Genetics and infectious diseases

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