Part II: PUBLIC HEALTH ASSESSMENT Chapter 10
necessarily represent the views of the funding agency.”
Genetics and Public Health in the 21st Century
Public Health Assessment of Genetic Susceptibility to Infectious Diseases: Malaria, TB and HIV
Janet M. McNicholl1, Marie V. Downer1, Michael Aidoo2, Thomas Hodge1, Venkatachalam Udhayakumar2
1Division of AIDS, STD and TB Laboratory Research, NCID, Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., MS A25, Atlanta, GA 30333
2Division of Parasitic Diseases, NCID, Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., Atlanta, GA 30333
Our understanding of the host genetic factors that influence susceptibility to and the course of infectious diseases is growing rapidly. However, even for the most common pathogens we have an incomplete understanding of all the important genes. As sequencing of the 80 -100,000 human genes continues and as technologies advance, new discoveries about host genes and their role in infectious diseases are made almost daily. Translating this knowledge into public health actions, particularly those aimed at combating and controlling infectious diseases, is a major challenge. This paper focuses on this downstream phase of genetics, particularly on how new knowledge can be integrated into existing public health programs and strategies.
It is likely that no one model for this translation phase will serve all public health agencies because the issues surrounding the prevention and control of infectious diseases vary among and within countries. One approach is to integrate host genetic factors into the classical three steps of primary, secondary, and tertiary prevention.1,2 This prevention model is adequate for many diseases, particularly those of a chronic nature. However, it is not comprehensive enough to capture the multiple requirements of an infectious disease public health program. A second approach is to integrate genetics into the areas outlined in the U.S. preventive strategic plan addressing emerging infectious diseases which was developed by the Centers for Disease Control and Prevention (CDC).3 This plan emphasizes four areas: (1) surveillance and response to identified infectious disease problems; (2) applied research integrating laboratory science and epidemiology to optimize public health practice; (3) infrastructure and training to support surveillance and research; and (4) prevention and control programs. These four areas overlap strongly with the four areas of emphasis outlined in the CDC’ s strategic plan for translating genetic advances into public health action.4 Because CDC’s plan for infectious diseases has been implemented in the United States for 4 years and has been widely adopted by many international agencies for the control and prevention of infectious diseases globally, we will use this plan to consider how new genetic knowledge may be integrated into infectious disease public health practice. Also, because infectious diseases are worldwide problems, we will examine aspects of host genes and infectious diseases relevant both in the United States and globally.
Three infectious diseases, malaria, tuberculosis (TB), and HIV/acquired immunodeficiency syndrome (AIDS) will be discussed in the context of this paradigm. These diseases are among the top five leading infectious causes of deaths5 and are considered emerging or re-emerging threats. In addition, and perhaps because of their global impact, more is known about the host genetic factors that influence susceptibility to and severity of these than of other diseases. For each of these pathogens, at least three different host genes that influence disease are known and, frequently, the same gene impacts more than one disease. Many parts of the world, particularly sub-Saharan Africa, have a high prevalence of the three pathogens. Because of its impact on the immune system, infection with HIV increases the risk for and severity of mycobacterial infections.6-8 Moreover malaria infection may increase the severity of HIV in coinfected persons because the parasite modifies HIV transcription rates.9 The coexistence of TB, HIV, and/or malaria in many individuals and populations poses unique challenges for public health officials to understand the complex interactions of host genes with other factors that influence the transmission of these pathogens and their disease course. Consideration of these diseases concurrently may lead to integrated perspectives for their prevention and control, for conservation of resources, and for improvements in public health.
Differences in the modes of transmission, life-cycles, replication rates, and available prevention and control measures for these pathogens influence strategies to discover host genes that influence susceptibility to and severity of the diseases. These differences also influence strategies to incorporate this knowledge into public health practice. Table 1 summarizes some concepts that provide a framework for these strategies.
A complete review of host genes and malaria, TB, and HIV is beyond the scope of this chapter and the reader is referred to several recent reviews and publications.10-22 We provide a brief description of the data below, some of which is summarized in Table 2. Genes that influence susceptibility and severity of disease are distinguished from resistance genes. It is important to note that the same genes or gene families may impact several diseases. It is also important to remember that, to date, most studies of host genes and their impact on these (and other) infectious diseases have been carried out only in certain populations or races. Thus, the relationship between a particular allele and disease susceptibility or severity may not be generalizable to all populations. Moreover, we only partly know the genetic factors that influence each infectious disease. Finally, as discussed in this chapter, limited data are available on the interaction of these genes with each other or with other risk factors or on their attributable risk for a particular outcome.
