Pharmacogenomics

A woman with ocular hypertension suffered from severe bradycardia, hypotension and syncope attacks in temporal relation with ophthalmic timolol application. Topically applied timolol is nasally absorbed and has been shown to reach potentially relevant systemic concentrations. Timolol is mainly metabolized by CYP2D6, which exhibits interindividual metabolic capacity due to genetic variations. A reactive pharmacogenetic panel test identified the patient as a CYP2D6 homozygous *4 allele carrier, which has been associated with a poor metabolizer phenotype and lacking enzyme activity...

Introduction: As the most distressing complication of sickle cell disease (SCD), pain is marked by considerable heterogenicity. In this study we explored the potential association of alcohol dehydrogenase 7 gene ( ADH7 ) polymorphism rs971074 with sickle cell pain. Methods: We analyzed clinical phenotypes and the rs971074 single-nucleotide polymorphism in ADH7 by MassARRAY-iPlex analysis in a cohort of SCD patients. Results: The synonymous rs971074 was significantly associated with both acute and chronic pain in SCD...

Background: ALK rearrangements account for around 5% of non-small-cell lung cancers. Aim: This study surveys physicians on the potential efficacy of a mobile application in improving the management of ALK-rearranged non-small-cell lung cancer, through knowledge, treatment adherence and real-time adverse events reporting. Materials & methods: A total of 118 physicians from 11 countries in the Middle East participated. Results & conclusion: Results indicate 94% support for enhancing team communication via an application, and 93% believe real-time adverse events reporting improves the quality of care...

Background: HLA-B*58:01 is strongly associated with allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Vietnam. This study assessed the cost-effectiveness of this testing to prevent SJS/TEN. Methods: A model was developed to compare three strategies: no screening, use allopurinol; HLA-B*58:01 screening; and no screening, use probenecid. A willingness-to-pay of three-times gross domestic product per capita was used. Results: Compared with 'no screening, use allopurinol', 'screening' increased quality-adjusted life-years by 0...

Background: Polymorphisms in the CYP2C9 , VKORC1 , MDR1 and APOE genes may impact warfarin dose. Aim: To investigate the influence of sociodemographic and clinical factors and polymorphisms *1 , *2 and *3 for CYP2C9 , -1639G>A for VKORC1 , 3435C>T for MDR1 , and ϵ2, ϵ3 and ϵ4 for APOE genes on the mean weekly warfarin maintenance dose in adults. Methods: This cross-sectional study recruited a calculated sample of 315 patients in three anticoagulation clinics in Brazil. A model containing the variables significantly associated with warfarin dose was estimated...

Precision medicine has revolutionized clinical care for patients with cancer through the development of targeted therapy, identification of inherited cancer predisposition syndromes and the use of pharmacogenetics to optimize pharmacotherapy for anticancer drugs and supportive care medications. While germline (patient) and somatic (tumor) genomic testing have evolved separately, recent interest in paired germline/somatic testing has led to an increase in integrated genomic testing workflows. However, paired germline/somatic testing has generally lacked the incorporation of germline pharmacogenomics...

Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes and SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e., CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient = 10.03; 95% CI: 1...

Background: This study investigated the use of COMT G1947A and OPRM1 A118G polymorphisms as predictive markers for sufentanil epidural analgesia. Methods: The visual analogue scale (VAS) score, and sufentanil consumption of 136 pairs of parturients using sufentanil with lidocaine and ropivacaine for epidural analgesia were used for analysis. Results: OPRM1 AG/GG had lower VAS score difference between fifth and 0 min (1.55 vs 1.87; p = 0.012) and higher consumption (19.65 μg vs 17.11 μg; p = 0...

Metformin, a hypoglycemic drug for Type 2 diabetes mellitus, shows variability in pharmacokinetics and response due to membrane transporters. This study followed 34 Type 2 diabetes mellitus patients on metformin treatment. Genetic variants in 11 metformin transport-related genes were analyzed, revealing associations. Specifically, SLC47A1 rs2289669 A/A and SLC22A4 rs1050152 T/T genotypes correlated with glycated hemoglobin values at 6 months. SLC47A1 rs2289669 G/A genotype influenced glucose levels at 6 months, while SLC29A4 rs3889348 A/A, SLC47A1 rs2289669 A/A, SLC22A4 rs1050152 C/T and SLC47A2 rs12943590 A/A genotypes were linked to glucose levels at 12 months...

Ethnicity is known to have an impact on drug responses. This is particularly important for drugs that have a narrow therapeutic window, nonlinearity in pharmacokinetics and are metabolized by enzymes that demonstrate genetic polymorphisms. However, most clinical trials are conducted among Caucasians, which might limit the usefulness of the findings of such studies for other ethnicities. The representation of participants from Saudi Arabia in global clinical trials is low. Therefore, there is a paucity of evidence to assess the impact of ethnic variability in the Saudi population on drug response...

