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Genetics and infectious diseases
1. GENETICS AND INFECTIOUS
DISEASES
Simba Takuva, MD, MSc.
Tropical Medicine – Host Week
School of Health Systems and Public Health
University of Pretoria
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. Background
Human infectious diseases have
been widely misunderstood to be
purely infectious i.e. purely due from
infection by an microbial agent.
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 variant
Types 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. 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. 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 twins
Sorensen, et al. N Engl J Med, 1988
7. Role of genetics in infectious diseases
UK Prophit Survey for Tb Susceptibility; Comstock, et al. Am Rev Respir Dis, 1978
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. 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 studies
Bornmann, et al. J Infect Dis, 2004 Wilkinson, et al. Lancet, 2000
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. Tuberculosis
Recent up-dated meta-analysis addressing 23 studies (Gao L, et al. Int
J 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)
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. Malaria
Role 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. 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
17. HIV/AIDS
CCR5 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. Future direction: Public health implications
Prevention 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. Future direction: Public health implications
Understanding of particular pathways used in host resistance
to 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. Future direction: Public health implications
Understanding of particular pathways used in agent
resistance to chemotherapy
or
(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. Future direction: Public health implications
Identification of molecules and pathways that are targets for
pharmacologic 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 receptors
Lalezari, et al. 2011. Wilen, et al. 2011
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
Hinweis der Redaktion
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
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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.