Malaria is a global problem that ranks second only to TB in the total number of human deaths attributable to an infectious agent. It accounts for 300 to 500 million annual infections, estimated to cause 1.5 to 2.7 million deaths annually,5 with about 90% of malaria-associated mortality occurring in sub-Saharan Africa.5,23 Malaria outbreaks are becoming frequent in other regions of the world, especially in the Newly Independent States,24 and cases of imported malaria are more often being reported in the United States and Europe because of increased travel. Malaria is caused by infection with any of the four known plasmodial species: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. Most malaria-associated mortality and severe morbidity, such as anemia and cerebral malaria, are attributable to P. falciparum.25 Anopheles mosquito vectors account for most malaria transmission, but human-to-human transmission can also occur through blood transfusion. Traditionally, malaria was contained through vector-control programs. The emergence of insecticide-resistant vectors and lack of economic resources to sustain traditional malaria control programs have led to the reemergence of malaria, even in regions where once it was controlled. Chloroquine, a cheap and effective drug to cure malaria, is no longer useful in most parts of the world because of drug resistance.24 Side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient persons also limit its use (see below). The re-emergence of malaria as a problem underlines the urgent need to develop a vaccine which along with vector-control measures will control malaria.26
Malaria resistance genes
Duffy antigen: The Duffy antigen negative genotype is the only genotype known to provide complete protection against P. vivax infection.27,28 It is now known that the Duffy antigen is a chemokine receptor29 essential for the invasion of merozoites into erythrocytes.30
Hemoglobin S gene: Homozygosity for a point mutation in the β-globin gene (Hb-S) causes sickle cell anemia (SS) and sickle cell disease. The carrier state for the sickle cell gene (AS genotype) provides partial protection against falciparum malaria as demonstrated in several studies.31-34 In a definitive large case control study in The Gambia it was shown to provide at least 90% protection from cerebral malaria, severe anemia and death.35 The protective associations of the AS genotype probably accounts for the high prevalence of the sickle cell gene in malaria-endemic regions of the world.
α-thalassaemia and β-thalassaemia genes: The thalassaemias are genetically complex disorders associated with hemolytic anemia. The great majority of α-thalassaemias are caused by deletions of one or more of the duplicated α chain genes due to nonhomologous crossing over. Like sickle cell anemia, α- thalassaemia is more commonly found in malaria endemic regions. It also decreases malaria-associated morbidity up to 10 fold as observed in the Tharu population of Nepal, where it has reached near fixation (gene frequency of 0.8).36,37 Paradoxically, in Vanuatu, a southwestern Pacific island, the incidence of both P. vivax and P. falciparum malaria were higher in α-thalassaemic children than in normal children.38 When compared to normal children, the risk of severe malaria was reduced to 0.40 in α-thalassaemia homozygotes and 0.66 in heterozygotes.39 Interestingly, the same study showed that the risk of overall hospital admission was also reduced to 0.36 and 0.63 in homozygous and heterozygous children respectively. The mechanism associated with this protection is unclear. It has been suggested that this genotype may provide protection against indirect mortality caused by other infections associated with malaria.
β-thalassaemia is another anemia caused by decreased synthesis of the beta chain of hemoglobin. Over 100 different genetic variations ranging from single point mutations to gene deletion can cause this condition. A case-control study conducted in Liberia showed that β-thalassaemia provides partial protection against clinical and severe malaria caused by P. falciparum.40
Melanesian ovalocytosis: A 27 base pair deletion in the gene encoding band 3 protein causes an erythrocyte membrane defect resulting in ovalocytosis. This genotype is confined to southeast Asian populations and to certain islands of the western Pacific. It has been associated with a lower incidence of both P. falciparum and P. vivax parasitemia.41 It also provides complete protection against mortality associated with severe malaria in children in Papua New Guinea.42
Glucose 6-phosphate dehydrogenase deficiency gene: Over 200 variants of the G6PD enzyme have been described, some of which have been linked to abnormalities of the G6PD gene. Because the gene is located on the X chromosome the deficiency is a sex-linked trait. G6PD plays a role in protecting red cells from oxidation-induced hemolysis, and consequently, persons with G6PD deficiency are at high risk of hemolytic anemia following exposure to some antimalarials including primaquine and chloroquine, and several other non-antimalarial antibiotics. G6PD deficiency provides a 46-58% reduction in risk of severe malaria for both male hemizygotes and female heterozygotes, as demonstrated in a case-control study conducted in children in the Gambia.43
Human Leukocyte Antigen (HLA) genes: These genes are part of the major histocompatibility complex (MHC) on chromosome 6 and include the HLA class I (A, B, C) and HLA class II (DR, DP, DQ) genes. They code for the HLA molecules that present antigens to T cells. Different HLA alleles influence susceptibility to malaria. In a large case-control study involving children in The Gambia, HLA-B53 and HLA-DRB1*1302 were less frequent among children with severe malaria.44 It has been proposed that the HLA-B53 mediated protection may involve an effective cytotoxic T cell immunity to liver stage antigen.
