Textbook of Personalized Medicine - Second Edition [2015]

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Other genetic biomarkers that can be used to predict ADRs are (Ingelman-
Sundberg 2008 ):

• UGT1A1*28 to predict ADRs to irinotecan in 30–40 % of cases.


• CYP2C9 and VKORC1 to predict ADRs to tricyclic antidepressants in 5–7 % of
  cases.


• HLA-B*5701 to predict ADRs to abacavir in 5–8 % of cases.


• HLA-B*1502 to predict ADRs to carbamazepine in 10 % of cases.


• HLA-DRB107 and DQA102 to predict ADRs to ximelagatran in 5–7 % of cases.

In some situations, genotyping information may enable the avoidance of use of a
drug in certain patients prone to serious adverse reactions such as azathioprine in
patients with TMPT defi ciency and malignant hyperthermia in patients undergoing
anesthesia. In other situations, it may help in the adjustment of dose of the drug such
as in warfarin therapy.

Malignant Hyperthermia

Malignant hyperthermia (MH) is a pharmacogenetic clinical syndrome that mani-
fests as a hypermetabolic crisis when a susceptible individual is exposed to an anes-
thetic triggering agent. Clinical signs include unexplained elevation of end-tidal

Table 4.7 Examples of genetically determined adverse reactions to drugs

Drug Adverse reaction Underlying gene/mutation
6-mercaptopurine Myelotoxicity, pancytopenia Thiopurine methyltransferase
Azathioprine Carcinogenicity (TMPT)
β2-agonists Increased airway reactivity β2-receptor
Debrisoquin Hypersensitivity CYP2D6
Fluorouracil Increased neurotoxicity Dihydropyrimidine dehydrogenase
Fructose Intolerance Aldolase B
Inhalation anesthetics Malignant hyperthermia Ryanodine receptor
Irinotecan Diarrhea Uridine diphosphate glucuronosyl
Myelosuppression transferase 1A1
Primaquine Hypersensitivity: favism Glucose-6-phosphate dehydrogenase
Proton pump inhibitors Reduced effi cacy in curing
ulcers

CYP2C19

Sulfonal Porphyria Porphobilinogen deaminase
Suxamethonium Hypersensitivity Pseudocholinesterase
Typical antipsychotic
drugs

Extrapyramidal effects,

confusion

Dopamine D3 receptor

Cardiotoxicity 5-HT 2C receptor
Warfarin
anticoagulation

Reduced clearance of the drug

leading to hemorrhage

CYP2C9

Interaction with NSAIDs
Interaction with Tramadol
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4 Pharmacogenetics