**8. Summary and conclusions**

Endothelial dysfunction is multifactorial, and ET-1 is a key regulator of ED. The genetic factors that modulate individual susceptibility to multifactorial diseases are common, functionally different forms of genes (polymorphisms), that have modest effects on physiology and disease biology at individual level but, because of their high frequency of occurrence in the population, can be associated with a high attributable risk. By definition, a mutation results in a significant phenotype, whereas an SNP, which represents a stable change in the genome, possesses mild or no phenotypic changes. SNPs whether they relate clinical end points or intermediate phenotypes such as endothelial dysfunction require careful analysis. Available evidence in literature suggests that most of the susceptibility genes from common diseases do not have a primary etilogical role in predisposition to disease, but rather act as response modifiers to exogenous factors such as stress, environment, disease, and drug intake. A better characterization of the interactions between environmental and genetic factors constitute a key issue in understanding of the pathogenesis of multifactorial diseases. For example, risk factors like oxidative stress, hyperlipidemia, and cytokines disrupt the vascular homeostasis in a dysfunctional endothelial cell leading to the production of ET-1 and consequent pathophysiological changes. Also, results from two independent studies ECTIM and Glasgow Heart Scan Study [53] on ET-1, BMI, and Blood Pressure suggested that obesity is a crucial factor influencing the association between the ET-1/ Lys198Asn polymorphism and BP levels. Obesity, predominantly governed by complex social and environmental factors, might enhance expression of ET-1 gene possibly through an upregulation by insulin, which is known to stimulate ET-1 production [78]. In common diseases, genetic effects can be considerably amplified in the presence of triggering factors and gene-environment interaction is a central concept in multifactorial diseases.

The potential usefulness of SNPs in medicine is unprecedented. Obtaining a detailed family history is often considered standard in clinical practice for characterizing the inherited component of individual's disease risk. SNPs allow us to look closely at the footprints of past generations of the families. SNPs of the endothelin-1 gene axis have the potential to help us in dissecting the genetic component of complex diseases like cardiovascular diseases of which vascular dysfunction is an early manifestation. Susceptibility to disease in such cases depends on the cumulative contribution of multiple genetic risk factors. SNPs provide the potential to interpret genetic risks associated with complex polygenic disorders by developing models based on quantitative genetic theory to analyze and compare family history and SNP-based models [79, 80].

The most difficult task will be to consider the implementation of SNPs in clinical decision-making, particularly as it relates to providing recommendations for interventional or preventional measures, based on the concept of "risk."