Malaria susceptibility genes
TNF- α gene and ICAM-1 gene: The TNF-α gene complex is also part of the MHC on chromosome 6, and has several polymorphisms, some of which may alter transcription and/or levels of tumor necrosis factor (TNF), an important cytokine in regulating immune responses. In The Gambia, children homozygous for the TNF-2 allele, a polymorphism in the promoter (-308) region of TNF-α gene, have a 7-fold increased risk for death or severe neurologic sequelae due to cerebral malaria.45 Another immune protein, intracellular adhesion molecule-1 (ICAM-1), which is involved in cell-to-cell communication, influences malaria severity. A new variant of the ICAM-1 gene with a point mutation in the N-terminal domain has been identified in some African populations and children homozygous for this variant in coastal Kenya have a two fold greater risk of having cerebral malaria.46 This association may be explained by the ability of ICAM-1 to enhance sequestration of parasitized erythrocytes in cerebral blood vessels as it is a ligand for adhesion of P. falciparum-infected erythrocytes to endothelial cells. Further studies on the role of this ICAM-1 variant in the pathogenesis of cerebral malaria will be important.46
According to the WHO, 7 to 8 million new cases of TB occur each year around the world and annually TB accounts for more than 3 million deaths.47 Almost 2 million TB cases per year occur in sub-Saharan Africa, 3 million in South East Asia and more than a quarter of a million in Eastern Europe. One third of the increase in incidence that has occurred during the past five years is related to HIV coinfection.47,48 TB is caused by Mycobacterium tuberculosis, an intracellular bacterium. The major route of transmission is person-to-person, through aerosols. Although many persons become infected with the pathogen (as can be shown by a positive skin test to the purified protein derivative [PPD]), clinical disease develops in only a minority of cases.47,49 Clinical disease includes pulmonary and extra-pulmonary disease and the latter can affect many organs including the brain.50,51 The only TB vaccine that is widely used is the attenuated strain of M. bovis called bacille Calmette-Guérin (BCG).52 Because of he limited efficacy of BCG vaccination,48,52 the reduced incidence and prevalence of TB, as well as the insensitivity of the PPD skin test in distinguishing vaccine, TB, or other mycobacterium-induced exposure in the developed world, widespread use of the BCG vaccine has decreased.53-56 Several challenges for the prevention and control of TB remain, particularly the long half life of the pathogen (such that prophylaxis and treatment regimes last for months to years) and the development of drug resistance worldwide.57,58 In March 1993, WHO declared TB a global public health emergency.52
TB resistance genes
The hypothesis of Tay-Sachs gene: As with malaria and the various hemoglobinopathies described above, genetic differences in host susceptibility to other pathogens including TB, leprosy, syphilis, cholera, measles, smallpox, plague and intestinal pathogens, are likely to have profoundly modified human genetic composition over the years.59,60 Individuals who lack resistance genes die more often during epidemics, resulting in selection of survivors who have resistance genes.59,60 Endemic infectious diseases such as TB and plague may have greater selective pressure than epidemic diseases.60 For TB, it has been suggested that certain populations, such as Ashkenazi Jews, may have accumulated TB resistance genes which may also be linked to other diseases such as Tay-Sachs disease (TS). Some authors60 have speculated that the proportion of Ashkenazi Jews who may be resistant to TB is higher than the frequency (4%) of the carriers for Tay-Sachs disease gene.60 Whether this gene per se is associated with TB resistance remains to be confirmed. One case-control study comparing death from TB among Jews who were carriers and noncarriers of the TS gene did not find evidence supporting that the TS allele is involved in resistance to TB in Ashkenazim.61
TB susceptibility genes
Studies of susceptibility to infection with M. tuberculosis are made complex by the fact that the majority of persons who become infected with the bacillus never develop clinical symptoms of TB. Thus studies using TB cases and uninfected (e.g. PPD negative) controls are unable to identify true susceptibility genes rather, these studies may identify genes that are associated with clinical TB disease.
HLA genes: Several case-control studies of TB disease, or the severity of TB have identified associations with HLA class II genes. A study in the former Soviet Union62 found an increased frequency of HLA-DR2 and a reduced frequency of HLA-DR3 in TB patients. Other studies noted HLA-DR2 associations with susceptibility to pulmonary tuberculosis as well as the radiographic extent of the disease.63,64 In an association study with sputum smear-positive TB conducted in Surabaya, Indonesia, the attributable risk (AR) for TB associated with HLA-DR2 was 36% and with HLA-DQw1 39% in patients with active TB while HLA-DQw3 had a preventive fraction of 57% against TB in the controls.65 Interestingly, while some HLA-DR2 positive patients have high levels of IgG antibodies to PPD the frequency of HLA-DR2 is higher in anergic patients and HLA-DR2 may be associated with reduced cell-mediated responses.62,66 It has also been suggested that low plasma levels of lysozyme may be one correlate of the susceptibility to TB in DR2 positive patients.67 These data indicate a complex effect of HLA-DR2 in relation to immunity to TB. Moreover, HLA-DR2 (DRB1*1501 and *1502) may also be associated with failure of anti-tubercular drugs.68 Association of HLA-B5 and HLA-DR5 with TB disease has also been reported60 while in Cambodians, DQB1*0503 was associated with TB susceptibility.50 In contrast, to these HLA-related findings, a Brazilian family study identified no linkage of TB susceptibility to HLA genes.69 The authors speculated that host vulnerability is under multigenic control with the major susceptibility locus outside the HLA complex and modifier genes located within the HLA system.
