Genetics of Coronary Artery Disease: Discovery, Biology and Clinical Translation !

Genetics

Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked approximately 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and functional studies have facilitated a better understanding of causal risk factors, elucidated underlying biology and informed the development of new therapeutics. Moving forwards, genetic testing could enable precision medicine approaches by identifying subgroups of patients at increased risk of coronary artery disease or those with a specific driving pathophysiology in whom a therapeutic or preventive approach would be most useful.

• Coronary artery disease is a heritable disorder that remains the leading cause of global mortality despite advances in treatment and prevention strategies. Human genetics studies have started to unravel the genetic underpinnings of this disorder.
• Gene discovery efforts have rapidly transitioned from family-based studies (for example, those that led to the discovery of familial hypercholesterolaemia) to large cohorts that facilitate both common and rare variant association studies.
• Common variant association studies have confirmed ∼60 genetic loci with a robust association with coronary disease, the majority of which are of modest effect size and in non-coding regions. Rare variant association studies have linked inactivating mutations in at least nine genes with risk of coronary artery disease.
• Human genetics and large-scale biobanks can facilitate drug development for coronary artery disease by highlighting causal biology and helping to understand the phenotypic consequences of lifelong deficiency of a given protein.
• Genomic medicine may provide patients and their health care providers with genetic data that will aid in coronary artery disease prevention and treatment.
• Genome editing to introduce mutations that are protective against coronary artery disease into the population could prove curative with a one-time injection, although substantial additional work is needed to confirm efficacy and safety, and to address the underlying ethics.

Observational epidemiology and translational research efforts have led to significant progress in improving the understanding of the pathophysiology underlying coronary artery disease (CAD). Prevention and treatment strategies developed on the basis of this knowledge led to a >50% decrease in age-adjusted CAD mortality rate in the United States between 1980 and 2000. However, despite these advances, CAD remains the leading global cause of mortality. Current predictions estimate that more than 900,000 individuals in the United States will suffer a myocardial infarction (heart attack) or die of CAD this year.

This review outlines research efforts to understand the genetic drivers of CAD, the role of human genetics in catalysing CAD drug discovery efforts and the promises and challenges of integrating genetic information into routine clinical practice.

Read More »

Human Microbiome and its Association With Health and Diseases

Human microbiota are distinct communities of microorganisms that resides at different body niches. Exploration of the human microbiome has become a reality due to the availability of powerful metagenomics and metatranscriptomic analysis technologies. Recent advances in sequencing and bioinformatics over the past decade help provide a deep insight into the nature of the host-microbial interactions and identification of potential deriver genes and pathways associated with human health, well-being, and predisposition to different diseases. In the present review, we outline recent studies devoted to elucidate the possible link between the microbiota and various type of diseases. The present review also highlights the potential utilization of microbiota as a potential therapeutic option to treat a wide array of human diseases.

Humans are viewed as composites of human and microbial cells. Human microbiota are complex and dynamic microbial communities composed mainly of bacteria, but also includes protozoa, archaea, viruses, and fungi that resides in and on different body niches such as oral cavity, throat, esophagus, stomach, colon, urogenital tract, respiratory tract, and skin. The number of microbial cells inhabiting human body is estimated to exceed the H.sapiens cells by 10-fold and estimated at 350 trillion microbial cells.

Read more: Human Microbiome and its Association With Health and Diseases

Microbiome-host interactions. Schematic representation showing the perplexed microbial-host
interactions due to different triggering factors on microbiota and their genetic material constitute;
the human microbiome.

Source: Wiley

MicroRNA: A Tiny Molecule Yields Big Insights Into Disease States

Regular readers of this column will know that there are two main categories of nucleic acids—DNA and RNA. They’ll also know that while for living organisms DNA acts as the genetic data repository, RNA has a messenger role (mRNAs, transcribed from DNA to direct protein synthesis). Most will also recall that there are other classes of RNA molecules, particularly tRNAs (used to tag and identify amino acids for protein synthesis) and rRNAs (structural components of the ribosome, the cellular “machinery” for protein synthesis). In addition to these, there’s increasing interest in the molecular diagnostics community in a less widely known but no less common RNA form, the microRNA or miRNA.

Read more: MicroRNA: A Tiny Molecule Yields Big Insights Into Disease States

Source: MedicalLaboratoryObserver

The Role of Diet and Exercise in the Transgenerational Epigenetic Landscape of T2DM

Epigenetic changes are caused by biochemical regulators of gene expression that can be transferred across generations or through cell division. Epigenetic modifications can arise from a variety of environmental exposures including undernutrition, obesity, physical activity, stress and toxins. Transient epigenetic changes across the entire genome can influence metabolic outcomes and might or might not be heritable. These modifications direct and maintain the cell-type specific gene expression state. Transient epigenetic changes can be driven by DNA methylation and histone modification in response to environmental stressors. A detailed understanding of the epigenetic signatures of insulin resistance and the adaptive response to exercise might identify new therapeutic targets that can be further developed to improve insulin sensitivity and prevent obesity. This Review focuses on the current understanding of mechanisms by which lifestyle factors affect the epigenetic landscape in type 2 diabetes mellitus and obesity. Evidence from the past few years about the potential mechanisms by which diet and exercise affect the epigenome over several generations is discussed.

Key points

• Epigenetic processes have been implicated in the pathogenesis of type 2 diabetes mellitus
• Diet and exercise might affect the epigenome over several generations
• Epigenetic changes can be driven by DNA methylation and histone modification in response to environmental stressors
• Regulation of gene expression by DNA methylation and histone modification occurs by a mechanism that impairs the access of transcriptional machinery to the promoters
• Studying the epigenetic signatures of insulin resistance and the adaptive response to exercise might provide insight into gene–environment networks that control glucose and energy homeostasis.

Read more: The Role of Diet and Exercise in the Transgenerational Epigenetic Landscape of T2DM

Figure 2: Putative effects of exercise and obesity on the predisposition to metabolic diseases.

Source: NatureReviewsEndocrinology

Tools for Lung Cancer Research

Recent advances in lung cancer research suggest a personalized approach to diagnostics and therapeutics to reduce mortality

Due to its high rate of mortality, lung cancer is a prominent area of research for scientists. Lung cancer is a complex disease with many subtypes resulting from factors such as family history, lifestyle and occupation-with each subtype requiring different treatment regimens. Thus, developing therapeutics for this disease requires vast research efforts.

The specific subtypes of the cancer must be paired to successful treatments, which can then be matched to individual patients. The American Type Culture Collection (ATCC) has responded to this initiative for personalized medicine by creating new drug screening and diagnostic test development tools, such as tumor cell panels based on genetic alteration, primary cells, gene-edited isogenic cell lines and cell line derivatives.

"Over the years, we have expanded our portfolio into the most diverse and unique collection of cancer cells to include thousands of human and animal cancer cell lines representing the diversity of the disease," said Fang Tian, PhD, lead scientist at ATCC. "Our growing collection of lung cancer cell lines is now just shy of 100 lines.

Read more: Tools for Lung Cancer Research

Source: laboratory-manager.advanceweb