Chapter 61

The beginning of the new millennium was marked by the announcement that the vast majority of the human genome had been sequenced. This milestone in the exploration of the human genome was preceded by numerous conceptual and technologic advances. They include, among others, the elucidation of the DNA double-helix structure, the discovery of restriction enzymes and the polymerase chain reaction (PCR), the development and automatization of DNA sequencing, and the generation of genetic and physical maps by the Human Genome Project (HGP). The consequences of this wealth of knowledge for the practice of medicine are profound. First, the most significant impact of genetics has been to enhance our understanding of disease etiology and pathogenesis. However, genetics is playing an increasingly prominent role in the diagnosis, prevention, and treatment of disease (Chap. 63). Genetic approaches have proven invaluable for the detection of infectious pathogens and are used clinically to identify agents that are difficult to culture such as mycobacteria, viruses, and parasites. In many cases, molecular genetics has improved the feasibility and accuracy of diagnostic testing and is beginning to open new avenues for therapy, including gene and cellular therapy (Chaps. 68 and 67). Molecular genetics has significantly changed the treatment of human disease. Peptide hormones, growth factors, cytokines, and vaccines can now be produced in large amounts using recombinant DNA technology. Targeted modifications of these peptides provide the practitioner with improved therapeutic tools, as illustrated by genetically modified insulin analogues with more favorable kinetics. There is hope that a better understanding of the genetic basis of human disease will also have an increasing impact on disease prevention.

Genetics has traditionally been viewed through the window of relatively rare single-gene diseases. Taken together, these disorders account for ∼10% of pediatric admissions and childhood mortality. It is, however, increasingly apparent that virtually every medical condition has a genetic component. As is often evident from a patient's family history, many common disorders such as hypertension, heart disease, asthma, diabetes mellitus, and mental illnesses are significantly influenced by the genetic background. These polygenic or multifactorial (complex) disorders involve the contributions of many different genes, as well as environmental factors that can modify disease risk (Chap. 63). Genome-wide association studies (GWAS) have elucidated numerous disease-associated loci and are providing novel insights into the allelic architecture of complex traits. These studies have been facilitated by the availability of comprehensive catalogues of human single-nucleotide polymorphism (SNP) haplotypes generated through the HapMap Project.

Cancer has a genetic basis since it results from acquired somatic mutations in genes controlling growth, apoptosis, and cellular differentiation (Chap. 83). In addition, the development of many cancers is associated with a hereditary predisposition. The prevalence of genetic diseases, combined with their severity and chronic nature, imposes great financial, social, and emotional burdens on society.

Genetics has historically focused predominantly on chromosomal and metabolic disorders, reflecting the long-standing availability of techniques to diagnose ...

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