Pharmacogenetics and disease susceptibility

Question 1

What percentage of the population is affected by schizophrenia?

Answer 1

Up to 1%

Schizophrenia is a severe psychiatric disease.

Question 2

What model does the genetic risk for schizophrenia appear to follow?

Answer 2

Polygenic model

Question 3

Which neurotransmitter systems are disturbed in schizophrenia?

Answer 3

Dopaminergic and 5-HT (serotonin) systems

Question 4

What do family studies and case-control studies investigate in relation to schizophrenia?

Answer 4

Susceptibility to schizophrenia

Question 5

What was the sample size of the large GWAS on schizophrenia?

Answer 5

74,776 cases and 1,011,023 controls

Question 6

What are ZNF804A and KLF6 in relation to schizophrenia?

Answer 6

Transcription factors

Question 7

Which gene encodes a calcium pump associated with schizophrenia?

Answer 7

ATP2A2

Question 8

What does the ACE risk variant associate with?

Answer 8

Low angiotensin converting enzyme expression

Question 9

What is ACE and where is it located?

Answer 9

A dipeptidyl-carboxy oligopeptidase located on the cellular membrane of neurons

Question 10

What role does ACE play in neurosignalling?

Answer 10

Catalyses degradation of neuropeptides

Question 11

What are the functions of ACE in the CNS?

Answer 11

Implicated in other phenotypes

Question 12

What is the effect of diuretics related to the a-adducin gene?

Answer 12

Lowered BP associated with Trp460 allele

Question 13

What is the effect of ACE inhibitors on cognitive function?

Answer 13

Increase cognitive function

Question 14

What is CYP2D6 associated with in relation to schizophrenia?

Answer 14

Aetiology is unknown

Question 15

What is the impact of CYP2D6 polymorphisms on drug metabolism?

Answer 15

Affects metabolism of numerous xenobiotics

Question 16

What percentage of clinically used drugs does CYP2D6 metabolize?

Answer 16

1 in 4 clinically used drugs

Question 17

What is the prevalence of Alzheimer’s disease in individuals over 65?

Answer 17

5%

Question 18

What percentage of dementia cases does Alzheimer’s disease account for?

Answer 18

60-80%

Question 19

What are the two forms of Alzheimer’s disease?

Answer 19

Early onset and late onset

Question 20

Which gene locus is identified as a susceptibility locus for Alzheimer’s disease?

Answer 20

Apoliprotein E (APOE) gene locus

Question 21

What is the total number of cases and controls in the Alzheimer’s disease GWAS?

Answer 21

90,338 cases and 1,036,225 controls

Question 22

What is the role of the HAVCR2 gene in Alzheimer’s disease?

Answer 22

Accumulates in aged microglia and binds to precursor beta-amyloid protein

Question 23

What does the BIN1 variant associate with in Alzheimer’s disease?

Answer 23

Endosome-size deregulation

Question 24

What is the contribution of the APOE locus to Alzheimer’s disease susceptibility?

Answer 24

Approximately 50%

Question 25

What amino acid substitution distinguishes APOE2 from APOE3?

Answer 25

Cys to Arg at 158

Question 26

What is the risk factor associated with APOE4 carrier status?

Answer 26

Increased risk for Alzheimer's disease

Question 27

What is the role of nicotine in smoking addiction?

Answer 27

Believed to be responsible for addiction

Question 28

What happens during nicotine withdrawal?

Answer 28

Symptoms include nausea, insomnia, and depressed concentration

Question 29

What enzyme is known as nicotine C-oxidase?

Answer 29

CYP2A6

Question 30

What is the interindividual variation reported for CYP2A6 activity?

Answer 30

Around 300 fold

Question 31

What is the main effect of nicotine on the brain?

Answer 31

Triggers the release of dopamine

Question 32

What is the significance of the CHR gene cluster in smoking behaviour?

Answer 32

Associated with smoking behaviour and lung cancer

Question 33

What is the link between smoking and schizophrenia according to James et al, 2017?

Answer 33

Bidirectional relationship

Question 34

What antidepressant is licensed for smoking cessation?

