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Human Molecular Genetics Nov 2019Prediction of disease risk is an essential part of preventative medicine, often guiding clinical management. Risk prediction typically includes risk factors such as age,... (Review)
Review
Prediction of disease risk is an essential part of preventative medicine, often guiding clinical management. Risk prediction typically includes risk factors such as age, sex, family history of disease and lifestyle (e.g. smoking status); however, in recent years, there has been increasing interest to include genomic information into risk models. Polygenic risk scores (PRS) aggregate the effects of many genetic variants across the human genome into a single score and have recently been shown to have predictive value for multiple common diseases. In this review, we summarize the potential use cases for seven common diseases (breast cancer, prostate cancer, coronary artery disease, obesity, type 1 diabetes, type 2 diabetes and Alzheimer's disease) where PRS has or could have clinical utility. PRS analysis for these diseases frequently revolved around (i) risk prediction performance of a PRS alone and in combination with other non-genetic risk factors, (ii) estimation of lifetime risk trajectories, (iii) the independent information of PRS and family history of disease or monogenic mutations and (iv) estimation of the value of adding a PRS to specific clinical risk prediction scenarios. We summarize open questions regarding PRS usability, ancestry bias and transferability, emphasizing the need for the next wave of studies to focus on the implementation and health-economic value of PRS testing. In conclusion, it is becoming clear that PRS have value in disease risk prediction and there are multiple areas where this may have clinical utility.
Topics: Alzheimer Disease; Breast Neoplasms; Coronary Artery Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Medical History Taking; Multifactorial Inheritance; Obesity; Prostatic Neoplasms; Reproducibility of Results; Risk Factors
PubMed: 31363735
DOI: 10.1093/hmg/ddz187 -
Nature Reviews. Endocrinology Oct 2022Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the... (Review)
Review
Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin-melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families.
Topics: Child, Preschool; Genetic Predisposition to Disease; Humans; Hyperphagia; Leptin; Melanocortins; Obesity; Phenotype; Receptors, Leptin
PubMed: 35902734
DOI: 10.1038/s41574-022-00716-0 -
Clinical Science (London, England :... Jun 2016In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a... (Review)
Review
In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity's aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine.
Topics: Epigenesis, Genetic; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Leptin; Metagenomics; Obesity
PubMed: 27154742
DOI: 10.1042/CS20160136 -
European Heart Journal Feb 2023Heart failure with preserved ejection fraction (HFpEF) is a major driver of cardiac morbidity and mortality in developed countries, due to ageing populations and the... (Review)
Review
Heart failure with preserved ejection fraction (HFpEF) is a major driver of cardiac morbidity and mortality in developed countries, due to ageing populations and the increasing prevalence of comorbidities. While heart failure with reduced ejection fraction is dominated by left ventricular impairment, HFpEF results from a complex interplay of cardiac remodelling, peripheral circulation, and concomitant features including age, hypertension, obesity, and diabetes. In an important subset, however, HFpEF is subtended by specific diseases of the myocardium that are genetically determined, have distinct pathophysiology, and are increasingly amenable to targeted, innovative treatments. While each of these conditions is rare, they collectively represent a relevant subset within HFpEF cohorts, and their prompt recognition has major consequences for clinical practice, as access to dedicated, disease-specific treatments may radically change the quality of life and outcome. Furthermore, response to standard heart failure treatment will generally be modest for these individuals, whose inclusion in registries and trials may dilute the perceived efficacy of treatments targeting mainstream HFpEF. Finally, a better understanding of the molecular underpinnings of monogenic myocardial disease may help identify therapeutic targets and develop innovative treatments for selected HFpEF phenotypes of broader epidemiological relevance. The field of genetic cardiomyopathies is undergoing rapid transformation due to recent, groundbreaking advances in drug development, and deserves greater awareness within the heart failure community. The present review addressed existing and developing therapies for genetic causes of HFpEF, including hypertrophic cardiomyopathy, cardiac amyloidosis, and storage diseases, discussing their potential impact on management and their broader implications for our understanding of HFpEF at large.
Topics: Humans; Heart Failure; Quality of Life; Stroke Volume; Myocardium; Cardiomyopathies; Ventricular Dysfunction, Left; Ventricular Function, Left
PubMed: 36582184
DOI: 10.1093/eurheartj/ehac764 -
Endocrine Reviews Mar 2023The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or...
The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.
Topics: Humans; Puberty, Precocious; Gonadotropin-Releasing Hormone; Hypothalamic Diseases; Hypothalamus; Puberty; Ubiquitin-Protein Ligases
PubMed: 35930274
DOI: 10.1210/endrev/bnac020 -
Journal of Diabetes Investigation Sep 2018Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment... (Review)
Review
Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment failure and development of diabetic complications. Recent advances in our understanding of the genomic architecture of diabetes and its complications have provided the framework for development of precision medicine to personalize diabetes prevention and management. In the present review, we summarized recent advances in the understanding of the genetic basis of diabetes and its complications. From a clinician's perspective, we attempted to provide a balanced perspective on the utility of genomic medicine in the field of diabetes. Using genetic information to guide management of monogenic forms of diabetes represents the best-known examples of genomic medicine for diabetes. Although major strides have been made in genetic research for diabetes, its complications and pharmacogenetics, ongoing efforts are required to translate these findings into practice by incorporating genetic information into a risk prediction model for prioritization of treatment strategies, as well as using multi-omic analyses to discover novel drug targets with companion diagnostics. Further research is also required to ensure the appropriate use of this information to empower individuals and healthcare professionals to make personalized decisions for achieving the optimal outcome.
