Pharmacogenetics: alcohol

Question 1

Define “heritability”

Answer 1

Heritability: the proportion of variability related to a particular trait or characteristics, that is due to genetic differences

Question 2

Explain alcohol metabolism

Answer 2

Alcohol metabolism starts in the stomach but is primarily in the liver. Ethanol is broken down by alcohol dehydrogenase to acetaldehyde (toxic). Acetaldehyde is then catalysed by aldehyde dehydrogenase to acetate (benign). A build up of acetaldehyde can be bad.

Question 3

What effects do variations of alcohol dehydrogenase (ADH) have?

Answer 3

ADH1B2 AND ADH1B3 variants have high enzyme activity and rapidly metabolize alcohol to acetaldehyde; accumulated acetaldehyde produces “flushing” found in higher frequency in East Asians and Jewish populations; protective variant

ALDH2 deficiency common in parts of Asia. Lower oxidation of acetaldehyde. Causes facial flushing, nausea, headache, tachycardia.
Disulfiram acts in a similar way.

Question 4

What is GWAS?

Answer 4

Genome-wide association studies. Different to looking at candidate genes no a priori reason to compare areas etc., just looking at patients and controls to see if there is a difference.

Question 5

What is Disulfiram?

Answer 5

1st pharmaceutical medication for alcohol use disorders. Based on aversive therapy. Induces flushing, sweating, headaches, nausea, and vomiting. But can cause serious side effects (inc. psychosis) and does not reduce craving. Leads to high non-compliance rate. Safer alternatives are naltrexone and acamprosate.

Question 6

What is Acamprosate?

Answer 6

Used to treat alcohol dependence. Antagonist for NMDA receptors and agonist for GABA receptors. Helps ameliorate withdrawal symptoms and affects processes related to reward. Works best with psychological therapies.

Question 7

What is Naltrexone?

Answer 7

Opioid antagonist, well tolerated with modest efficacy. Reduces heavy drinking and total amount of alcohol. People with G allele in OPRM1 show longer time to relapse (or no relapse) to heavy drinking when treated with Naltrexone. Effect is shown in caucasian but not black americans.

Question 8

Explain the COMBINE study

Answer 8

Largest trial assessing efficacy of medications with/without behavioural therapy. Almost 1400 people with alcohol dependence given acamprosate or naltrexone over 4 months, half the group also given CBT or motivation enhancement therapy.
Nalterxone + behavioural therapy had the best outcome