Pharmacogenomics Practice Questions

Q: Which enzyme deficiency is associated with severe reactions to sulfonamides in HIV patients?

Glucose-6-phosphate dehydrogenase. ***Glucose-6-phosphate dehydrogenase*** - **G6PD deficiency** is the key enzyme deficiency associated with severe hemolytic reactions to sulfonamides - G6PD is essential for protecting RBCs against **oxidative stress** by maintaining glutathione in its reduced form - Sulfonamides (especially cotrimoxazole used for PCP prophylaxis in HIV) cause **oxidative damage** leading to **acute hemolytic anemia** in G6PD-deficient patients - In **HIV patients**, this is particularly important as sulfonamides are commonly prescribed *N-acetyltransferase* - NAT enzyme is involved in Phase II metabolism of sulfonamides through acetylation - Deficiency leads to **slow acetylator phenotype** with higher drug levels - Associated with different toxicities like hypersensitivity reactions and lupus-like syndrome - Does not cause the acute hemolytic anemia characteristic of G6PD deficiency *Cytochrome P450 2D6* - CYP2D6 metabolizes codeine, tramadol, antidepressants, and antipsychotics - Plays **minimal role** in sulfonamide metabolism - Deficiency affects metabolism of its specific substrates, not sulfonamides *Glutathione S-transferase* - GST enzymes conjugate glutathione to xenobiotics for detoxification - While involved in oxidative stress protection, GST deficiency is not the primary cause of severe sulfonamide reactions - G6PD deficiency is the specific enzymatic defect causing acute hemolytic crisis with sulfonamides

Q: Best predictor of varenicline response in smoking cessation is:

CHRNA5 gene variant. ***CHRNA5 gene variant*** - Genetic variations in the **CHRNA5 gene** (part of the CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25) encode subunits of nicotinic acetylcholine receptors and influence nicotine dependence and smoking behavior. - In the context of **pharmacogenomics**, CHRNA5 variants represent the **biological/genetic predictor** of treatment response, distinguishing individual variability in varenicline efficacy. - Among the options provided, this is the only **genetic factor** that can predict differential drug response at a molecular level. *Nicotine dependence score* - While a higher **nicotine dependence score** (measured by tools like Fagerström Test) indicates greater addiction severity and may correlate with treatment outcomes, it is a **clinical assessment**, not a biological predictor. - It reflects the phenotype (observable addiction) rather than the underlying genetic mechanism affecting drug response. *Pack-years* - **Pack-years** quantify cumulative tobacco exposure (packs per day × years smoked), indicating health risk and damage burden. - This is a **historical exposure metric**, not a predictor of varenicline's pharmacological efficacy or individual response variability. *Previous quit attempts* - The number of **previous quit attempts** reflects **behavioral patterns** and motivation but does not predict how an individual's nicotinic receptors will respond to varenicline. - This is a psychosocial factor rather than a pharmacogenomic predictor of drug response.

Q: In patients undergoing INH therapy, which group is least likely to develop neuropathy?

Fast acetylators. ***Fast acetylators*** - **Fast acetylators** metabolize INH more quickly, leading to lower systemic drug levels and thus a reduced risk of adverse effects like neuropathy. - Neuropathy associated with INH is primarily due to **pyridoxine (vitamin B6) depletion**, which is less pronounced if the drug is rapidly cleared. *Having malnutrition* - **Malnutrition** often involves deficiencies in essential vitamins, including vitamin B6, which is crucial for preventing INH-induced neuropathy. - Patients with poor nutritional status are at a **higher risk** of developing neuropathy during INH therapy due to pre-existing vitamin B6 depletion. *Alcoholics* - **Alcoholism** is strongly associated with deficiencies in various B vitamins, particularly **pyridoxine (vitamin B6)**, due to poor diet and impaired absorption. - This pre-existing deficiency makes alcoholics **highly susceptible** to INH-induced neuropathy. *Vitamin B complex deficiency* - A **deficiency in vitamin B complex**, especially pyridoxine (B6), is a known risk factor for INH-induced neuropathy. - Isoniazid interferes with **pyridoxine metabolism**, and those with pre-existing deficiency are more vulnerable to this adverse effect.

Q: Which drug is contraindicated in G6PD deficiency?