NRAMP-1 gene: The NRAMP-1 gene was first identified as a candidate gene for TB susceptibility in murine studies which showed its association with increased susceptibility to mycobacterial and other intracellular infections.70 The function of this gene is as yet unknown. In humans it is associated with susceptibility to a variety of pathogens, including M. tuberculosis, M. leprae and Leishmania donovani.19,70,71 At least 11 NRAMP-1 polymorphisms72 have been identified in humans. In a west African case-control study, individuals possessing one of 4 variants [INTR4, 3’UTR, 5′(CA)n and D543N] of the NRAMP1 gene had an increased susceptibility to clinical tuberculosis and persons heterozygous for the INTR4 and 3’UTR polymorphisms had the greatest risk.17 In contrast, analysis of multicase TB families in Brazil showed that gene markers tightly linked to NRAMP-1, such as IL8RB and D2S1471 are associated with susceptibility to TB disease while NRAMP-1 itself was not.73 These studies suggest that several genes may influence TB susceptibility, and that their effects may differ in different populations depending on other genetic or environmental factors.19,21,69,73,74 It has been speculated that NRAMP-1 genes could also influence the efficacy of BCG immunotherapy in patients with bladder cancer.75
Cytokine genes: Some cytokine genes may play a role in TB susceptibility or in influencing the course of TB disease, although no studies have yet reported such associations. However, individuals with mutations in the IL-12 or IFN-γ receptors76,77 are particularly susceptible to disseminated non-TB mycobacterial diseases76-78 and unfortunately, some individuals with IFN-γ receptor polymorphisms develop severe disseminated BCG disease following BCG vaccination.79
Vitamin D receptor gene: In addition to its well established role in calcium metabolism the active vitamin D metabolite 1,25 dihydroxyvitamin D3 (1,25D3 ) following interaction with Vitamin D receptor (VDR) appears to also stimulate cell-mediated immunity and suppress lymphocyte proliferation, immunoglobulin production and cytokine synthesis.19 Several alleles of the VDR exist, including T and t, and these genotypes are also associated, in some studies, with altered osteoporosis risk.19,80-82 Recent studies have now shown that tt homozygosity may be associated with an increased risk of tuberculosis.19,83,84
As of late 1997, more than 30 million persons were reported to be infected with HIV type 1 (HIV-1) or to have acquired immunodeficiency syndrome (AIDS).85 While the HIV epidemic was first noted in the early 1980’s in the United States and Europe, HIV infection of humans occurred in Africa decades earlier.86 Currently, the highest prevalence of HIV is in sub-Saharan Africa and parts of Asia. In 1997 almost 90 percent of children <15 years of age newly infected with HIV lived in sub-Saharan Africa (590,000 children infected worldwide of whom 530,000 are African). In the same region almost 30 percent of childbearing age women are infected with HIV.87 The global burden of HIV disease is expected to worsen with the16,000 new HIV infections occurring daily.87 The major routes of HIV transmission are through sexual contact, intravenous drug abuse, or blood products. There is no vaccine for preventing HIV infection, and while new drugs have become available with remarkable effects on decreasing viral burden, delaying progression to AIDS, and reducing transmission from mother to child, their expense limits use to developed countries. The transmission of and course of HIV disease is known to be influenced by several genes, of which the most consistent and widely observed associations have been with HLA and chemokine receptor genes.
HIV resistance genes
HLA genes: HLA class I allele discordance, or mismatch, between mother and child has recently been shown to reduce vertical HIV transmission by up to 10 fold in a Kenyan population.88 Interestingly, the effect of a 3 allele mismatch in reducing HIV transmission was greater than the reduction observed with current antiretroviral therapy suggesting that, if this observation is confirmed in other studies, new HLA-based strategies might be developed to compliment antiretroviral therapy to reduce HIV transmission. Recently, heterozygosity for HLA class I alleles has been shown to delay progression of HIV disease to AIDS, 89 while previous work from many groups has shown that individual, or combinations of, HLA class I (e.g. HLA-B27) or class II alleles are associated with delayed progression to AIDS90 and reviewed in 18,20,91. These effects may be modified by antigen processing genes such as the transporter associated with antigen processing, TAP 90 and reviewed in. 20
Chemokine receptors: Chemokines and their receptors are important in cell movement and trafficking in response to inflammation. The receptors are also HIV-ligands, and normal chemokine receptor expression is usually required for HIV entry into cells. There is a very strong association of homozygosity for the Δ32 CCR5 gene(a 32 bp deleted form of the chemokine receptor gene coding for the chemokine receptor, CCR5) with resistance to HIV infection (reviewed in 18,20). However, persons with this genotype are susceptible to infection with strains of HIV that use other chemokine receptors (reviewed in 18,20). Protection against vertical transmission of HIV from mothers to Δ32 CCR5-homozygous children has not been conclusively demonstrated. Inconsistent associations have been observed with heterozygosity of Δ32 CCR5 and reduced heterosexual or vertical HIV transmission. The Δ32 CCR5 allele is found in up to 20% of some northern European populations and it is rare or absent in African or Asian populations. This geographical observation and mathematical estimates dating the origin of the deleted CCR5 gene to about 700 years ago have led to speculation that individuals carrying this allele may have enjoyed an evolutionary advantage in the face of other infections widespread in Europe during the pre-HIV era 92,93 and reviewed in18,20,94.
