Infectious disease Flashcards
What region of the genome is MHC?
region on chromosome 6 - 6p21.3
why is a high level of polymorphism important in the MHC?
Some of the genes encoded in the MHC have a central role in the immune response and encodes numerous different immuno-regulatory genes for innate and adaptive immunity. High levels of HLA polymorphisms guarantees the broadest diversity of recognised antigens and therefore reactivity against pathogens.
Many of HLA polymorphisms result in amino acid substitutions that have the potential to affect the functional characteristics of the peptide binding grove and thus can change the peptides the HLA binds. Inherited genetic variation can therefore determine which peptides bind and the orientation of the binding, resulting in alternative peptide presentation to T-cells
What T-cells do HLA class I present to?
CD8+ - Cytotoxic T-cell.
Expressed on all cells apart from RBCs.
What T-cells do HLA class II present to?
CD4+ - T-helper cells
What percentage of people are asymptomatic when infected with leprosy?
90% are asymptomatic when infected with the leprosy mycobacterium
what is the twin concordance for leprosy?
MZ >60% and DZ >20%
Clear contribution of genetic factors to disease outcome.
Polymorphisms in which gene are linked to leprosy?
NOD2 polymorphisms
What are the two most common causes of malaria?
- Plasmodium vivax (most common and less severe)
2. Plasmodium falciparum (severe disease)
What hemoglobinopathies change susceptibility to malaria?
- Sickle cell anaemia
2. Thalassemia
What are sickle cell anaemia and thalassemia?
Hemoglobinopathies
How are hemoglobinopathies inherited?
Follow mendelian pattern of inheritance
How are hemoglobinopathies linked to complex disease?
Although the hemoglobinopathies follow a mendelian pattern of inheritance, they alter the susceptibility to infection - they are an example of a gene acting alone or in concert to alter the susceptibility of a disease.
What is the mt. that causes sickle cell anaemia?
Point mutation, single amino acid substitution in the B-globulin chain of haemoglobin
GLUTAMIC ACID –> VALINE at amino acid position 6 of the beta-chain.
Valine is hydrophobic so this causes RBC to polymerise and leads to sickle cell shape
what is the advantage conferred by being heterozygous for sickle cell mt?
10 fold increased resistance to P. falciparum malaria
HETEROZYGOTE ADVANTAGE (homozygotes have sickle cell disease- severe and often fatal)
What theories explain the HbS heterozygote advantage?
No clear answer to why confers an advantage but epidemiology suggests maintained in populations in areas of high risk.
- SUPPRESSION OF PARASITE GROWTH in RBCs: plasmodium degrades Hb as a nutrient source and so HbS not as available restricts parasites replication cycle or the parasite has restricted room to grow.
- PARASITE INFECTED RBCS MORE READILY CLEARED: parasite infected sickle cells are more readily cleared by immune response - they have different properties (shape, size, mechanical properties) that are easier to detect.
- REDUCED EXPRESSION OF PfEMP-1: cytoadherance depends on the parasite protein PfEMP-1 (P.falciparum erythrocyte membrane protein, cytoadherance causes blockages of capillaries that lead to the more severe symptoms associated with malaria (haemorrhage)
What causes thalassemia?
Arises from defective production of the alpha chain (alpha thalassemia) or defective production of the B-chain (Beta thalassemia). Alpha chain encoded by two genes and if only one mt then get relatively mild form of thalassemia.
What theories explain the HbE heterozygote advantage?
Heterozygotes for HbE (AE) have a four times reduction in P.falciparium invasion compared to AA cells. One theory is that changes to the AE cell membrane interfere with invasion and get reduced parasitic invasion of the HbEs. Also evidence that this hemoglobinopathy (like alpha + thalassemia) makes children more susceptible to
How can changes in the duffy antigen confer an advantage for malaria infection?
- acts as receptor for P.vivax - binds cytokines but also bines p.vivax. Red blood cells that don’t have the duffy antigen are resistant to invasion.
> The FY gene encodes the duffy antigen. Two major codominant alleles (FYa and FYb) -33 T–>C SNP in the promoter region of the FYb results in no expression of the duffy antigen and resistance to P.vivax infection.
What is the duffy antigen?
Acts as receptor for P.vivax - cells that lack this receptor are resistant
How might a TNF- alpha polymorphism effect individuals infected with malaria?
> TNF-alpha highly involved in immune function and inflammation
Cerebral malaria associated with TNFalpha increase
Two promoter polymorphisms associated with increased susceptibility to cerebral malaria.
What are the challenges for GW studies of infectious disease?
- Need large number of well-phenotypes individuals which can be difficult to achieve in developing countries.
- Often levels of high genetic diversity and low linkage disequilibrium, especially in African populations.
- False positives may arise as a result of population stratification and multi-centre studies by compromised by differences in haplotypes of the participating communities.
- Hard to compare and repeat GW studies in these populations due to completely dive
Give an example of successful malaria GWAS?
MalariaGEN - genome wide association for malaria.
> investigated 500,000 SNPs in 1060 children with severe malaria in comparison with 1500 controls
In first instance association with HbS region was relatively weak (in candidate gene approach identified 10 fold increase) but when did high resolution mapping of 62 subjects as a reference for an imputation analysis then the association was greatly increased. This imputation approach can now be applied to future GWAS studies and there have been novel genes identified. but still evident that denser, population specific arrays are needed to investigate infectious disease adequately.
