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GENETICS AND INFECTIOUS       DISEASES          Simba Takuva, MD, MSc.      Tropical Medicine – Host Week School of Health...
Outline of presentation   Background   Role of genetics in infectious diseases   Specific examples: referring to the “B...
BackgroundHuman infectious diseases havebeen widely misunderstood to bepurely infectious i.e. purely due frominfection by ...
Background Genetic mutations may be harmful or beneficial A variant (mutation) is common (>1% of chromosomes in  the gen...
Role of genetics in infectious diseases Diversity in the presentation of infectious diseases 1/3 of world’s population i...
Role of genetics in infectious diseases  In the early 1900’s – buzz about coexistence of   symptomatic and asymptomatic i...
Role of genetics in infectious diseasesUK Prophit Survey for Tb Susceptibility; Comstock, et al. Am Rev Respir Dis, 1978
Specific examples: Tuberculosis (TB) Growing body of evidence suggests that host genetic  factors play an important role ...
Tuberculosis (TB)  Several genes have now been associated with   susceptibility to mycobacterium (TB and leprosy)     Vi...
Tuberculosis (TB)Vitamin D receptor polymorphisms (VDRP) Recently, the Vitamin D Receptor (VDR) gene has been   heavily s...
TuberculosisRecent up-dated meta-analysis addressing 23 studies (Gao L, et al. IntJ TB Dis, 2010). Candidate         Asian...
Specific examples: MalariaAdapted from the Journal of Clinical Investigation, slide set, 2007.
Malaria Genetic factors account for about 25% of the variability of  the incidence of malaria in the general population ...
MalariaRole of CNPs in malaria treatment The cytochrome pigment 450 (CYP) 2A6 of the P450  family that is involved in the...
Specific examples: HIV/AIDS Varying susceptibility to HIV acquisition : “Elite HIV  controllers” Varying rates of HIV di...
HIV/AIDSFrom the University of Washington Library.
HIV/AIDSCCR5 chemoreceptor 32 –bp deletion gene Found in up to 20% of Caucasian populations Not seen among Africans Ind...
Future direction: Public health implicationsPrevention or risk prediction Personalized medicine “Personomics”    using i...
Future direction: Public health implicationsUnderstanding of particular pathways used in host resistanceto infection Exam...
Future direction: Public health implicationsUnderstanding of particular pathways used in agentresistance to chemotherapyor...
Future direction: Public health implicationsIdentification of molecules and pathways that are targets forpharmacologic int...
Conclusions Evidence for the causal association of gene  polymorphisms in infectious diseases is accumulating Applicatio...
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Genetics and infectious diseases

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  • Polymorphisms are used as genetic markers
  • Also for many years, Leprosy has been known to cluster in families900 adoptees followed up in Scandanavia: early death of a biologic parent from an infectious disease (rather than adoptive parent) was was associated with 6 fold increase in risk of infectious death in the adoptee monozygotic twins share 100 % of genes whereas dizygotic share on average 50%
  • Reference is opposite sex twins.
  • Illustrates variability of host response to same dose of pathogen. Provided insight into genetic susceptibility251 children were accidentally immunized with a virulent strain of M.TB instead of BCG.QuAppelle –TB introduced into previously unexposed population, and over time the frequency of TB decreased. Implies natural selection of resistant genes
  • Vitamin D is metabolized in the liver to 25(OH)2D3 then transported to the kidneys were it is metabolized to 1,25(OH)2D3, its active metabolite. The 1,25(OH)2D3 enters into the circulation were it targets the intestines and bones and interacts with the vitamin D receptor to enhance intestinal calcium absorption and mobilize osteoclastic activity. In addition, it has an immunodulatory function In that 1,25 (OH) 2D3activates monocytes, suppresses lymphocyte proliferation,supresses immunoglobulin production suppresses cytokine synthesis In this way it plays a vital role in human innate immunity to certain infectious agents. in the presence of adequate 1,25(OH)2D3, VDR upregulation leads to cathelcidin induction, an antimicrobial peptide which has direct action against intracellular pathogens including Mycobacterium Tuberculosis in macrophages
  • The VDR gene is a well studied gene on the long/short arm of chromosome 12. There are over 490 single nucleotide polymorphisms (SNPs) in this gene, however, many have low allele frequencies and are not suited for genetic epidemiologic studies. The most commonly studied polymorphisms on the VDR gene have been the Fok1, Taq1, Apa1 and Bsm1. Other less frequently studied polymorphisms include the Cdx-2, GATA, Poly (A) and the A1012G polymorphism.