Heterozygosity for Δ 32 CCR5, polymorphisms of the CCR5 promotor, of another chemokine receptor gene (CCR2, 64I) and of the gene coding for SDF-1, a ligand for CXCR4, influence the rate of progression of HIV disease. 18,20,95 These effects appear to be independent and additive and result in approximately 2-4 additional years of AIDS-free survival in persons with one or more protective genotypes.95 The close linkage of the CCR5 promoter and the CCR2 gene on chromosome 3 may indicate important evolutionary relationships between these genes.96 Conflicting data for the role of the SDF-1 gene 3’UTR polymorphism in delaying progression to AIDS have been reported and require additional studies in larger and diverse populations (reviewed in 20).
Lewis Blood Group Antigens and Hemoglobinopathies: Blood group secretor status for the Lewis antigens may influence heterosexual transmission of HIV 97, possibly through effects at mucosal surfaces. Persons with sickle cell anemia may have a delayed progression of HIV disease to AIDS. 98 This observation needs to be confirmed in larger studies, but may relate to a reduction in the available target cells for HIV replication because of the frequent autosplenectomy observed in SS patients. 98
TNF-α: Inconsistent associations of polymorphisms at the TNF locus have been observed with the rate of HIV disease progression, although one study reported that some microsatellite alleles at the TNFc locus may be associated with slower progression to AIDS. 99
HIV Susceptibility Genes
No genes that increase susceptibility to HIV infection have been reported. However the inverse of the HLA associations with HIV transmission and progression to AIDS noted above is true: i.e. a high degree of match between mother and infant HLA class I alleles is associated with higher rate of vertical HIV transmission and homozygosity for HLA class I alleles is associated with more rapid progression to AIDS. 88,89 In addition, individual HLA class I or class II alleles, or combinations of these (e.g. the extended haplotype HLA-A1, B8, DR3) with or without TAP are associated with rapid progression to AIDS, or with particular manifestations of HIV disease such as Kaposi’s sarcoma or lymphadenopathy syndromes. 18,20,90,91
Although small numbers of persons who are homozygous for Δ 32 CCR5 have been reported to become HIV infected (e.g. with HIV strains that use CXCR4 for cell entry), paradoxically, once infected, some of these persons appear to have a very rapid progression of their disease course (reviewed in18).
Mannose Binding Lectins Known as MBL or MBP (mannose binding protein) genes, these genes code for MBL, a glycoprotein important in clearance of some pathogens. Levels of MBL appear to be influenced by MBL genotype, and some low-MBL secreting genotypes are associated with more rapid progression to AIDS. 100
As alluded to earlier, the majority of the genes that influence infectious diseases remain to be discovered. The process of gene-discovery is complex, and many approaches can be taken e.g. using linkage or association studies, and different laboratory tools. These approaches are well described in some recent reviews. 11,21,22 Although not a primary focus of the translation phase of genetics discussed in this chapter, public health agencies play an important role in this discovery process, through epidemiological studies, cohort design, data collection, and laboratory studies, often in collaboration with academia or industry. An integrated collaborative approach to both gene discovery and to translating new knowledge into public health action should be rewarding. The translation phase should also be strongly linked to the biologic studies that follow gene-discovery, such as functional studies of genes or alleles, and biotechnological studies and advances that translate the functional data into new therapies or interventions.
