Introduction

Genetics is challenging the traditional approach to infectious diseases. Until recently, research was mostly directed to the analysis of the pathogen and of its virulence factors. However, we are now in a position to investigate the pathogen in the context of the host genetic make-up. Concepts, such as colonization versus infection and life-threatening infection versus contained disease, will be revisited to better define pathogen-specific virulence versus host-specific susceptibility. Thus, genetic susceptibility (Table 1) will be the initial step in defining the need for treatment, to be completed by analysis of pharmaco-genetic determinants in order to choose the most effective and least toxic therapy for the individual patient (Fig. 1).

Both genetics of disease susceptibility and pharmacogenetics are of major interest in the field of infectious diseases: (i) tuberculosis (TB), HIV, malaria, pneumonia, diarrheal diseases, and sepsis, are among the great medical problems in the world, (ii) all can be treated but not always effectively or without toxicity, (iii) standard guidelines are drafted based on drug development and trials in Caucasian populations, although different ethnic groups may present significant differences in the frequency of the alleles modifying the drug metabolism (1,2), and (iv) many infectious diseases are treated by complex multidrug regimens. Here the issue of pharmacokinetics and drug interactions becomes critical. Genetic prediction would be of interest in preventing toxicity and also for identifying the most likely component of a multidrug regimen leading to toxicity or lack of efficacy.

The fields of genetics of disease susceptibility and of pharmacogenetics overlap with the field of immunogenetics (the genetic factors contributing to differences in immune

Table 1 Association of Genetic Polymorphisms with Disease Severity

Gene/protein

Role

Polymorphism/ allele

Associated disease

Mannose-binding lectin

Toll-like receptor 4 Fc gamma receptor

IIA CD14

Tumor necrosis factor A

Tumor necrosis factor B Interleukin-1B Interleukin-1-ra C reactive protein

Pathogen sensing Codons 52, 54, 57

Interleukin-10

Interleukin-12

Interleukin-12 receptor

CC chemokine receptor 5

CC chemokine receptor 2

Macrophage inflammatory prot-1a Rantes

HLA class I

Pathogen sensing Pathogen sensing

Pathogen sensing Inflammation

Inflammation

Inflammation Inflammation Inflammation

Interferon-y receptor 1 Inflammation

Inflammation

Inflammation Inflammation Inflammation

Inflammation Inflammation Inflammation Immunity

D299G H131R

C160T TNF2

TNFB2

134 bp dinucleotide repeat polymorphism IFNGR1

nonfunctional alleles Promoter polymorphism

Deficiency Mutation CCR5 D32 CCR5 pi /p1

CCR2-I64

MIP-1a459T

Rantes In1.1C

Meningococcemia, respiratory infections Gram-negative shock Meningococcemia, pneumococcemia Septic shock Meningococcemia, septic shock, cerebral malaria Severe sepsis

Meningococcal disease Severe sepsis Invasive pneumococcal disease Susceptibility to mycobacteria

Persistence of hepatitis B and altered response to INF-a therapy in hepatitis C treatment. Accelerated progression of HIV infection Susceptibility to mycobacteria Susceptibility to mycobacteria Protection from HIV

Accelerated progression of HIV infection Accelerated progression of HIV infection Accelerated progression of HIV infection Accelerated progression of HIV infection Susceptibility to tuberculosis

(Continued )

Table 1 Association of Genetic Polymorphisms with Disease Severity (Continued)

Gene/protein

Role

Polymorphism/ allele

Associated disease

HLA class II

Immunity

Plasminogen activator inibitor-1 Solute carrier family 11 (NRAMP1, SLC11A1) Vitamin D receptor

Coagulation Transporter

Metabolism

B35 B53

B5701 Cw*04 DRB1* 1302

DRB1* 1352

DRB1* 1101

DRB1*04

DR7 4G/4G

TaqI restriction polymorphism

Susceptibility to AIDS Protection from severe malaria Protection from AIDS Susceptibility to AIDS Clearance of hepatitis B Protection from severe malaria Clearance of hepatitis C Protection from typhoid fever Susceptibility to tuberculosis and leprosy Susceptibility to hepatitis B Meningococcemia, severe sepsis Susceptibility to tuberculosis

Protection from tuberculosis and leprosy

response among individuals). The study of immunogenetic determinants may become central for those investigating allergic and hypersensitivity reaction and also disease susceptibility (3,4). The present chapter will focus on current knowledge of inherited differences in the metabolism, transport, and disposition of anti-infective drugs, and drugs' targets (pharmacogenetics sensu stricto). However, attention will also be given to other genetic determinants of disease progression, as they will help define the need for treatment or the likelihood of response.

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