Pharmacogenetic Variants Can Influence Optical Medication Use

Diana Alves; Filipa Ferreira; Cristina Pereira; Altina Lopes; Célia Nogueira; Laura Vilarinho

doi:10.2174/0118715303271934231211085226

Pharmacogenetic Variants Can Influence Optical Medication Use

Endocr Metab Immune Disord Drug Targets. 2023 Dec 18. doi: 10.2174/0118715303271934231211085226. Online ahead of print.

Authors

Diana Alves¹, Filipa Ferreira², Cristina Pereira², Altina Lopes², Célia Nogueira³, Laura Vilarinho^{2

3}

Affiliations

¹ Medical Science Department, University of Aveiro, 3810- 193 Aveiro, Portugal.
² Newborn Screening, Metabolic and Genetics Unit, Department of Human Genetics, National Institute of Health Dr Ricardo Jorge, 4000-055 Porto, Portugal.
³ Research and Development Unit, Department of Human Genetics, National Institute of Health Dr Ricardo Jorge, Porto, Portugal.

PMID: 38111112
DOI: 10.2174/0118715303271934231211085226

Abstract

Introduction: Single Nucleotide Polymorphisms (SNPs) are used as drug susceptibility biomarkers in metabolic diseases. Alterations in the gene encoding triggers the enzyme flavin monooxygenase 3 (FMO3), involved in the Sulindac metabolization, which also is responsible for the inherited metabolic disorder. Trimethylaminuria (TMAu, OMIM: 602079). DPYD gene variants are associated with the enzyme dihydropyrimidine dehydrogenase deficiency (DPD; OMIM: 274270). This autosomal recessive metabolic disorder, ultimately leads to the inability to metabolize fluoropyrimidines, which causes severe toxicity in individuals treated with these drugs.

Methods: Variants in genes responsible for the expression of enzymes that encode transporters or receptors involved in the metabolization pathways of certain drugs may condition the individuals response to certain drugs, compromising the therapeutic response and clinical prognosis. Thus the sequencing and identification of variants become relevant, not only gain knowledge on effects of these variants' on disease causality but also in terms of its side effects resulting from the coding enzymes responsible for drug metabolization.

Results: It was found that patients with the c.472G>A (p.Glu158Lys) and c.923A>G (p.Glu308Gly) polymorphisms, in homozygosity, in FMO3 gene did not develop polyps, thus have a protective effect in the treatment of Familial Adenomatous Polyposis (PAF). However, in the case of the DPYD gene, c.1905+1G>A (IVS14+1G>A), c.1679T>G (p.Ile560Ser), c.2846A>T (p.Asp949Val) e c.1236G>A/HapB3 variants can be lethal in cancer patients indicated for fluoropyrimidine-based chemotherapy.

Conclusion: Knowledge on the drug mechanisms will affect the therapeutic response of patients treated with a given drug. Thus, pharmacogenetics is an essential tool in personalized medicine, since molecular studies allows the clinician to predict the probability of efficacy and toxicity of certain drugs, resulting higher efficiency in individualizing treatment and also improving the safety of the patient. From a personalized medicine perspective, the study of the characteristics of the drug and its metabolization site, the genes involved in the encoding of enzymes responsible for its metabolization will be of great interest.

Keywords: Dihydropyrimidine dehydrogenase deficiency; Metabolic diseases; Personalized Medicine; Pharmacogenetics; Single Nucleotide Polymorphis; Trimethylaminuria.