Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research extends to drug-target genes, with significant attention to polymorphisms influencing both efficacy and adverse effects.
The β₂-adrenergic receptor (β₂AR), a G protein-coupled receptor, is central to cardiovascular and pulmonary regulation. Several polymorphisms in this receptor are linked to differential therapeutic outcomes. Among the most studied are those at amino acid positions 16 (Arg16Gly) and 164 (Thr164Ile). For instance, patients homozygous for Arg16 often show heightened responses to β₂-agonists like albuterol, despite similar plasma levels compared to Gly16 carriers. Conversely, the 164Ile variant has been correlated with reduced β₂AR function and adverse outcomes in heart failure patients. These findings underscore the complex influence of β₂AR genotypes on receptor function and responsiveness, especially under pathophysiological stress.
Apolipoprotein E (apoE) polymorphisms, particularly the apoE4 allele, are implicated in both lipid metabolism and neurodegenerative disease treatment responses. ApoE4 is associated with increased risk for cardiovascular diseases and reduced efficacy of lipid-lowering therapies. Moreover, in Alzheimer’s disease treatment, patients with the apoE4 genotype exhibit diminished cognitive improvement with drugs like acetylcholinesterase inhibitors compared to non-carriers. This has led to genotype-based stratification in therapeutic approaches, with the apoE4 allele also being considered in trials evaluating agents such as S12024.
Thymidylate synthase (TS), an enzyme critical in DNA synthesis, is targeted by chemotherapeutic agents such as 5-fluorouracil. A polymorphism in the TS gene involving variable tandem repeats (2R or 3R) in its 5'-untranslated region affects TS expression. The 3R/3R genotype is associated with increased TS mRNA and protein levels, often resulting in reduced efficacy of 5-fluorouracil due to enhanced DNA synthesis capacity. Clinical studies show poorer treatment outcomes in colorectal and leukemia patients with the 3R/3R genotype, reinforcing the importance of TS genotyping in guiding chemotherapy decisions.
These examples illustrate how genetic profiling of drug targets can inform clinical strategies, enhancing therapeutic precision and minimizing adverse effects.
Polymorphisms in genes that encode for drug targets can significantly contribute to inter-individual variability in drug response and toxicity.
The β₂-adrenergic receptors regulate key functions in the heart and lungs.
Two common polymorphisms in this receptor are linked to heart failure outcomes and differences in bronchodilator effectiveness.
Polymorphism in apolipoprotein E, involved in lipid transport and neurobiology, also influences drug response.
The apoE4 variant is associated with reduced efficacy of lipid-lowering drugs and poorer cognitive outcomes in the treatment of Alzheimer’s disease.
Thymidylate synthase, or TS, is an enzyme targeted by chemotherapy drugs such as 5-fluorouracil.
A polymorphism in the TS gene, particularly the 3R/3R genotype, is linked to poor cancer treatment outcomes.
Understanding these genetic variations helps tailor safer and more effective personalized therapies.
繁體中文
