Successfully reported this slideshow.
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...
Upcoming SlideShare
Loading in …5
×

Genetics and infectious diseases

650 views

Published on

Published in: Technology, Health & Medicine
  • Be the first to comment

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

×