  • Sporozoites injected by anopheline mosquitoes travel through the dermis and enter the bloodstream to invade hepatocytes. Each infected hepatocyte generates tens of thousands of merozoites, which then break out and reenter the bloodstream to invade erythrocytes. Numerous rounds of asexual reproduction follow, with repeated invasion of erythrocytes every 48 hours. Some parasites in the erythrocytes develop into sexual stage gametocytes, which circulate in the bloodstream and are taken up by female mosquitoes during a blood meal. In the mosquito midgut, gametes emerge from the gametocytes and cross-fertilize . The resulting zygote develops into an ookinete that crosses the midgut wall and grows into an oocyst. Mitotic division within the oocyst produces thousands of sporozoites that break out and travel through the hemolymph to the mosquito salivary glands, from which they are injected into a human host. (Figure 2 and commentary adapted from Journal of Clinical Investigation @@@).
  • -duffy chemokine receptor gene-protection is complete as vivax is unable to infect duffy negative erythrocytes
  • -
  • Binding and Fusion: HIV begins its life cycle when it binds to a CD4 receptor and one of two co-receptors on the surface of a CD4+ T- lymphocyte. The virus then fuses with the host cell. After fusion, the virus releases RNA, its genetic material, into the host cell.
  • Binding and Fusion: HIV begins its life cycle when it binds to a CD4 receptor and one of two co-receptors on the surface of a CD4+ T- lymphocyte. The virus then fuses with the host cell. After fusion, the virus releases RNA, its genetic material, into the host cell.
  • Hiv positive with undetectable viral load and disease progression despite absence of HAARTThe small phase 1 study involved six HIV-positive patients. All were taking HIV treatment and had an undetectable viral load. However, they had had a poor immune response to treatment and their CD4 cell counts were in the 200 to 500 cells/mm3 range. Blood was drawn from the patients, the T-cells were filtered out, and the blood was then returned. These cells were treated in the laboratory with a type of gene therapy called zinc finger technology that disables the CCR5 co-receptor.Modification of cells was successful in about a quarter of cases. These cells were then re-introduced into the patients.Five of the six patients experienced good increases in their CD4 cell count, and their immune profiles improved. PHASE I TRIALS: Initial studies to determine the metabolism and pharmacologic actions of drugs in humans to gain early evidence of effectiveness; may include healthy participantsPHASE II TRIALS: Controlled clinical studies conducted to evaluate the effectiveness of the drug and to determine the common short-term side effects and risks. PHASE III TRIALS: Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling. PHASE IV TRIALS: Post-marketing studies to delineate additional information including the drug's risks, benefits, and optimal use.
  • Transcript of "Genetics and infectious diseases"

    1. 1. GENETICS AND INFECTIOUS DISEASES Simba Takuva, MD, MSc. Tropical Medicine – Host Week School of Health Systems and Public Health University of Pretoria
    2. 2. Outline of presentation Background Role of genetics in infectious diseases Specific examples: referring to the “Big 3” Future direction: Public health implications Conclusions
    3. 3. BackgroundHuman infectious diseases havebeen widely misunderstood to bepurely infectious i.e. purely due frominfection by an microbial agent.
