Genetics of Cardiomyopathy

Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional (systolic and diastolic) abnormalities of the myocardium and are either confined to the cardiovascular system or are part of a systemic disorder. CMs represent a leading cause of morbidity and mortality and account for a significant percentage of death and cardiac transplantation. The 2006 American Heart Association (AHA) classification grouped CMs into primary (genetic, mixed, or acquired) or secondary (i.e., infiltrative or autoimmune). In 2008, the European Society of Cardiology classification proposed subgrouping CM into familial or genetic and nonfamilial or nongenetic forms. In 2013, the World Heart Federation recommended the MOGES nosology system, which incorporates a morpho-functional phenotype (M), organ(s) involved (O), the genetic inheritance pattern (G), an etiological annotation (E) including genetic defects or underlying disease/substrates, and the functional status (S) of a particular patient based on heart failure symptoms. Rapid advancements in the biology of cardio-genetics have revealed substantial genetic and phenotypic heterogeneity in myocardial disease. Given the variety of disciplines in the scientific and clinical fields, any desired classification may face challenges to obtaining consensus. Nonetheless, the heritable phenotype-based CM classification offers the possibility of a simple, clinically useful diagnostic scheme. In this chapter, we will describe the genetic basis of dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), LV noncompaction cardiomyopathy (LVNC), and restrictive cardiomyopathy (RCM). Although the descriptive morphologies of these types of CM differ, an overlapping phenotype is frequently encountered within the CM types and arrhythmogenic pathology in clinical practice. CMs appear to originate secondary to disruption of “final common pathways.” These disruptions may have purely genetic causes. For example, single gene mutations result in dysfunctional protein synthesis causing downstream dysfunctional protein interactions at the level of the sarcomere and a CM phenotype. The sarcomere is a complex with multiple protein interactions, including thick myofilament proteins, thin myofilament proteins, and myosin-binding proteins. In addition, other proteins are involved in the surrounding architecture of the sarcomere such as the Z-disk and muscle LIM proteins. One or multiple genes can exhibit tissue-specific function, development, and physiologically regulated patterns of expression for each protein. Alternatively, multiple mutations in the same gene (compound heterozygosity) or in different genes (digenic heterozygosity) may lead to a phenotype that may be classic, more severe, or even overlapping with other disease forms.

DNA Methylation in Adipose Tissue and Metabolic Syndrome

Epigenetics is the study of heritable phenotype changes that do not involve alterations in the DNA sequence with the processes including DNA methylation, histone modifications and RNA-associated silencing [...]

The genetic and physiological basis of total energy budget in different nutritional environments

Organisms need to adapt to dynamic environments over time. An organism consumes and stores a finite amount of resources that are used for all daily tasks. In order to survive and thrive, they must allocate these finite resources to different life history traits like reproduction or somatic growth. In order to understand this process, I examined the genetic and phenotypic variation in macromolecule content, estimated heritability for these phenotypes, and studied the effects of selection on macromolecule content. In my first study, I used the genetic mapping population, the Drosophila Synthetic Population Resource (DSPR), to measure macromolecule content and mapped the genetic loci responsible for carbohydrate, lipid and protein storage on different diets in Drosophila melanogaster. I measured the effect of nutritional environment on overall fly composition. By using the energy budget assays, I showed that there is phenotypic variation in response to diet, the genotypes responsible for nutrient content storage are plastic and that there are multiple genomic loci of interest. Nutrient acquisition increased according to diet composition, with DR having the lowest amount and HS having the highest. The exception to this pattern was glycogen. On the C diet, lipid and carbohydrate amounts correlated together. Overall, protein consistently correlated with all other macromolecules between 0.2 and 0.3 correlation. In my second study, I estimated the heritability of lipid, carbohydrate, glycogen, and protein contents across three different diets using a half-sibling design experiment, using flies from a genetically diverse outbred population generated from the DSPR. I showed differing heritability for different macromolecule contents across nutritional environments. This suggesting not only does nutrient content change based on the particular environment a genotype is in, but that these phenotypes are heritable. In my final study, I tested the effects of female fruit flies undergoing selection for 30 generations. I measured protein, lipid, soluble carbohydrates, and glycogen amount in ovaries and somatic tissue across three different diets across three different selection regimes and found that selection treatments did not significantly impacted macromolecule content. However, diet did. Strikingly, for carbohydrates specifically, patterns of acquisition remained the same in both the base population and after thirty generations of selection regardless of selection regimen. Unlike previous studies, I focused on the impact of diet and measured all four energy budget components on the same individual flies. This allows a wider understanding of resource allocation in different environments. I found that there was variation in macromolecule content acquisition. It is a heritable phenotype, and that diet was more influential in macromolecule content allocation than selection treatment.

