genetics and infectious diseases
DESCRIPTION
TRANSCRIPT
GENETICS AND INFECTIOUS DISEASES
Simba Takuva, MD, MSc.
Tropical Medicine – Host Week
School of Health Systems and Public Health
University of Pretoria
Outline of presentation
Background Role of genetics in infectious diseases Specific examples: referring to the “Big 3” Future direction: Public health implications Conclusions
Background
Human infectious diseases have been widely misunderstood to be purely infectious i.e. purely due from infection by an microbial agent.
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.
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
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
Role of genetics in infectious diseases
UK 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 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
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
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.
Tuberculosis
Recent up-dated meta-analysis addressing 23 studies (Gao L, et al. Int J TB Dis, 2010).
Candidate AsiansOR (95% CI)
AfricansOR (95% CI)
South AmericansOR (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)
Specific examples: Malaria
Adapted 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
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
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
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
HIV/AIDS
From the University of Washington Library.
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
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.
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
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
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
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