Pharmacogenomic Biomarkers of Susceptibility to Adverse Drug Reactions: Just Around the Corner or Pie in the Sky?

Mark I. Avigan

Personalized Medicine. 2009;6(1):67-78.

Inheritance Characteristics of Genetically Determined ADR Susceptibility

In developing a vision for future discovery of new pharmacogenomic biomarkers that will improve drug risk management, it should be noted that there are two general types of inheritance for genetic susceptibility to ADRs. As discussed below, the way in which the phenotypic trait can be genetically transmitted will have a strong impact on the predictive value for ADR susceptibility of the individual biomarker.

The first category of hereditary transmission of disease or ADR susceptibility is the classical Mendelian form. In this case, a single allelic locus carries the trait that is transmitted either in a dominant or recessive fashion. For a well-defined ADR phenotype, correlation with a specific gene locus is relatively straight forward. It is no surprise that one of the earliest discovered pharmacogenomic markers for ADR susceptibility was the X-linked locus linked to G6PD deficiency.^[104] Specific genetic mutations in the G6PD gene in males have strong predictive value for transmission of susceptibility to hemolysis induced by certain drugs.^[18,19,104] The other category of hereditary transmission of disease or ADR susceptibility is more complex and reflects potential combinatorial effects of genomic variations at multiple genetic loci, as well as nongenetic risk factors.^[20,21] It appears that a number of genetically transmitted disease or drug-related ADR susceptibility markers fall into this category.^[21]

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Cite this: Pharmacogenomic Biomarkers of Susceptibility to Adverse Drug Reactions: Just Around the Corner or Pie in the Sky? - Medscape - Jan 01, 2009.

Abstract and Personalized Medicine: A Framework for the Development of Pharmacogenomic Predictors of Drug Treatment Responses
Genomic Biomarkers of Risk for Idiosyncratic Adverse Drug Reactions
Steps in the Development & Utilization of Genomic Biomarkers for ADRs
Biomarkers of ADR Susceptibility in US FDA-approved Product Labels
Inheritance Characteristics of Genetically Determined ADR Susceptibility
Challenges for Future Discovery of Genomic ADR Biomarkers
Conclusion & Future Perspective
References
Sidebar: Executive Summary

Table 1. Altered Enzyme Activity and Genomic Biomarkers Associated with Adverse Drug Reaction Susceptibility: Examples Incorporated into US FDA-approved Product Labels
Drug(s)	Biomarker DNA locus or enzyme	Test(s)	Prevalence	Adverse event	Product label
Thioridazine	CYP2D6 PMs	PCR/DNA hybridization; enzyme activity	Multiple alleles; Caucasians ~7%; other ethnic groups 1-3%	Ventricular arrhythmia	Use contraindicated
Atomoxetine	CYP2D6 PMs	PCR/DNA hybridization; enzyme activity	Multiple alleles; Caucasians ~7%; other ethnic groups 1-3%	Ventricular arrhythmia	Information
Voriconazole	CYP2C19 PMs	PCR/DNA hybridization	Multiple alleles; Caucasians & Blacks ~3-4%; Asians 14-21%	Ventricular arrhythmia	Information
Irinotecan	UGT1A1 low activity	UGT1A128*	~10%	Diarrhea & neutropenia	Homozygotes: low initial dose
Azathioprine	TPMT low activity	TPMT2, 3, 3C*	Demographic variability; 0-4%	Myelosuppression	Homozygotes: use other treatment; Heterozygotes: use with caution
5-fluorouracil	DPD deficiency	Enzyme activity	0-1%	Neutropenia, diarrhea, stomatitis, neurotoxicity	Information
Primaquine	G6PD deficiency	Fluorescent spot test; enzyme activity	High: certain Black and Mediterranean populations	Hemolysis	Observe patient closely
Rasburicase	G6PD deficiency	Fluorescent spot test; enzyme activity	High: certain Black and Mediterranean populations	Hemolysis	Contraindicated
Carbamazepine	HLA-B1502*	High-resolution HLA typing/PCR	Demographic variability; Han Chinese ~8%	SJS/TEN	Screen prior to treatment; avoid use if positive unless benefit > risk
Abacavir	HLA-B5701*	High-resolution HLA typing/PCR	Demographic variability; Caucasians ~5%	Moderate/severe hypersensitivity reactions	Screen in high prevalence population prior to treatment; avoid use if positive unless benefit > risk
Isoniazid	NAT2 deficiency	Enzyme activity	Demographic variability	Hepatotoxicity	Information
Warfarin	VKORC1	-1639 G>A	AA genotype: Chinese ~80% Caucasians ~14%	Bleeding	Consider low initial dose
Warfarin	CYP2C9 PMs	Cyp2C9 2, 3	Caucasians 8-12% Blacks 1-3% Asians <1%	Bleeding	Consider low initial dose

CYP = Cytochrome P450; DPD = Dihydropyrimide dehydrogenase; G6PD = Glucose-6-phosphate dehydrogenase; HLA = Human leukocyte antigen; NAT2 = N-acetyltransferase-2; PM = Poor metabolizer; SJS = Stevens-Johnson syndrome; TEN = Toxic epidermal necrolysis; TMPT = Thiopurine S-methyltransferase; UGTA1 = Uridine diphosphate-glucuronosyl transferase A1; VKORC1 = Vitamin K 2,3-epoxide reductase complex subunit 1.