Insights into novel emerging epigenetic drugs in myeloid malignancies

Epigenetics has been defined as ‘a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence’ and several epigenetic regulators are recurrently mutated in hematological malignancies. Epigenetic modifications include changes such as DNA methylation, histone modifications and RNA associated gene silencing. Transcriptional regulation, chromosome stability, DNA replication and DNA repair are all controlled by these modifications. Mutations in genes encoding epigenetic modifiers are a frequent occurrence in hematologic malignancies and important in both the initiation and progression of cancer. Epigenetic modifications are also frequently reversible, allowing excellent opportunities for therapeutic intervention. The goal of epigenetic therapies is to reverse epigenetic dysregulation, restore the epigenetic balance, and revert malignant cells to a more normal condition. The role of epigenetic therapies thus far is most established in hematologic malignancies, with several agents already approved by the US Food and Drug Administration. In this review, we discuss pharmacological agents targeting epigenetic regulators.

Why Darwin would have loved evolutionary game theory

Humans have marvelled at the fit of form and function, the way organisms' traits seem remarkably suited to their lifestyles and ecologies. While natural selection provides the scientific basis for the fit of form and function, Darwin found certain adaptations vexing or particularly intriguing: sex ratios, sexual selection and altruism. The logic behind these adaptations resides in frequency-dependent selection where the value of a given heritable phenotype (i.e. strategy) to an individual depends upon the strategies of others. Game theory is a branch of mathematics that is uniquely suited to solving such puzzles. While game theoretic thinking enters into Darwin's arguments and those of evolutionists through much of the twentieth century, the tools of evolutionary game theory were not available to Darwin or most evolutionists until the 1970s, and its full scope has only unfolded in the last three decades. As a consequence, game theory is applied and appreciated rather spottily. Game theory not only applies to matrix games and social games, it also applies to speciation, macroevolution and perhaps even to cancer. I assert that life and natural selection are a game, and that game theory is the appropriate logic for framing and understanding adaptations. Its scope can include behaviours within species, state-dependent strategies (such as male, female and so much more), speciation and coevolution, and expands beyond microevolution to macroevolution. Game theory clarifies aspects of ecological and evolutionary stability in ways useful to understanding eco-evolutionary dynamics, niche construction and ecosystem engineering. In short, I would like to think that Darwin would have found game theory uniquely useful for his theory of natural selection. Let us see why this is so.

Decline in blood hemoglobin concentrations is associated with familial longevity

Hemoglobin(HGB)in the blood carries oxygen from the lungs to other organs to produce energy. Calorie restriction has been shown to slow aging and extend lifespan. Thus, we hypothesized that HGB maybe associated with human longevity as a link to energy metabolism. To test this hypothesis, HGB levels in the blood of 60 centenarian(CEN) families were measured and its association with age(20-80 and 20-100 years)was studied, as well as the associations of CEN HGB with levels in first generation offspring (F1) and their spouses (F1SP). The results showed no association of HGB with age between 20 and 80 years (r=-0.097, p=0.160); however a strikingly inverse relationship with age between 20 and 100 years (r=-0.526, p<0.001)was revealed. After dividing the samples into four age groups (20-39, 40-59, 60-80 and ?100 years), the HGB in CEN were significantly lower than that of F1SP(p<0.001). Interestingly, the HGB levels of CEN were significantly associated with that of F1(r=0.379, p=0.015)but not with F1SP(r=0.022, p=0.451), suggesting that HGB could be a heritable phenotype. Furthermore, the genes methylenetetrahydrofolate reductase(MTHFR), nuclear receptor subfamily 2, group C, member 1(NR2C1)and NR2C2were differentially expressed in CEN when compared to F1SP, which may likely be responsible for the changes in HGB levels. In conclusion, our results suggest that HGB is a heritable phenotype which associates with familial longevity.

Epigenetic background of the most common non-oncologic gynecological diseases

Epigenetic effects influence the function of genes regulating the main physiological mechanisms. Some of these environmental factors may reduce or inhibit the function of these genes. The environmental effects on gene function may result in a change of the DNA structure leading to non-heritable phenotype changes. Epigenetic factors play an important etiological role in the development of numerous diseases in obstetrics and gynecology. Uterine fibroids probably have a complex etiological background including epigenetic mechanisms. The multifactorial aetiology of endometriosis suggests key roles for immunological and hormonal factors in the development of the diseases. These mechanisms are influenced by epigenetic factors, which may serve as therapeutic targets in the future. The possible in utero origin of polycystic ovary syndrome determines the main directions of research concerning epigenetic factors in the etiological background, with the hope of eventual prevention and/or treatment in the preconceptional period as well as during pregnancy care. Orv. Hetil., 2014, 155(13), 492–499.

Feeling of Cold Hands and Feet is a Highly Heritable Phenotype

The prevalence of the feeling of cold hands and feet (FCHF) is high in the general population but the etiology of FCHF is largely unknown. The aim of the present study was to explore whether the FCHF is heritable. Eight hundred and ninety-four pairs of twins completed a question about FCHF. Tetrachoric correlations for FCHF were .58, .29, .67, .52, and .04 for monozygotic male, dizygotic male, monozygotic female, and dizygotic female twins, respectively. Model-fitting analyses suggested that in the best fitting model, additive genetic and nonshared environmental variance including measurement error were 64% (95% CI: 55%-72%) and 36% (28%-45%), respectively. Sex differences in genetic and environmental influences were not significant.