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Genetics of Complex Disease > Genetics of Infectious Disease > Flashcards

Genetics of Infectious Disease Flashcards

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Biology 101 flashcards
0
Q

studies of genetic links in families give evidence for a genetic basis for infectious disease - give two examples

A

1) adoption study in 960 adult adoptees - relative risk of child dying from infection at young age was six times higher if parent had died from infection at young age
2) odds ratio for primary sibling death due to infection = >9

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1
Q

genetics are the biggest cause of death worldwide: true or false?

A

true

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2
Q

what is malaria?

A

a parasitic infectious disease transmitted by anopheline mosquitoes

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3
Q

what parasites are responsible for malaria?

A

humans can be infected by five species of plasmodium that cause malaria - mainly plasmodium falciparum (most severe) and plasmodium vivax (most common)

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4
Q

how many clinical episodes of malaria and malaria-related deaths per annum are estimated?

A

250 million clinical episodes of malaria and 1 million deaths per annum

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5
Q

how is resistance or clinical immunity to malaria achieved?

A

through genetically-based mechanisms, via repeated infection or via continuous exposure

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6
Q

in endemic areas, what percentage of children are estimated to be chronically infected with malaria?

A

50%

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7
Q

what disorders can confer resistance to malaria?

A

some blood group polymorphisms - e.g. haemoglobinopathies, erythrocyte polymorphism and immunogenetic variants

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8
Q

what are haemoglobinopathies?

A

disorders characterised by abnormalities in haemoglobin structure and production

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9
Q

what are typical symptoms of malaria?

A

fever chills and sweating

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10
Q

haemoglobinopathies are the most common single-gene disorders: true or false?

A

true

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11
Q

what are thalassemias?

A

disorders resulting from alterations in the synthesis of the alpha or beta globin chains

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12
Q

what is a-thalassemia? what is it a result of?

A

abnormal a-globin chain synthesis due to deletions of one of four duplicated a-globin genes on chromosome 16

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13
Q

what are the two types of a-thalassemia?

A

a+-thalassemia and ao-thalassemia

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14
Q

what is a+thalassemia a result of? what does it result in?

A

a loss of one a-globin gene

  • a/aa = clinically normal
  • a/-a = mild anaemia and decreased haemoglobin content in RBCs
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15
Q

what is ao-thalassemia the result of?

A

a loss of both a-globin genes i.e. aa/– or –/– (lethal and not compatible with life)

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16
Q

which form of a-thalassemia has been most linked to malarial protection?

A

a+ thalassemia

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17
Q

why is a+ thalassemia thought to provide protection against malaria?

A

1 - produces microcytic anaemia
2 - induces increased anti-parasitic immune mechanisms (e.g. phagocytosis) against the red blood cells
3 - increases early susceptibility to p.vivax and therefore reduces late susceptibility to p.falciparum
4 - associated with CR1 deficient red blood cells (therefore ⬇️ ability to form rosettes)

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18
Q

what is erythrocyte rosetting in malaria?

A

a pathogenic marker of severe malaria - a clustering of infected red blood cells around a central cell (e.g. an uninfected red blood cell) due to an immunological reaction between an epitope on the central cell surface and a receptor/antibody on the infected red blood cells

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19
Q

what receptor is thought to mediate rosetting (clumping) of parasited red blood cells in malaria?

A

the complement receptor 1 (CR1) on uninfected red blood cells

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20
Q

polymorphisms associated with CR1 deficiency are thought to increase susceptibility to malaria: true or false?

A

false - CR1 deficiency has been shown to confer protection against severe malaria (RBC CR1 deficiency is extremely common in malaria-endemic regions)

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21
Q

how is microcytic anaemia in a+-thalassemia thought to be protective against malaria?

A

parasite growth is impaired in a+thalassemia red blood cells as they have ~15% reduction in surface area than normal RBCs

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22
Q

what is sickle cell disease a result of?

A

mutations in the HBB gene

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23
Q

what two genotypes does HBB mutation in sickle cell disease produce? what are the consequences of these genotypes?

