INDEX

Chapter 5: Molecular biology and genetics

Molecular biology and genetics

Great progress has been made in single-gene disorders. Since a single gene is in large part responsible for the phenotype, it is possible through genetic linkage analysis to map the chromosomal location of the gene responsible for a disease segregating in a two- to three-generation family. This is not possible in a polygenic disease such as atherosclerosis or hypertension. Atherosclerosis is due to multiple genes each contributing a small percentage to the phenotype. Thus, no one gene is responsible for the phenotype. The two approaches to atherosclerosis have been case control association studies of either the direct or the indirect method. Most studies to date have been indirect assessing the frequency of a polymorphism in individuals with the disease versus its frequency in controls. Studies that have been performed generally involved sample sizes that were inadequate. The indirect approach consisting of genome-wide scans has not been feasible due to inadequate number of markers and inadequate sample size. Studies performed to date have included 50,000 to 100,000 markers but it requires hundreds of thousands of markers. Second, the population should be analyzed in at least two independent populations utilizing 400,000 to 500,000 SNPs as markers in an initial population of at least 2000 (1000 affected, 1000 controls) followed by a population of at least 12,000.

It is easy to imagine possible applications of the current and evolving state of genomics and genetics to the diagnosis, prognosis, and treatment of cardiovascular disease. Indeed, there is a growing sense that identification of the monogenic and more common polygenic factors for acute and chronic disease will lead to a refined and more effective personalized medicine. This understandable enthusiasm should be tempered by the real challenges to the concept that genotype exclusively determines phenotype. Obviously, environmental influences play powerful and modifiable roles in the determination of disease phenotypes. Differences in genetic background and epigenetic factors can profoundly modify the phenotypic expression of disease due to monogenic or polygenic mutations or polymorphisms. The complex interaction among genetic, genetic background, epigenetic, and disease progression is an area of current intense interest and research. Future progress in this area requires interdisciplinary research among geneticists, cell biologists, computational biologists, physiologists, and clinicians. As always, the future is bright but increasingly complicated.