    4. 4. Background Genetic mutations may be harmful or beneficial A variant (mutation) is common (>1% of chromosomes in the general population) = genetic polymorphism If allele frequencies < 1% = rare variantTypes of Polymorphisms  Single Nucleotide Polymorphisms (SNP) : substitution of one or the other of 2 bases of DNA at a single location  Insertion-deletion Polymorphisms (Indel): insertion or deletion of 2 to 100 nucleotides i.e. presence or absence of a short segment of DNA  Copy Number Polymorphisms (CNP): typically the presence or absence of 200-bp to 500-Mbp segments of DNA . Also, gene duplications.
    5. 5. Role of genetics in infectious diseases Diversity in the presentation of infectious diseases 1/3 of world’s population is infected with M. tuberculosis; however, only a minority (10%) of those infected ever develop clinical disease Factors other than bacterial infection alone determine disease development. Widely studied are environmental and host immune status Host genetic variation has a substantial influence on the course of infectious diseases
    6. 6. Role of genetics in infectious diseases  In the early 1900’s – buzz about coexistence of symptomatic and asymptomatic infections in humans  Epidemiological evidence accumulated, since 1930s, that human genetic factors play a role in immunodeficiency and susceptibility to infectious diseases  Follow-up studies of adoptive children also showed that predisposition to infectious diseases was largely inherited  The concordancy of infectious diseases rates has been shown to be higher in monozygotic twins than in dizygotic twinsSorensen, et al. N Engl J Med, 1988
    7. 7. Role of genetics in infectious diseasesUK Prophit Survey for Tb Susceptibility; Comstock, et al. Am Rev Respir Dis, 1978
    8. 8. Specific examples: Tuberculosis (TB) Growing body of evidence suggests that host genetic factors play an important role in the development of TB Lubeck disaster in Germany, 1930  Illustrates variability of host response  251 children received same dose of MTB  47, had no indication of disease ; 127 showed radiological features; and 77 died Qu’Appelle Indians of Saskatchewan  Previously unexposed to TB  Almost 10% died per annum from TB  After 40 years, more than ½ of families were eradicated but TB rates dropped 50 fold (to <0.2%)Motulsky, Hum Bio, 160. Reider, et al. Pneumologie 2003
    9. 9. Tuberculosis (TB)  Several genes have now been associated with susceptibility to mycobacterium (TB and leprosy)  Vitamin D receptor gene (VDR)  Natural resistance-associated macrophage protein-1 gene (NRAMP1)  Human Leukocyte Antigen gene (HLA-DR)  Interferon gamma gene  Study designs: case-control association and genome- wide association studiesBornmann, et al. J Infect Dis, 2004 Wilkinson, et al. Lancet, 2000
    10. 10. Tuberculosis (TB)Vitamin D receptor polymorphisms (VDRP) Recently, the Vitamin D Receptor (VDR) gene has been heavily studied as candidate gene for TB susceptibility There are over 490 single nucleotide polymorphisms (SNPs) in this VDR gene Commonly studied have been Fok1, Taq1, Apa1 and Bsm1 polymorphism. Less commonly Cdx-2, GATA, Poly (A) and the A1012G polymorphism.
    11. 11. TuberculosisRecent up-dated meta-analysis addressing 23 studies (Gao L, et al. IntJ TB Dis, 2010). Candidate Asians Africans South Americans OR (95% CI) OR (95% CI) OR (95% CI) Fok1 2.0 (1.3-3.2) 1.0 (0.7-1.3) 0.8 (0.4-2.0) Apa1 1.3 (0.4-4.5) 1.8 (1.2-2.8) 0.9 (0.7-1.2) Taq1 1.4 (0.9-2.1) 1.1 (0.6-2.1) 1.8 (0.5-6.4) Bsm1 1.4 (0.6-3.4) 1.2 (0.8-1.6) 0.8 (0.6-1.3)
    12. 12. Specific examples: MalariaAdapted from the Journal of Clinical Investigation, slide set, 2007.
