Project description:Cardiovascular diseases are the main cause of death worldwide. The ability to accurately define individual susceptibility to these disorders is therefore of strategic importance. Linkage analysis and genome-wide association studies have been useful for the identification of genes related to cardiovascular diseases. The identification of variants predisposing to cardiovascular diseases contributes to the risk profile and the possibility of tailored preventive or therapeutic strategies. Molecular genetics and pharmacogenetics are playing an increasingly important role in the correct clinical management of patients. For instance, genetic testing can identify variants that influence how patients metabolize medications, making it possible to prescribe personalized, safer and more efficient treatments, reducing medical costs and improving clinical outcomes. In the near future we can expect a great increment in information and genetic testing, which should be acknowledged as a true branch of diagnostics in cardiology, like hemodynamics and electrophysiology. In this review we summarize the genetics and pharmacogenetics of the main cardiovascular diseases, showing the role played by genetic information in the identification of cardiovascular risk factors and in the diagnosis and therapy of these conditions.
Project description:Anorexia nervosa (AN) is a serious mental illness characterized by severe dietary restriction that leads to high rates of morbidity, chronicity, and mortality. Unfortunately, effective treatment is lacking and few options are available. High rates of familial aggregation and significant heritability suggested that the complex etiology of AN is affected by both genetic and environmental factors. In this paper, we review studies that reported common and rare genetic variation that influence susceptibility of AN through candidate gene studies, genome-wide association studies, and sequencing-based studies. We also discuss gene expression, methylation, imaging genetics, and pharmacogenetics to demonstrate that these studies have collectively advanced our knowledge of how genetic variation contributes to AN susceptibility and clinical course. Lastly, we highlight the importance of gene by environment interactions (G×E) and share our enthusiasm for the use of nutritional genomic approaches to elucidate the interaction among nutrients, metabolic intermediates, and genetic variation in AN. A deeper understanding of how nutrition alters genome stability, how genetic variation influences uptake and metabolism of nutrients, and how response to food components affects disordered eating, will lead to personalized dietary interventions and effective nutraceutical and pharmacological treatments for AN.
Project description:Molecular biology and medical genetics, one of the most dynamically developing fields of medicine, nowadays is also a base for development of basic and clinical research in internal medicine. Understanding of crucial genetic pathomechanisms of many common diseases was possible due to the newest and modern molecular methods and tools. Moreover, development of genetics also made possible the discovery and understanding of the pathogenesis of many different diseases. However, not so long ago, we discovered precise pathomechanisms leading from damage of a single gene to a related pathological phenotype. Now, we have just started to explain molecular mechanisms of complex, multifactorial diseases. To achieve these goals, we need permanent development of genetic tests, genomics and proteomics. After fulfilling these conditions, we will get a chance to implement all molecular and genetic hopes, particularly their practical application in the clinic.
Project description:Background/aimsWe evaluated the contemporary use of lipid-lowering therapy (LLT) in Korean patients with atherosclerotic cardiovascular disease (ASCVD), and identified factors associated with statin non-prescription.MethodsUsing the Korean Health Insurance Review and Assessment data, we identified LLT-naïve subjects newly diagnosed with ASCVD between 2011 and 2012, and followed up until 2015. LLT-naïve status was defined as no LLT prescription for 1 year before ASCVD diagnosis. ASCVD was defined as first hospitalization or emergency room visit for coronary artery disease (CAD), acute cerebrovascular disease (CVD), or peripheral artery disease (PAD). Statin intensity was defined per the 2013 American College of Cardiology/American Heart Association guideline for cholesterol treatment.ResultsThe study enrolled 80,884 subjects newly diagnosed with ASCVD, of whom only 48,725 (60.2%) received LLT during the follow-up period. Statin, combination of statin and non-statin, and non-statin LLT were administered in 50.5%, 9.7%, and 0.1% of all subjects, respectively. Statins were prescribed to 80.4% of CAD patients but only to 50.2% and 46.8% of CVD and PAD patients. Statin-based LLT usually had moderate- (77.2%) or high-intensity (18.5%). Subjects not prescribed statins were younger or older (< 40 or ≥ 70 years), more commonly female, and more likely to have comorbidities. Statins were prescribed at the time of ASCVD diagnosis in 45.5% of all subjects, and in 53.0% within 90 days of diagnosis.ConclusionOnly 60% of LLT-naïve Korean patients newly diagnosed with ASCVD received statins. Statins were often prescribed in subjects with CAD but less commonly in those with CVD or PAD. Moderate-intensity statins were most frequently used.
Project description:Linkage studies and genome-wide linkage analyses, which use polymorphic DNA markers throughout the genome, provide a useful method for identifying genes related to cardiovascular disease (CVD). Many genome-wide linkage studies have contributed to identify quantitative genetic loci influencing variables involved in the pathogenesis of CVD.Meta-analyses of genetic studies provide the measure of association studies, so contributing to identify candidate genes which might influence the susceptibility to the disease. Really, candidate genes have been investigated, in relation to lipid metabolism (APOE), fibrinolytic proteins (PAI-1), renin-angiotensyn system (ACE) and homocysteine metabolism (MTHFR). Recently, genome-wide panels of common single nucleotide polymorphisms (SNPs), based on the use of SNPs spread throughout the genome, are also becoming available. This approach contributes to finely investigate the gene-gene and gene-environment interactions in CVD, and to look for the involvement of genetic polymorphisms in drug response.
Project description:Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients' quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies.
Project description:Chronic heart failure (CHF) remains the only cardiovascular disease with an increasing hospitalization burden and an ongoing drain on health care expenditures. The prevalence of CHF increases with advancing life span, with diastolic heart failure predominating in the elderly population. Primary prevention of coronary artery disease and risk factor management via aggressive blood pressure control are central in preventing new occurrences of left ventricular dysfunction. Optimal therapy for CHF involves identification and correction of potentially reversible precipitants, target-dose titration of medical therapy, and management of hospitalizations for decompensation. The etiological phenotype, absolute decrease in left ventricular ejection fraction and a widening of QRS duration on electrocardiography, is commonly used to identify patients at increased risk of progression of heart failure and sudden death who may benefit from prophylactic implantable cardioverter-defibrillator placement with or without cardiac resynchronization therapy. Patients who transition to advanced stages of disease despite optimal traditional medical and device therapy may be candidates for hemodynamically directed approaches such as a left ventricular assist device; in selected cases, listing for cardiac transplant may be warranted.
Project description:Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks.
Project description:Polygenic diseases, which are genetic disorders caused by the combined action of multiple genes, pose unique and significant challenges for the diagnosis and management of affected patients. A major goal of cardiovascular medicine has been to understand how genetic variation leads to the clinical heterogeneity seen in polygenic cardiovascular diseases (CVDs). Recent advances and emerging technologies in artificial intelligence (AI), coupled with the ever-increasing availability of next generation sequencing (NGS) technologies, now provide researchers with unprecedented possibilities for dynamic and complex biological genomic analyses. Combining these technologies may lead to a deeper understanding of heterogeneous polygenic CVDs, better prognostic guidance, and, ultimately, greater personalized medicine. Advances will likely be achieved through increasingly frequent and robust genomic characterization of patients, as well the integration of genomic data with other clinical data, such as cardiac imaging, coronary angiography, and clinical biomarkers. This review discusses the current opportunities and limitations of genomics; provides a brief overview of AI; and identifies the current applications, limitations, and future directions of AI in genomics.