Answer 34

Bupropion

Question 35

What is the role of CYP2D6 in the metabolism of TCAs?

Answer 35

Better substrates for CYP2D6

Question 36

What is recommended for therapeutic drug monitoring of TCAs?

Answer 36

By the European Consortium

Question 37

What is the role of CYP3A4 and CYP3A5 in organ transplantation?

Answer 37

Metabolize cyclosporine and tacrolimus

Question 38

Which enzyme polymorphisms affect the pharmacokinetics of NSAIDs?

Answer 38

CYP2C9

Question 39

What is the effect of omeprazole on CYP2C19?

Answer 39

Higher affinity than pantoprazole

Question 40

What is the impact of CYP2C19 genotypes on treatment success for GI disorders?

Answer 40

Strong determinant in success rate

Question 41

What is the effect of CYP2C19*17 allele on PPI treatment?

Answer 41

Investigated effect on ulcer treatment

Question 42

What is the impact of CYP2C9*3 on warfarin therapy?

Answer 42

Major bleeding complications

Question 43

What is the primary metabolism route of efavirenz?

Answer 43

Hepatic CYP2B6

Question 44

What polymorphism is associated with efavirenz metabolism?

Answer 44

516G>T (Q172H)

Question 45

What can happen if treatment with a compound is discontinued?

Answer 45

They can develop side effects ## Footnote Discontinuation of treatment may lead to withdrawal symptoms or exacerbation of the condition being treated.

Question 46

What is the effect of the CYP2B6*16 allele in African patients?

Answer 46

Results in a less efficient CYP2B6*1 enzyme ## Footnote This can lead to higher plasma levels of certain medications at standard doses.

Question 47

How does the combination of CYP2B6*16 and CYP2D6*6 alleles affect plasma levels?

Answer 47

Leads to much higher plasma levels at standard dosing compared with other CYP2B6 genotypes ## Footnote This may enhance the effectiveness of anti-HIV treatment.

Question 48

What is the role of Nelfinavir in HIV treatment?

Answer 48

Used to treat HIV and metabolized by CYP2C19 ## Footnote Plasma exposure is associated with defective CYP2C19*2 allele.

Question 49

Which enzyme metabolizes oral antidiabetics like sulphonyureas?

Answer 49

CYP2C9 ## Footnote This enzyme plays a significant role in drug metabolism for diabetes management.

Question 50

What effect does the CYP2C9*3/*3 genotype have on sulphonyureas?

Answer 50

Oral clearance has 20% of the wild-type genotype CYP2C9*1/*1 ## Footnote This can impact the effectiveness of the medication.

Question 51

What is the oral clearance for heterozygous carriers of CYP2C9?

Answer 51

Between 50-80% of the wild-type genotype ## Footnote This variability can lead to differences in drug response.

Question 52

How can adverse effects of sulphonyureas be reduced?

Answer 52

By CYP2C9 genotype-based dose adjustments ## Footnote Tailoring doses based on genetic makeup can improve safety and efficacy.

Question 53

What is the effect of CYP2C19 on Diazepam clearance?

Answer 53

PMs of CYP2C19 almost double the time to emerge from general anaesthesia ## Footnote This results in longer sedation periods for these patients.

Question 54

What is the effect of CYP2C19 genotype on Etizolam?

Answer 54

Affects PKs of single dose ## Footnote Pharmacokinetics can vary based on the individual's genetic makeup.

Question 55

What is Clobazam used for?

Answer 55

Treatment of epilepsy ## Footnote It is mainly converted to N-desmethylclobazam.

Question 56

What is the half-life of N-desmethylclobazam compared to Clobazam?

Answer 56

Longer half-life than parent drug ## Footnote This can lead to prolonged effects in the body.

Question 57

What enzyme catalyzes the further metabolism of N-methylclobazam?

Answer 57

CYP2C19 ## Footnote Impaired metabolism in PM subjects can increase drug levels.

Question 58

What is a potential risk for PM subjects taking Clobazam?

Answer 58

Increased risk of side effects such as drowsiness ## Footnote Genetic variations can lead to significant differences in drug responses.