Pharmacogenetics is an emerging field of genetics in which pharmacological therapies are optimized based on the individual genetic characteristics. 101 For infectious diseases, this field is already providing some important knowledge that influences public health and clinical practice. For example, knowledge of the host’s G6PD status is a critical to determining choice of antimalarial drug. Similarly, in the treatment of TB, the isoniazid-associated peripheral neuropathy is known to have a pharmacogenetic basis. Persons who are slow isoniazid acetylators 102 are at particularly high risk of neuropathy. The rate of acetylation (of isoniazid and many other drugs) is influenced by polymorphisms in the N-acetyltransferase gene, NAT2. 60,103 Conversely, persons who rapidly acetylate isoniazid may be at greater risk of developing drug failure or drug-resistant mycobacteria when given typical once-weekly isoniazid dosage regimens104 and may require higher therapeutic doses of isoniazid. Missense mutations of the NAT2 gene are responsible for instability and inefficiency of NAT and three variants, M1, M2, M3 of NAT2 account for about 95% of slow acetylator status.60 The slow acetylator phenotype is inherited in an autosomal recessive pattern. Thus slow acetylators are homozygous and rapid acetylators are either homozygous or heterozygous.103 Eskimos, Japanese and Chinese populations have high frequencies (80-90%) of rapid acetylators genotypes, while some Arab, Indian and European populations are predominantly (~70%) of the slow acetylator genotype. 102 Future studies of drug efficacy or adverse events, particularly when the drugs are gene-targeted therapies (e.g. chemokine-receptor or cytokine based) are likely to incorporate pharmacogenetics into drug trials. The attractiveness of this approach to industry, insurance companies and public health is obvious: targeting of drug therapy to appropriate genotypes in the clinic or in populations may lead to cost savings and reductions in adverse events.
Ecogenetics is another relatively new field that is somewhat related to pharmacogenetics. The discipline attempts to explain why some exposed individuals develop adverse events following exposure to environmental agents (e.g. carcinogens, foods, insecticides) and how people adapt to the environment in different manners.60 Nutritional factors, toxins and other environmental factors may alter the host immune response, or cause organ damage in genetically determined ways. For example, host genes influence susceptibility to hepatitis from a number of environmental toxins, and this susceptibility may influence the risk of or severity of hepatitis following exposure to hepatitis viruses. Concurrent consideration of the influence of host genetics on environmental factors as well as directly on pathogens may discover additive or multiplicative interactive effects of genetic and environmental risks on infectious diseases. An advantage of this approach is that many of the environmental risk factors are modifiable through behavior, diet and other measures.
One of the most difficult decisions facing public health officials or agencies is in choosing which genes to target for their infectious disease program, and in deciding which aspects of the program, (e.g. surveillance, applied research, infrastructure and prevention) should have the highest priority. Before these decisions can be made certain information is needed for each gene and disease. Of utmost importance is whether safe, effective interventions or preventions for the infectious disease are available that can be targeted to persons with the genotype.105 Additional information necessary for such decision making includes knowledge of the magnitude of the relationship between the genotype and the outcome, the prevalence of the genotype, the burden of the disease or outcome, the target populations, and the interaction of the genotype with other genes and with other risk factors. In the face of a rapidly expanding body of knowledge about genes and infectious diseases and the development of new gene-directed therapies a second challenge is to ensure communication and collaboration between the partners involved in all phases from gene discovery to public health action. Communication is being made easier through online and easily accessible databases such as the National Center for Biotechnology Information Web site, which provides links to many data sources such as the Online Mendelian Inheritance in Man (OMIM),106 the Cochrane Collaborations including those on HIV/AIDS 107 and proposed databases such as the HuGE Net.108
In the following sections, we consider specifically how current or future knowledge about host genes and infectious diseases may impact and be integrated into the four areas of infectious disease programs for malaria, TB, and HIV, and how they may impact primary, secondary and tertiary prevention (Table 3).
1. Surveillance and Response
For malaria, TB, and HIV, classical surveillance is based on the incidence and prevalence of these diseases and their associated mortality in certain populations. Constant vigilance enables rapid detection of outbreaks. Current reporting systems are typically based on geographic boundaries, with reporting to a centralized state, regional, or national database. Additional surveillance and reporting is performed based on risk groups. For example, HIV surveillance is targeted to risk groups defined by sexual or drug-using practices, while TB surveillance is heightened in immunocompromised persons, such as those with HIV/AIDS. The knowledge that certain populations (defined racially, geographically, or otherwise) may have genotypes that increase or decrease risk for infectious diseases may modify classical surveillance and control measures.
For example, the association of particular NAT2 and G6PD genotypes with adverse drug events may warrant particular vigilance for these problems in genetically at-risk populations as well as more systematic surveillance of populations for these and other risk-associated genotypes. This information could also be useful in determining appropriate prophylactic or treatment regimens for certain populations or regions and may be critical to encouraging the pharmaceutical industry to develop new drugs.
Although genotype-based preventions and/or therapies for TB, malaria, and HIV are not currently available for the other genotypes listed in Table 2, new gene-based drugs and vaccines for these diseases are in clinical and preclinical trials and may soon be more widely used. Surveillance of populations for genotypes on which these therapies are based (e.g. HLA-based vaccines and chemokine or cytokine-based therapies discussed below) may allow targeting and optimization of particular vaccines or therapies to the appropriate populations, as well as targeted monitoring of these populations for gene-related adverse events.
