Dr. István Balogh, Dr. János Kappelmayer, Dr. József Tőzsér (2011)
University of Debrecen
Monogenic diseases fall into the very heterogeneous group of rare diseases. By contrast, multifactorial diseases affect a large number of individuals. In almost all cases, multifactorial diseases have genetic components, but the relationship between the genotype and the phenotype is not a direct one. It means that the genetic factor does not cause the disease directly, but rather it contributes to its development together with the environmental factors (like diet, lifestyle, etc.). Although they have no significant role to play in in the decision-making processes of the healthcare system and in therapy, defining these genetic factors are of great importance because the increasing knowledge about the pathogenetic routes might prove promising in terms of planning and designing future interventions.
The molecular genetic testing of the genetic risk factors of multifactorial disorders can be performed within the framework of either case-control or prospective studies. Methodologies in detecting the most common polymorphisms are highly developed, genome-wide association studies are frequently performed in order to define novel, previously unknown risk factors. Two different multifactorial diseases with different interesting aspects are detailed below.
Age-related macular degeneration (AMD) is a typical multifactorial disease. In addition to the numerous environmental factors (smoking, long-term sun exposure) that play a significant role in the development of the disease, AMD has a strong genetic predisposition. Those established risk SNPs are located in genes encoding proteins with unknown functions (for example LOC387715) and in a gene that is involved in the complement system (complement factor H (CFH) Y402H polymorphism). The disease that affects the region responsible for the detailed central vision in the eye is the most prevalent cause of blindness in the population above the age of 65 in the developed countries. The left-hand side of Figure 7.1. shows the more benign dry form of AMD with the typical lipid-rich deposits so called drusens. The wet form shown in the right-hand side of the figure is much more severe. Pathogenesis of the wet AMD involves neovascularization, therefore blocking the vascular endothelial growth factor effect using monoclonal antibodies is of great therapeutic importance.
Alzheimer disease is the most common cause of dementia, accounting for 2/3 of the cases. It is a progressive neurological disease with irreversible loss of neurons. Pathologically, Alzheimer disease shows loss of neurons and deposition of extracellular plaques with beta-amyloid peptides. These peptides are the result of a proteolytic cleavage of the beta-amyloid precursor protein. The pathogenesis of Alzeimer disease involves important genetic factors. The left-hand side of Figure 7.2. shows the genes and syndromes with proven association. However, mutations in the amyloid precursor protein gene (APP, chromosome 21) or in presenilin 1, 2 genes (PS1, PS2 in chromosomes 14, 1, respectively) can be detected in less than 2% of all cases, their discoveries are important milestones in acquiring more detailed information in understanding the pathomechanism. In the case of Down syndrome patients it is known that they have a life-long continuous mild production of beta-amyloid. Other genes labelled with a question mark highlight the fact that there are still unknown genetic factors to be discovered. In general, the familiar causes that are shown on the left-hand side of the figure lead to an early appearance of the disease, already at the age of 40-50. In the case of the nongenetic, environmental factors that are shown on the right-hand side of the figure, their pathogenetic role is not proved yet. In the general population, the most probable way of pathogenesis is shown in the middle, where both environmental factors together with genetic predisposition (for example epsilon 4 allele of apolipoprotein E gene) and the physiological ageing process lead to the development of the disease. Alzheimer disease has a prevalence of 1% in the age group 65-69 and 40-50% above 95.
Under normal circumstances, alpha, beta and gamma secretase enzymes cleave the beta-amyloid precursor protein (Figure 7.3. left panel). When the Ala692Gly mutation occurs in the beta-amyloid precursor protein gene, the consequence will be interference with the cleavage site as the 692nd position is close to the alpha secretase cleavage site (figure middle panel). Mutations Val717Gly, Val717Ile, Val717Phe interfere with the cleavage site used by the gamma secretase, which is the presenilin 1 itself or an essential cofactor of it (figure right panel). The consequence of the pathogenic mutations will be that instead of the 40 kD cleavage fragment, the 42 kD toxic beta-amyloid peptide will be the dominant cleavage product (red arrows show the dominant cleavage direction). Discoveries of the pathogenesis and the molecular genetic background make directed drug development possible.
Figure 7.3. Figure 7.3. One type of familial Alzheimer disease. Genetics and the consequence of the mutation