Sirolimus is an antiproliferative and immunosuppressive compound inhibiting the mTOR pathway, which is often activated in congenital low-flow vascular malformations. Studies have demonstrated the efficacy of sirolimus for this disease. Studies in kidney transplant patients suggest that genetic variants can influence these pharmacokinetic parameters. Therefore, a systematic literature search was performed to gain insight into pharmacogenetic studies with sirolimus. Most studies investigated  CYP3A4 and CYP3A5 , with inconsistent results...

Aim: Antimalarial primaquine (PQ) eliminates liver hypnozoites of Plasmodium vivax.   CYP2D6 gene variation contributes to PQ therapeutic failure. Additional gene variation may contribute to PQ efficacy. Information on pharmacogenomic variation in Madagascar, with vivax malaria and a unique population admixture, is scanty. Methods: The authors performed genome-wide genotyping of 55 Malagasy samples and analyzed data with a focus on a set of 28 pharmacogenes most relevant to PQ. Results: Mainly, the study identified 110 coding or splicing variants, including those that, based on previous studies in other populations, may be implicated in PQ response and copy number variation, specifically in chromosomal regions that contain pharmacogenes...

Background: The cytokine IL-4 plays vital role in the intercellular signalling network during immune responses to allergen exposure. Methods: This cross-sectional study involved 202 chronic obstructive pulmonary disease (COPD) patients and 203 healthy individuals. The genotyping of IL4RAQ576R gene polymorphism was determined using polymerase chain reaction restriction fragment length polymorphism analysis. Results: Significant association between mutant genotype (GG) and combined (AA+AG) genotype for the risk of COPD was found (odds ratio [OR]: 4...

The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) studies Latin American populations to benefit from the implementation of personalized medicine. Since 2006, it has studied ethnicity to apply pharmacogenetics knowledge in autochthonous populations of Latin America, considering ancestral medicine. The meeting 'Pharmacogenetics: ethnicity, Treatment and Health in Latin American Populations' was held in Mexico City, Mexico, and presented the relevance of RIBEF collaboration with Latin American researchers and the governments of Mexico, Spain and the Autonomous Community of Extremadura...

Background: Cytochrome P450 (CYP) genetic variation largely impacts drug response. However, many CYP star alleles (haplotypes) lack functional annotation, impeding our understanding of drug metabolism mechanisms. We aimed to investigate the impact of missense variant combinations on CYP protein structures. Methods: Normal mode analysis was conducted on 261 missense variants within 91 CYP haplotypes. CYP2D6*2 and CYP2D6*17 were prioritized for molecular dynamics simulation. Results: Normal mode analysis and molecular dynamics highlight the effects of known CYP missense variants on protein stability and conformational dynamics...

Aim: We investigated if single-nucleotide polymorphisms (SNPs) in ATP-binding cassette (ABC) drug transporters alter gene expression and tenofovir disposition in South African women taking Truvada® for HIV prevention. Materials & methods: In 393 women, real-time PCR was used to determine the associations between six SNPs in ABC transporter genes, mRNA expression and circulating-tenofovir. Results: Univariable and multivariable analyses showed that CT and TT relative to CC genotypes for the  ABCC4 (3463C/T) SNP had significantly higher tenofovir levels...

Aim: Examining the association between HLA-A/B alleles and different carbamazepine (CBZ)-induced cutaneous adverse reactions in the Chinese population. Methods: A systematic review and meta-analysis of case-control studies was conducted. A systematic search was conducted of PubMed, Embase, the Cochrane Library, National Knowledge Infrastructure, the Chinese Biomedical Literature database and Wanfang Digital Periodicals. Results: 23 studies with a total of 1174 patients were included. In the Han population, HLA-B*15:02 is significantly associated with the increased risk of CBZ-related Stevens-Johnson syndrome/toxic epidermal necrolysis, and this correlation was not related to geographic distribution...

Tweetable abstract Pretreatment UGT1A1 genotyping and a 70% irinotecan dose intensity in poor metabolizers is safe, feasible, cost-effective and essential for safe irinotecan treatment in cancer patients. It is time to update guidelines to swiftly enable the implementation of UGT1A1 genotype-guided irinotecan dosing in routine oncology care.

Background: Bladder cancer is a common urogenital malignancy characterized by frequent genetic alterations. Histone demethylase gene KDM6A is commonly mutated in bladder cancer. Aim: To review the characteristics of KDM6A and its mutation consequences, and to introduce a potential KDM6A-targeted treatment. Methods: We conducted a comprehensive literature search using two electronic databases, MEDLINE and Cochrane Library, to retrieve topic-related articles from July 2013 to July 2022 using keywords 'KDM6A', 'bladder cancer', 'UTX', 'treatment' and 'mutation'...

Aim: To understand how attitudes toward pharmacogenomic (PGx) testing among healthcare providers varies by specialty. Methods: Providers reported comfort ordering PGx testing and its perceived utility on web-based surveys before and after genetics education. Primary quantitative analyses compared primary care providers (PCPs) to specialty providers at both timepoints. Results: PCPs were more likely than specialty care providers to rate PGx testing as useful at both timepoints. Education increased comfort ordering PGx tests, with larger improvements among PCPs than specialty providers...