When genotype-based prevention and intervention approaches become more widely available for any of these diseases, appropriately designed and collected surveillance information about these genotypes will be required for informed decision making. Population-based as well as risk- group-targeted surveillance may be useful. Data collection could be performed through the use of databases such as National Health and Nutrition Examination Surveys (NHANES) in the United States or through the development of other national or global repositories. The surveillance for genotypes of interest and the development of DNA banks should be based on partnerships between local, federal and international agencies, and should build on the CDC, USAID (U.S. Agency for International Development), WHO, and other programs for infectious disease surveillance and response.24,109 These programs include strategies for developing networks, collecting efficient data, building laboratory capacity and tools, and studying patterns of disease trends and outbreaks, into which host genetic knowledge and surveillance can be integrated.
2. Applied research
The highest priority areas for applied research in relation to translating current knowledge about host genes and HIV, TB and malaria into public health action relates to development of vaccines, new drugs and therapies.
Because no effective vaccines exist for HIV, TB or malaria, development of these vaccines for primary or even secondary or tertiary prevention is an extremely high priority area for public health research. Using knowledge about HLA class I and II disease associations for these diseases and by dissecting the immune response in exposed or infected individuals, vaccines are being developed for TB, HIV and malaria using a reverse immunogenetic approach. 110-114 For example, identification of HLA-B53 as a gene associated with protection against severe malaria 35,44 led to the use of this approach to determine the molecular basis of such protection. This included HLA-binding studies for the rapid identification of immunologically protective cytotoxic T-cell (CTL) epitopes in malarial parasites.115,116 Based on this information, a new generation of synthetic recombinant vaccines has been developed for malaria, and these vaccines may soon undergo clinical trials.117,118 Similarly, studies of persons infected with HIV or TB, or apparently resistant to HIV are generating HLA-based data useful for vaccine design. 119-121 Tools such as the EpiMatrix algorithm122 can predict allele-specific or promiscuous HLA-binding epitopes that may be important for developing subunit HIV, TB or malaria vaccines. These HLA-based approaches may provide new vaccines for HIV and malaria and alternatives to the BCG vaccine for TB. These new vaccines may be live recombinant vaccines,123,124 DNA vaccines125-127 or others. Population based-HLA allele frequencies generated through surveillance may be relevant for interpreting the overall efficacy of these vaccines and in monitoring vaccine failures since vaccine-induced pressure could result in the loss of binding of pathogen epitopes to the relevant HLA molecule.44,128,129
In the area of drugs for the prophylaxis or treatment of TB, HIV and malaria, several areas of applied research are of high priority. As mentioned above and in the pharmacogenetics section, continued studies of the relationship of host-genotype (G6PD, NAT2) to nonresponse or drug toxicity in the host or to the emergence of drug-resistant pathogens are very important. For example, if confirmed in other studies the recent observation that HLA-DR2 is more strongly associated with the development of drug-resistant forms of TB68 might suggest that this genotype would be a useful target for surveillance and or intervention programs. An important applied research objective in relation to antibiotics as tertiary prevention might be the development of simple, reliable diagnostic tests that can be used in primary health centers to identify individuals at potential risk for adverse drug reactions or altered drug efficacy (e.g., genotyping for G6PD before using primaquine for malaria or genotyping for HLA DR2 and NAT2 for TB).
An exciting area of gene-based drug development is in relation to biologic drugs such as chemokines, cytokines or their analogs, and agonists or antagonists of their receptors. As the function of genes such as NRAMP-1 are elucidated, additional new therapies may be added to the armamentarium. For HIV the new chemokine receptor knowledge has led to a burgeoning of therapeutic strategies including molecular mimics and receptor blocking drugs.130 In the classical prevention model, these new therapies might provide either primary prevention (e.g., for persons at high risk of acquiring HIV infection) or secondary prevention (e.g., treatment of HIV-infected persons). Other secondary preventions based on chemokine receptors, such as bone marrow replacement or gene therapy,94 are potential long-term genetic strategies. For HIV-infected persons, applied research to determine the efficacy of and any adverse events associated with new receptor-targeted biotechnological drugs will be of vital importance. Similarly for malaria and TB, where cytokine gene polymorphisms have or may be associated with different outcomes (TNF-malaria, IFN and IL12 receptor-mycobacterial diseases) cytokine based therapies are now being considered and in some cases moving into clinical trials. Already, cytokine treatment of persons with these genotypes has been shown to result in rapid clearance of non-TB mycobacterial disease.131,132 Drugs that induce or modify cytokine-production are also attractive candidates. In the case of TB and HIV coinfection, trials of cytokine inhibitors gave encouraging results but warrant further assessment.133,134
Much applied research effort should be place in the area of genetic epidemiology, where new candidates are tested, where preliminary gene-pathogen associations are confirmed in larger studies and where the interactions with other known genes or risk factors can be carefully examined to determine attributable risk.
For malaria, a priority is to investigate the role of host genetics in malaria-associated death, as currently about 1/3 of patients die despite medical intervention. 135 In association or other types of epidemiological study design, one gene to examine might be the common African polymorphism in the complement-receptor 1 [Sl(a-)]. 136 This polymorphisms influences rosetting of P. falciparum infected erythrocytes to normal erythrocytes137 and therefore may influence the risk of cerebral malaria. The inducible nitric oxide synthetase gene (INOS), some alleles of which have recently been shown to be associated with the risk of fatal severe malaria.138 should also be further evaluated.
