healthy lifestyle, such as food responsiveness, slowness in eating, satiety responsiveness, physical activity, screen time, sleep duration, and sugar-sweetened beverages consumption, and which was classified as healthy (
P ) lifestyle. Linear and logistic regression analyses were conducted.
RESULTS
Children carrying additional BMI susceptibility alleles increased the BMI by 0.11 kg/m , after adjusting gender, age and socio-economic status (SES). A healthy lifestyle was associated with a substantially lower risk of obesity than an unhealthy lifestyle, regardless of the polygenic risk category. Among children at high polygenic risk, a healthy lifestyle was associated with an 85% lower risk of obesity than an unhealthy lifestyle (odds ratio, 0.15; 95% CI, 0.04 to 0.59; p = 0.007).
CONCLUSIONS
Our findings suggest that increased polygenic risk might be largely offset by healthy lifestyle as early as in childhood.
Topics: Alleles; Body Mass Index; Child; Child Behavior; China; Cohort Studies; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Healthy Lifestyle; Humans; Male; Patient Compliance; Pediatric Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Risk Assessment
PubMed: 30515989
DOI: 10.1111/ijpo.12489 -
Clinical Gastroenterology and... Mar 2022A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content...
BACKGROUND & AIMS
A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content [PRS-HFC]). Here, we hypothesized that the addition of PRS-HFC to clinical fibrosis scores may improve risk stratification and prediction of severe liver disease (SLD).
METHODS
We used data from 266,687 individuals in the UK Biobank, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation during a median follow-up period of 9 years. Nonalcoholic fatty liver disease fibrosis score, Fibrosis-4, aspartate aminotransferase-to-platelet ratio, BARD, and Forns scores, and PRS-HFC, were computed. All analyses were stratified according to the presence of diabetes, obesity, and a positive fatty liver index (≥60).
RESULTS
Unfavorable genetics (PRS-HFC, ≥0.396) further stratified the risk of SLD in subjects in intermediate-/high-risk classes of fibrosis scores, with a higher effect in those with metabolic risk factors, and the prediction was improved by integrating PRS-HFC (areas under the receiver operating characteristic increased for all scores with a P value of approximately 10 to 10, except for the aspartate aminotransferase-to-platelet ratio in the overall population and in subjects with obesity). PRS-HFC improved diagnostic accuracies and positive predictive values for SLD in intermediate-high clinical score risk classes. Risk stratification and prediction were not affected or were poorly affected by unfavorable genetics in subjects without metabolic risk factors.
CONCLUSIONS
Integration of genetics with clinical fibrosis scores refines individual risk and prediction for SLD, mainly in individuals at risk for nonalcoholic fatty liver disease. These data provide evidence from a prospective cohort that common genetic variants capture additional prognostic insights not conveyed by validated clinical/biochemical parameters.
Topics: Fibrosis; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Prospective Studies; Risk Assessment; Risk Factors
PubMed: 34091049
DOI: 10.1016/j.cgh.2021.05.056