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)

12. Specific examples: Malaria
Adapted from the Journal of Clinical Investigation, slide set, 2007.

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

16. HIV/AIDS
From the University of Washington Library.

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