9.3 Genomic Variation in Drug Response

Genetic variation affects whether a patient reacts badly to a medicine or how well a patient responds to a medicine by changing a drug’s pharmacokinetics and pharmacodynamics. Genetic variation in genes encoding proteins involved in a drug’s pharmacokinetics can alter how a drug is metabolized. If a drug is metabolized too quickly, it might be less effective. Alternatively, if the drug is metabolized too slowly, it may build up in the body and cause dangerous side effects.

Genes involved in a drug’s pharmacodynamics can encode proteins that the drug may need to bind to to affect the body. Genetic variation can change the structure of a protein, affecting how well the drug binds to the protein. This can change how well the drug works.

Below, find out more about how variation in different types of genes can affect pharmacokinetics and pharmacodynamics:

Drug transporters

Transporters move molecules in and out of cells. Variation in genes encoding drug transporters can affect their function, changing how well drugs can enter or exit cells and increasing or decreasing drug concentrations in different body parts. If the concentration of the drug at the site of action is too low, the drug may not work as well. If the drug concentration becomes too high, it could cause toxic side effects.

Drug metabolizing enzymes

Variations in drug-metabolizing enzymes can affect how quickly a drug is broken down in the body. This can have different effects depending on the specific drug. If an active drug is metabolized too quickly, it will be inactivated too quickly and may not work well. If it is metabolized too slowly, toxic concentrations of the drug might build up. Alternatively, some drugs have to be metabolized to become active. For medications like these, being metabolized too quickly increases the concentrations of active molecules in the body and increases the risk of toxic side effects while being metabolized too slowly can reduce how effective the drug is.

Human leukocyte antigen (HLA) genes

HLA proteins form part of your immune system. Some HLA alleles are associated with an increased risk for an allergic response to certain medications, which can result in severe skin reactions such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).

Drug targets

Variations in genes coding for proteins which are drug targets can affect how well a drug works by altering the amount of the target protein in the body or by preventing the drug from being able to bind to the protein. For example, the anti-coagulant drug warfarin prevents the vitamin K recycling needed for blood clotting. Warfarin does this by blocking the protein that controls the recycling (VKORC1). Genetic variation that increases or decreases the amount of VKORC1 can affect the dose of warfarin needed to prevent blood clotting.

Most work in pharmacogenomics focuses on variation in DNA that is passed down through your family (germline variation). However, somatic variation is also important within pharmacogenomics. Somatic variations are genetic changes that arise spontaneously within cells but are only passed on to other cells and are not passed on to children. Somatic variation is involved in the development of cancer, and some anticancer drugs target specific somatic variations to try to treat the cancer.