A 
HbS/HbS = HbSS ➡️ fatal in early life if untreated
HbS/HbA = HbAS ➡️ sickle cell trait i.e. clinically normal and protective against malaria (p.falciparum)
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24
Q

structurally, what do mutations in the HBB gene cause (in sickle cell disease)?

A

a mutant B-globin chain (Ba ➡️ Bs) = an amino acid change from glutamic acid to valine at position 6

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25
Q

what does the amino acid change in position six of the HBB gene (in sickle cell disease) result in?

A

the glutamic acid ➡️ valine substitution results in the exposure of a hydrophobic residue on the B-globin chain and polymerisation of red blood cells on deoxygenation

26
Q

how is HbAS (sickle cell trait) though to be protective against malaria?

A

1) limited parasitic growth within RBCs due to ⬇️ surface area
2) increased anti-parasitic immune mechanisms against infected sickle RBCs
3) HbS/HbAS RBCs have ⬇️PfeMP-1 expression and therefore show ⬇️ cytoadherance and sequestration in small blood vessels

27
Q

what three SNPs were shown to be associated with malarial resistance in the MalariaGEN GWAS and other GWAS?

A

a HbS SNP (rs334), a SNP in a region close to the SCO1 gene and a SNP in a region close to the DDC gene

28
Q

what class of virus is HIV?

A

a retrovirus

29
Q

with relation to receptor/cell specificity, there are two strains of HIV - what are they?

A

M-tropic: able to infect macrophages by recognition of CCR5 receptor
T-tropic: able to infect T cells by recognition of CXCR4 receptor

30
Q

which HIV strain typically mediates early HIV infection?

A

M tropic strains

31
Q

depletion of CD4 T cells and progression to AIDS occurs after infection with which strain of HIV?

A

T tropic strain

32
Q

what is the primary receptor for HIV infection?

A

CD4 on macrophages and T cells

33
Q

what are the co-receptors for HIV infection?

A

CCR5 and CXCR4

34
Q

individuals with immunity to HIV can be split into two classes - what are they?

A

exposed-uninfected and long term non-progressors

35
Q

how is the CCR5 receptor linked to resistance to HIV infection?

A

a 32 base pair deletion in the CCR5 gene confers resistance to HIV via the production of a non-functional CCR5 receptor that is not trafficked to the cell surface and therefore is not able to be used as a co-receptor for HIV entry to the cell

36
Q

what percentage of the Caucasian population carries the /\32 CCR5 mutation?

A

10%

37
Q

homozygotes for the /\32 CCR5 mutation are ___% protected from infection by M-tropic HIV strains

A

100%

38
Q

homozygotes for the /\32 CCR5 mutation are 100% resistant to infection by T-tropic strains of HIV: true or false?

A

false - the /\32 CCR5 is only protective against infection from M-tropic strains of HIV

39
Q

heterozygotes for the /\32 CCR5 show no resistance to infection with M-tropic HIV strains: true or false?

A

false - heterozygous show delayed disease progression due to ⬇️ production of the CCR5 receptor

40
Q

why is CCR5 an attractive target for therapeutic intervention in HIV?

A

individuals with the /\32 CCR5 mutation are completely healthy and show no adverse effects on the immune system

41
Q

why does the /\32 CCR5 mutation have no adverse effect on the immune system?

A

the chemokine system is highly redundant

42
Q

why is CCR5 not an attractive target for therapeutic intervention in HIV?

A

individuals with the /\32 CCR5 mutation show increased susceptibility to cerebral complications of West Nile virus

43
Q

CCR5 mutations account for all exposed-uninfected phenotypes in HIV: true or false?

A

false - the /\32 CCR5 is rarely found in the African/Asian population but exposed-uninfected individuals occur in these populations

44
Q

which natural ligands for CCR5 and CXCR4 are associated with susceptibility/protection against HIV?

A 
CCR5 = RANTES and Mip-1a/B
CXCR4 = SDF1
45
Q

what SNP in the RANTES gene is associated with acceleration in AIDS progression during HIV infection?

