Conclusions

The current state of knowledge of pharmacogenetics in the area of infectious diseases mainly includes the identification of genetic polymorphism leading to changes in the activity of phase I and phase II metabolic pathways and in transporters. These polymorphisms were the first to be recognized because research was specifically directed to relevant metabolic or transport genes. As a result of genome-wide investigations, a new generation of markers will be found associated with specific toxicities or lack-of-efficacy pheno-types. These labor-intensive analyses will lead to identification of additional polymorphisms with potential functional relevance. Polymorphisms may remain remote to the gene of interest (e.g., regulators, suppressor genes) or be present in noncoding regions

(promoter, intron, 3' untranslated region), contributing to modified expression, splicing, or protein stability. Transcriptome analysis using microarrays also promises to deliver information about individual expression profiles that may lead to genes participating in complex regulatory or signaling cascades. These cascades may be investigated in detail to identify polymorphims and modification of function distant to the key metabolic or transport genes.

Understanding of the genetics of disease susceptibility may also help in the development of new drugs. Identification of a polymorphism of the HIV cellular receptor CCR5 that resulted in the absence of a functional protein and high-level protection from HIV infection led to the initiation of an intense research in drug development, including that of an orally active CCR5 receptor antagonist that blocks the entry of HIV-1, currently in clinical trial.

Importantly, pharmacogenetics and immunogenetics of anti-infective chemotherapy will complement the field of genetics of susceptibility to a pathogen. For major pathogens, such as HIV, malaria, and TB, this has the potential to dramatically improve management and limit the number of patients requiring therapy. Fortunately, knowledge acquired on inherited differences in the metabolism, transport, and disposition of anti-infective drugs will be to a significant extent shared by drugs used in other disciplines. The fields will thus move forward together.

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