Primaquine. ***Primaquine*** - **Primaquine** is an antimalarial drug that generates **severe oxidative stress** in red blood cells. - It is **definitively contraindicated** in **G6PD deficiency** as it consistently causes **acute hemolytic anemia**. - Among antimalarials, primaquine poses the **highest risk** and should **never be used** in G6PD-deficient patients. - It is used for radical cure of P. vivax and P. ovale malaria, but alternative regimens must be used in G6PD deficiency. *Chloroquine* - **Chloroquine** can cause hemolysis in **G6PD deficiency**, though the risk is **lower than primaquine**. - It is **not considered fully safe** and should be used with **caution** in G6PD-deficient patients. - At standard doses, the risk is moderate, but hemolysis can occur, especially in certain G6PD variants. - However, it is not absolutely contraindicated and may be used when benefits outweigh risks with close monitoring. *Quinine* - **Quinine** can also cause **hemolysis** in patients with **G6PD deficiency**. - The risk varies with G6PD variant severity and dosage. - In **severe G6PD deficiency**, quinine should be avoided when alternatives are available. - While less consistently problematic than primaquine, it still requires caution and monitoring. *All of the options* - This option is incorrect in the context of this question because **primaquine** is the **most consistently and severely contraindicated** drug. - While chloroquine and quinine can cause hemolysis, they have **variable risk profiles** and may be used cautiously in some situations, unlike primaquine which is **absolutely contraindicated**. - The question asks for "which drug" (singular), indicating primaquine as the primary answer due to its consistent and severe risk.

Q: HLA-B*5701 is an allele associated with hypersensitivity to abacavir. Which of the following is the parent allele of HLA-B*5701?

HLA-B*57. ***HLA-B\*57*** - **HLA-B*57** is the parent allele for **HLA-B*5701**, indicating it is the broader serotype under which specific alleles like *5701 are classified [1]. - The notation **HLA-B\*57** signifies a specific **HLA class I** allele group [1]. *HLA-B\*5* - This option is **incomplete** as an HLA allele notation; it lacks the specific group designation often indicated by two or three digits following the asterisk. - While "B5" exists as a serotype, **"HLA-B*5"** itself is not a standard, complete allele designation reflecting a specific gene variant. *HLA-B\*51* - **HLA-B\*51** is a specific **HLA class I** allele, but it is not directly related to or the parent group of **HLA-B\*5701**. - It is known to be associated with Behcet's disease, a different clinical condition not related to abacavir hypersensitivity. *HLA-DQ2* - **HLA-DQ2** is an allele of **HLA class II**, while **HLA-B\*5701** is an **HLA class I** allele. - Though both are HLA alleles, they belong to different classes and are associated with different disease contexts, with **HLA-DQ2 typically linked to celiac disease**.

Q: Hemolysis in G6PD deficiency is precipitated by all of the following except:

Penicillin. ***Penicillin*** - **Penicillin** is generally considered safe in individuals with G6PD deficiency and typically does not precipitate **hemolysis**. - Its mechanism of action does not involve the generation of **oxidative stress** that would overwhelm the deficient G6PD pathway. *Dapsone* - **Dapsone** is known to cause **oxidative stress** in red blood cells, making it a strong precipitating agent for hemolysis in G6PD deficient individuals. - It is an **antimicrobial** agent often used in conditions like leprosy. *Cotrimoxazole* - **Cotrimoxazole**, a combination of **trimethoprim** and **sulfamethoxazole**, is a potent oxidizing agent. - It can induce significant **hemolysis** in patients with G6PD deficiency due to its oxidative properties. *Quinine* - **Quinine**, an **antimalarial** drug, is another agent that can cause oxidative stress in red blood cells. - It is recognized as a drug that can precipitate **hemolytic crises** in G6PD deficient individuals.

Q: The risk of carbamazepine-induced Stevens-Johnson syndrome is increased in the presence of which of the following genes?

HLA-B* 1502. ***HLA-B\* 1502*** - The **HLA-B\*1502** allele is strongly associated with an increased risk of **carbamazepine-induced Stevens-Johnson syndrome (SJS)** and **toxic epidermal necrolysis (TEN)**, particularly in individuals of Asian ancestry. - Screening for this allele is often recommended before initiating **carbamazepine** in at-risk populations. *HLA-B\* 5801* - The **HLA-B\*5801** allele is associated with an increased risk of **allopurinol-induced severe cutaneous adverse reactions (SCARs)**, including SJS and TEN. - It is not directly linked to carbamazepine-induced SJS. *HLA-B\* 5701* - The **HLA-B\*5701** allele is strongly associated with a higher risk of **abacavir hypersensitivity reaction** [1]. - It is recommended to screen for this allele before starting abacavir therapy. *HLA-B 27* - **HLA-B27** is primarily associated with **seronegative spondyloarthropathies**, such as **ankylosing spondylitis** and **reactive arthritis**. - It does not have a known association with carbamazepine-induced SJS.