    13. 13. Malaria Genetic factors account for about 25% of the variability of the incidence of malaria in the general population Epidemiologic data has since demonstrated the following:  Hb-S, protective role of the sickle-cell trait against P.falciparum  Hb-E is associated with a reduction in disease severity in south-east Asia  Hb-C, is also associated with reduced malaria susceptibility and severity in West Africa  Duffy antigen negative phenotype confers resistance to P.vivax  HLA-B53, independent protective effects of this genetic variant found in West Africa but rare elsewhere
    14. 14. MalariaRole of CNPs in malaria treatment The cytochrome pigment 450 (CYP) 2A6 of the P450 family that is involved in the metabolism of the drug artesunate: may be present in the genome as multiple copies (CNPs) hence may metabolize drug faster Resistance mechanism for artemesinin: conferred by an increase in the number of gene copies for the multi-drug resistance (pfmdr) gene A decrease in CNPs for this gene results in susceptibility to drugs like quinine, mefloquine, lumefantrine, halofantrine and artemesinin mutations in pfcrt gene also multiply the pfmdr gene thus leading to chloroquine resistance
    15. 15. Specific examples: HIV/AIDS Varying susceptibility to HIV acquisition : “Elite HIV controllers” Varying rates of HIV disease progression Important host genes found to influence HIV-1 acquisition and AIDS progression include CCR5, CCR2, and HLA-B, genes A recent report has, identified an additional 9 new candidate genes associated with HIV disease progression and acquisition O’Brien, et al. CROI, 2011
    16. 16. HIV/AIDSFrom the University of Washington Library.
    17. 17. HIV/AIDSCCR5 chemoreceptor 32 –bp deletion gene Found in up to 20% of Caucasian populations Not seen among Africans Individuals with this polymorphism have absent CCR5 receptors Also, they never get infected by normal HIV-1 Those that are infected (usually by variant virus, X4) exhibit persistently low viral load and very slow disease progression Mutations in CXCR4 may protect Africans
    18. 18. Future direction: Public health implicationsPrevention or risk prediction Personalized medicine “Personomics”  using information about a person’s genetic make-up to tailor strategies for detection, treatment, and prevention of disease Genetic counselling of affected families Genetic Information Non-Discrimination Act of 2007-2008  Prohibits health insurers from requesting or requiring genetic information of an individual or their family members or using it for decisions on coverage, rates, etc.
    19. 19. Future direction: Public health implicationsUnderstanding of particular pathways used in host resistanceto infection Example  HLA-B53 association with resistance to malaria, supports a protective role for CD8+ T cells in this disease. This encourages efforts to develop vaccines that ellicit this immune response  VDRPs provide mechanistic insights into pathways by which vitamin D may modulate host response to opportunistic infections like TB
    20. 20. Future direction: Public health implicationsUnderstanding of particular pathways used in agentresistance to chemotherapyor(Preventing drug resistance) monitoring changes in CNPs in the parasite population may help to recognize emerging drug resistance quickly and early Investigating CNPs of drug-metabolizing P450 may lead to personalized adjustment of drug dosage to compensate for increased degradation of drugs if a surplus of copies is present
    21. 21. Future direction: Public health implicationsIdentification of molecules and pathways that are targets forpharmacologic intervention The cure for HIV probably lies in gene therapy  The “Berlin patient”  Proof of concept study : gene therapy used (zinc finger technology disables the CCR5 co-receptor). Immune profiles improved  Studies underway that will genetically modify the CCR5 and the CXCR4 receptorsLalezari, et al. 2011. Wilen, et al. 2011
    22. 22. Conclusions Evidence for the causal association of gene polymorphisms in infectious diseases is accumulating Application of products of genomics research such as susceptibility assessment and pharmacogenomics holds promise though currently some barriers persist Genetics has the role of identifying the missing component in a given individual patient’s immunity to infection
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