Topics: Diabetes Mellitus; Disease Management; Humans; Pharmacogenetics; Precision Medicine; Risk Factors
PubMed: 29499103
DOI: 10.1111/jdi.12830 -
Gastroenterology Clinics of North... Dec 2023Similar to the general population, lifestyle interventions focused on nutrition and physical activity form the foundation for treating obesity caused by rare genetic... (Review)
Review
Similar to the general population, lifestyle interventions focused on nutrition and physical activity form the foundation for treating obesity caused by rare genetic disorders. Additional therapies, including metreleptin and setmelanotide, that target defects within the leptin signaling pathway can effectively synergize with lifestyle efforts to treat monogenic disorders of leptin, leptin receptor, proopiomelanocortin (POMC), and proprotein convertase subtilisin/kexin type 1 (PCSK1) and syndromic conditions, such as the ciliopathies Bardet-Biedl and Alström syndromes, whose pathophysiological mechanisms also converge on the leptin pathway. Investigational treatments for Prader-Willi syndrome target specific defects caused by reduced expression of paternally derived genes within the chromosome 15q region.
Topics: Humans; Leptin; Obesity; Prader-Willi Syndrome
PubMed: 37919024
DOI: 10.1016/j.gtc.2023.08.005 -
Nature Nov 2021Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes, underscoring the conserved metabolic benefits of oestrogen that inevitably...
Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes, underscoring the conserved metabolic benefits of oestrogen that inevitably decrease with age. In rodents, the preovulatory surge in 17β-oestradiol (E2) temporarily increases energy expenditure to coordinate increased physical activity with peak sexual receptivity. Here we report that a subset of oestrogen-sensitive neurons in the ventrolateral ventromedial hypothalamic nucleus (VMHvl) projects to arousal centres in the hippocampus and hindbrain, and enables oestrogen to rebalance energy allocation in female mice. Surges in E2 increase melanocortin-4 receptor (MC4R) signalling in these VMHvl neurons by directly recruiting oestrogen receptor-α (ERα) to the Mc4r gene. Sedentary behaviour and obesity in oestrogen-depleted female mice were reversed after chemogenetic stimulation of VMHvl neurons expressing both MC4R and ERα. Similarly, a long-term increase in physical activity is observed after CRISPR-mediated activation of this node. These data extend the effect of MC4R signalling - the most common cause of monogenic human obesity - beyond the regulation of food intake and rationalize reported sex differences in melanocortin signalling, including greater disease severity of MC4R insufficiency in women. This hormone-dependent node illuminates the power of oestrogen during the reproductive cycle in motivating behaviour and maintaining an active lifestyle in women.
Topics: Animals; Brain; CRISPR-Cas Systems; Energy Metabolism; Estrogen Receptor alpha; Estrogens; Female; Gene Editing; Hippocampus; Male; Melanocortins; Mice; Neurons; Obesity; Physical Exertion; Receptor, Melanocortin, Type 4; Rhombencephalon; Sedentary Behavior; Sex Characteristics; Signal Transduction; Ventromedial Hypothalamic Nucleus
PubMed: 34646010
DOI: 10.1038/s41586-021-04010-3 -
Journal of Diabetes and Its... Jan 2021Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the... (Review)
Review
Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the common subtypes of MODY (MODY-1, 2, 3 and 5) little is known about its rare subtypes (MODY4, 6-14). With the advent of next-generation sequencing (NGS) there are several reports of the rarer subtypes of MODY emerging from across the world. Therefore, a greater understanding on these rarer subtypes is needed. A search strategy was created, and common databases were searched, and 51 articles finally selected. INS-(MODY10) and ABCC8-(MODY12) mutations were reported in relatively large numbers compared to the other rare subtypes. The clinical characteristics of the rare MODY subtypes exhibited heterogeneity between families reported with the same mutation. Obesity and diabetic ketoacidosis (DKA) were also reported among rarer MODY subtypes which presents as a challenge as these are not part of the original description of MODY by Tattersal and Fajans. The treatment modalities of the rarer subtypes included oral drugs, predominantly sulfonylureas, insulin but also diet alone. Newer drugs like DPP-4 and SGLT2 inhibitors have also been tried as new modes of treatment. The microvascular and macrovascular complications among the patients with various MODY subtypes are less commonly reported. Recently, there is a view that not all the 14 forms of 'MODY' are true MODY and the very existence of some of these rarer subtypes as MODY has been questioned. This scoping review aims to report on the clinical characteristics, treatment and complications of the rarer MODY subtypes published in the literature.
Topics: Diabetes Mellitus, Type 2; Humans; Insulin; Pharmaceutical Preparations; Sulfonylurea Compounds
PubMed: 32763092
DOI: 10.1016/j.jdiacomp.2020.107640 -
Acta Bio-medica : Atenei Parmensis Sep 2019Obesity is highly heritable and arises from the interplay of many genes and environmental factors. It can be defined as the result of prolonged imbalance between calorie... (Review)
Review
Obesity is highly heritable and arises from the interplay of many genes and environmental factors. It can be defined as the result of prolonged imbalance between calorie intake and energy utilization. About 5% of cases of non-syndromic obesity are monogenic (Mendelian obesity). The amount of adipose tissue in the body is mainly regulated by leptin, a hormone produced by adipocytes, and Mendelian obesity is mainly caused by mutations that disrupt the leptin/melanocortin pathway. In this article, we summarize the genes involved in genetic obesity and the test we use for genetic analysis.
Topics: Adipogenesis; Genetic Predisposition to Disease; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Leptin; Melanocortins; Mutation; Obesity
PubMed: 31577261
DOI: 10.23750/abm.v90i10-S.8766