Clinical phenotyping, importance

It is important to realize, that diseases such as myocardial infarction or type 2 diabetes represent a heterogeneous group of several distinct subphenotypes definable by clinical or biochemical characteristics. Thus, contradictory findings in pharmacogenomic studies may only not be the consequence of a lack of a major isolated gene effect (of the gene variant studied) and chance findings, but also be caused by the variability in the mix of distinct clinical phenotypes hidden beneath a common characterization such as type 2 diabetes and modulated by differences in the environment between studies. 

It is important to point out that deletion of individual genes is not providing animal models for certain behavioral pathologies that are caused by a manifold of minor changes in a series of so-called susceptibility genes. To make a clinical phenotype overt, a number of exogenous factors, e.g., stressful life events and a susceptible genetic endowment, need to interact in at least most of the cases... 

Rationally, 5/3-reduclase deficiency would not be a cause of MPH, but it seems appropriate to place this disorder adjacent to its 5a-counterpart. 5/3-Reductase (AKR1D1) is an essential bile-acid biosynthetic enzyme and patients with disabling mutations in this enzyme have a clinical phenotype associated with cholestasis and fiver failure. In addition to its importance in bile-acid synthesis, this aldoketo-reductase is responsible for reducing approximately two-thirds of the mass of synthesized androgens, corticosteroids, and aldosterone prior to their excretion, so has a vital role in steroid metabolism. 

In this review we discuss the relationships between serum lipid profile levels, major depression, and suicide attempts, as well as the interactions between lipid profiles, stress, HPA axis, and inflammation/immunity in depressive disorders. The conclusion emphasizes the importance of integrated data between clinical phenotypes and molecular mechanisms in depressive disorders. 

Genetic alterations or abnormalities of germ cells, some of which can be caused by toxicant exposure, can be manifested by adverse effects on progeny. The important health effects of these kinds of alterations may be appreciated by considering the kinds of human maladies that are caused by inherited recessive mutations. One such disease is cystic fibrosis, in which the clinical phenotype has thick, dry mucus in the tubes of the respiratory system such that inhaled bacterial and fungal spores cannot be cleared from the system. This results in frequent, severe infections. It is the consequence of a faulty chloride transporter membrane protein that does not properly transport Cl ion from inside cells to the outside, where they normally retain water characteristic of healthy mucus. The faulty transporter protein is the result of a change of a single amino acid in the protein. 

Another important question which is often forwarded to the medical geneticist is whether the identification of a mutation can predict the individual clinical course. There are diseases where a rough correlation between the type or localization of a mutation and the clinical phenotype exists, often, however, an individual prediction is impossible. A recently described example is again ADPKD with an unusual early manifestation in a child where all family members, including those with a mild onset in adulthood, share the same mutation. It is still unknown which other genetic or non genetic factors may influence the severity of the disease. 

Systolic pressure, or maximum blood pressure, occurs during left ventricular systole. Diastolic pressure, or minimum blood pressure, occurs during ventricular diastole. The difference between systolic and diastolic pressure is the pulse pressure. While diastolic blood pressure has been historically been used as the most relevant clinical blood pressure phenotype, it has now been clearly established that systolic blood pressure is the more important clinical predictor for cardiovascular morbidity and mortality. More recently, additional attention is focussed on the importance of pulse pressure, i.e. the blood pressure amplitude, as a predictive factor for cardiovascular disease. 

It is generally accepted (based on clinical and in vitro studies) that mast cells (and basophils), IgE and FceRI are involved in most cases of allergen-induced anaphylaxis in humans. However, it is difficult to define the exact roles and relative importance of mast cells, basophils, and other potential effector cells (e.g monocytes/macrophages, dendritic cells) in either IgE-dependent or IgE-independent human anaphylaxis. Unlike in mice, we neither have access to mast cell- or basophil-deficient humans nor can we genetically manipulate human subjects to produce such phenotypes. 

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