Q: Which of the following is not considered a pharmacogenetic condition?

Adenosine deaminase deficiency. ***Adenosine deaminase deficiency*** - **Adenosine deaminase deficiency** (ADA deficiency) is an **autosomal recessive** metabolic disorder causing severe immunodeficiency, primarily affecting gene function rather than drug response. - While it can be treated with enzyme replacement therapies or gene therapy, it is not primarily characterized by an altered response to standard therapeutic drugs. *Coumarin insensitivity* - **Coumarin insensitivity** refers to an individual's reduced response to **warfarin (a coumarin derivative)**, requiring higher doses to achieve effective anticoagulation. - This is a well-documented **pharmacogenetic condition**, often linked to variations in genes like *CYP2C9* and *VKORC1*. *G6PD deficiency* - **Glucose-6-phosphate dehydrogenase (G6PD) deficiency** is an X-linked genetic disorder that can lead to **hemolytic anemia** upon exposure to certain drugs (e.g., antimalarials, sulfonamides, aspirin) and fava beans [1]. - It is a classic example of a **pharmacogenetic condition** where genetic variations dictate drug-induced adverse reactions [1]. *Malignant hyperthermia* - **Malignant hyperthermia** is a life-threatening, inherited disorder triggered by certain **inhalation anesthetics** (e.g., halothane, isoflurane) and the **depolarizing muscle relaxant succinylcholine**. - This condition is caused by mutations in genes involved in calcium regulation in muscle cells (e.g., *RYR1*) and is a critical **pharmacogenetic response**.

Question 1

Which enzyme deficiency is associated with severe reactions to sulfonamides in HIV patients?

Accepted Answer

Glucose-6-phosphate dehydrogenase

Answer

N-acetyltransferase

Answer

Cytochrome P450 2D6

Answer

Glutathione S-transferase

Question 2

Best predictor of varenicline response in smoking cessation is:

Accepted Answer

CHRNA5 gene variant

Answer

Nicotine dependence score

Answer

Pack-years

Answer

Previous quit attempts

Question 3

In patients undergoing INH therapy, which group is least likely to develop neuropathy?

Accepted Answer

Fast acetylators

Answer

Having malnutrition

Answer

Alcoholics

Answer

Vitamin B complex deficiency

Question 4

Which drug is contraindicated in G6PD deficiency?

Accepted Answer

Primaquine

Answer

Chloroquine

Answer

Quinine

Answer

All of the options

Question 5

What does the Dibucaine number indicate in clinical practice?

Accepted Answer

Indicates the percentage inhibition of pseudocholinesterase activity by dibucaine

Answer

Gives percentage of lignocaine levels in blood

Answer

Gives percentage of metabolised lignocaine levels

Answer

Gives percentage of succinylcholine in blood

Question 6

HLA-B*5701 is an allele associated with hypersensitivity to abacavir. Which of the following is the parent allele of HLA-B*5701?

Accepted Answer

HLA-B*57

Answer

HLA-B*5

Answer

HLA-B*51

Answer

HLA-DQ2

Question 7

Hemolysis in G6PD deficiency is precipitated by all of the following except:

Accepted Answer

Penicillin

Answer

Cotrimoxazole

Answer

Quinine

Answer

Dapsone

Question 8

The risk of carbamazepine-induced Stevens-Johnson syndrome is increased in the presence of which of the following genes?

Accepted Answer

HLA-B* 1502

Answer

HLA-B* 5801

Answer

HLA-B* 5701

Answer

HLA-B*27

Question 9

Which of the following is not considered a pharmacogenetic condition?

Accepted Answer

Adenosine deaminase deficiency

Answer

Coumarin insensitivity

Answer

G6PD deficiency

Answer

Malignant hyperthermia

Pharmacogenomics — MCQs

Pharmacogenomics — MCQs

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