A

In1.1C - a SNP within the intron of the RANTES gene

46
Q

what is the consequence of the In1.1C SNP in the RANTES gene with relation to HIV?

A

the In1.1C SNP results in:
4-fold ⬇️ regulation of RANTES transcription
altered affinity of RANTES for nuclear binding proteins

47
Q

why does the In1.1C SNP in the RANTES gene result in acceleration of AIDS progression from HIV?

A

In1.1C SNP = ⬇️ RANTES levels and therefore ⬆️ CCR5 receptors available for HIV binding and entry into cells

48
Q

what variant in the SDF1 gene is associated with protection from HIV?

A

the 3’A variant = a G ➡️ A substitution in the 3’UTR of the SDF1 transcript

49
Q

what is the result of the 3’A variant in the SDF1 transcript with relation to HIV?

A

the 3’A variant occurs in the 3’UTR of the SDF1 transcript and therefore may result in ⬆️ mRNA stability, ⬆️ SDF1 levels, ⬆️ CXCR4 binding and therefore ⬇️ HIV binding to CXCR4

50
Q

what three polymorphisms are known to influence HIV outcome?

A 
V64I polymorphism (valine ➡️ isoleucine) in CCR2
polymorphisms in the CCR5 promotor regions
51
Q

the frequency and effect of HIV outcome-related haplogroups varies considerably between ethnic and racial groups: true or false?

A

true

52
Q

which HLA alleles are associated with delayed onset to AIDS?

A

HLA-B27 and HLA-B57

53
Q

HLA class 1 homozygosity is generally associated with accelerated progression to AIDS: true or false?

A

true - homozygosity of HLA genes (i.e. ⬇️ polymorphism) = MHC molecules are able to present only a limited range of viral peptides to CTLs therefore ⬇️ CTL*

54
Q

“HLA homozygosity is generally associated with accelerated progression to AIDS” - is there an exception to this?

A

yes - HLA-Bw4 allele homozygosity is associated with delayed progression to AIDS
(possibly by enchanting NK control of HIV-I infection as the HLA-Bw4 MHC molecule appears to be particularly good at interacting with natural killer cells)

55
Q

which HLA allele is associated with rapid progression to AIDS in Caucasians but protection from AIDS in African Americans?

A

HLA-B*35

56
Q

how is the DARC antigen (Duffy antigen) related to malaria?

A

individuals lacking DARC are 100% resistant to malarial infection

57
Q

how is the DARC Fy-/Fy- genotype brought about?

A

a T to C nucleotide substitution at position -46 within the GATA promotor preceding the DARC gene

58
Q

what is the consequence of the T49C nucleotide substitution GATA promotor preceding the DARC gene?

A

the substitution disrupts a binding site for the GATA-1 erythroid transcription factor and therefore transcription of the DARC gene is not activated, resulting in a lack of DARC expression on red blood cells

59
Q

individuals with the Fy-/Fy- genotype for the DARC gene are 100% resistant to infection by p.vivax: true or false?

A

true - Fy-/Fy- results in a complete lack of DARC expression on the surface of red blood cells and therefore p.vivax merozoites cannot invade red blood cells

60
Q

why is does the Fy-/Fy- DARC genotype confer protection against p.vivax infection specifically?

A

because DARC is the erythrocyte receptor for p.vivax (and not p.falciparum)

61
Q

the Fy-/Fy- DARC genotype prevents infection of hepatocytes with p.vivax sporozoites: true or false?

A

false - DARC expression is only suppressed in RBCs and therefore hepatocytes can still be infected with sporozoites
HOWEVER symptoms of malaria (fever, chills, sweating and anaemia) do not occur until red blood cells are infected with p.vivax merozoites

62
Q

what other polymorphisms is the /\32 CCR5 mutation thought to be in high linkage disequilibrium with?

A

SNPs within the CCR5 promotor region and the CCR2-V641 variant

Genetics of Complex Disease (6 decks)

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