For HIV and TB one candidate for evaluation is the gene controlling iron overload (e.g. the genes associated with hereditary hemochromatosis139 or as yet unidentified iron overload genes) because iron overload appears to impair macrophage function and pathogen clearance. A recent study in Africa suggested that iron overload may explain death from pulmonary TB.140 Because simple cheap measures to reduce iron overload exist (e.g. diet, phlebotomy), incorporation of studies of these genes in candidate or other studies to identify risk-associated genes for HIV and TB are important. Similarly, confirmation and further study of the role of vitamin D receptor genes in HIV or TB disease would also be rewarding, as dietary supplementation with Vitamin D might be a simple public health measure to reduce disease risk or severity.
For all three diseases, continued effort in evaluating the role, in disease susceptibility or pathogenesis, of polymorphism in the many cytokine genes that influence the immune response is likely to be fruitful, as biologic therapies are or are becoming available for IL-2, IL-10, TNF, other cytokines and their receptors.
3. Infrastructure and Training
Infrastructure and training underlies and is critical in all areas of public health action including surveillance, research, and the eventual development of programs that are targeted to persons with certain genotypes. Providing the tools (laboratory, epidemiology, surveillance) needed to perform applied research and gene-based surveillance in state, regional, or other settings will become more important in the future. The rapid integration of molecular diagnostic surveillance of pathogens in many laboratories throughout the world109 should facilitate this process since many of the tools and techniques are equally applicable to host and pathogen. This infrastructure development is best achieved through integrated efforts of many international and national organizations. A second challenge is the maintenance and updating of population-based information on the relationship of genes to infectious diseases. Databases such as OMIM and HuGE Net, as previously mentioned, are a crucial part of this infrastructure. One area that is becoming increasingly important is the education of public health officials about the principles of genetics and about current knowledge of how host genes impact infectious disease risk and outcome in individuals or populations. Examples of existing genetic and infectious disease professional education programs are those developed by CDC, WHO, USAID, the National Institute of Health (NIH), and academia in the form of workshops, conferences, or fellowships.
4. Prevention and control
We have already outlined the few situations in which existing prevention and control programs for malaria, TB, or HIV have been impacted by genetic knowledge. As outlined in preceding sections, current laboratory and epidemiological research into the relationship of host genes to all aspects of infectious disease prevention and control are moving gene-based prevention and intervention into several public health settings. As more genes-based therapies and strategies emerge based on this knowledge, prevention and control programs can be modified appropriately (Table 3).
One element of translating this genetic knowledge into public health action that should be concurrently addressed is the education of the public. For example, it is important that persons with particular genetic traits are knowledgeable about their risk of developing infectious diseases or adverse outcomes from antibiotics or other therapies. These educational strategies may range from recommendations for action (e.g. avoiding certain animalarial drugs in G6PD deficient persons) or also recommendations that persons adhere to traditional public health practices. For example, the new findings about chemokine receptor genes and HIV generated public interest in whether genetic testing for the Δ 32 CCR5 gene should be used to predict disease course or select therapeutic strategies. In the absence of adequate attributable risk and population-based information about this genotype and outcomes, or of CCR5 targeted therapies, public health agencies can only recommend the usual HIV prevention and intervention strategies regardless of genotype.18,100 In addition to this type of education, it is also important to educate the public about the general principles of genetics and infectious diseases (mutations, selection, disease risk). These efforts could be incorporated into other general strategies to translate genetic research into public health actions. For example, the Ethical, Legal, and Social Implications program at the U.S. National Human Genome Research Institute has coordinated public retreats and town meetings to provide education and other forums for scientists and the public to discuss the impact of new discoveries in biotechnology and genetic testing and the role of the media in informing the public about genetics.141
The great challenge of controlling or eradicating HIV, TB or malaria has remained with us for many years. Basic principles of prevention, treatment and education in the control of these diseases still remain the cornerstone of achieving this goal, while development of vaccines for these diseases is an urgent need. The discovery of genes which influence susceptibility and outcomes from these infectious diseases provides new opportunities for intervention and prevention and new strategies for vaccine development that may speed us to this ultimate goal. Many models for integrating the genetic knowledge into a public health program for infectious diseases may proposed, and in this review we have discussed but one. Whatever approach is taken, it is important to remember that the ethical, legal, and social issues described in the early chapters of this book must be addressed in concert with advances in knowledge and opportunities for prevention.
Table1. Malaria, TB, and HIV/AIDS: transmission, prevention and risk groups
Table 2. Host genes, impact on infectious diseases, and population frequency
Table 2 (cont.) Host genes, impact on infectious diseases, and population frequency
Table 2 (cont.) Host genes, impact on infectious diseases, and population frequency
Table 3. From Host Genes to Public Health Actions: Prevention and Control of Infectious Diseases
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