Pharmacogenomics最新文献

Background: Macrolides are widely used antibiotics, but adverse drug reactions (ADRs), particularly in genetically predisposed individuals, can compromise their safety. This study examines the impact of pharmacogenetic markers on macrolide safety in participants with bacterial complications of influenza.

Objective: To evaluate how polymorphisms in genes encoding transporter proteins (ABCB1) and enzymes (CYP3A4, CYP3A5) influence ADR risk during macrolide therapy.

Methods: A prospective study included 100 participants with lower respiratory tract bacterial complications of influenza treated with azithromycin or erythromycin for five days. Genotyping targeted ABCB1 (3435C>T), CYP3A4 (C>T intron 6), and CYP3A5 (6986A>G) polymorphisms. ADRs were monitored daily and correlated with genetic markers.

Results: The ABCB1 (3435C>T) polymorphism was associated with higher rates of abdominal pain and diarrhea in CT and TT genotypes (OR = 2.12, p = 0.043). The CYP3A4 (C>T intron 6) polymorphism increased ADR risk in erythromycin-treated participants (OR = 24.0, p = 0.0339). No significant effects were observed for CYP3A5 (6986A>G).

Conclusion: Genetic polymorphisms in ABCB1 and CYP3A4 genes predict macrolide-related ADRs. Pharmacogenetic screening could improve macrolide safety, particularly for genetically susceptible individuals.

Aims: To ascertain and describe pharmacogenomic concepts included in the intended curriculum of accredited Australian medical schools.

Methods: Content analysis of curriculum learning objectives of Australian medical schools was conducted, focusing on keywords and phrases pertaining to pharmacogenomic education. Learning objectives related to pharmacogenomics were categorized using (1) undergraduate medical genomic competencies per the Association of Professors in Human and Medical Genetics (2) Bloom's Taxonomy for cognitive and knowledge dimensions and (3) knowledge translation (enabling science, translation science and clinical implementation).

Results: The curricula of 19 accredited medical schools in Australia were analyzed. Two-thirds (68%) contained genomic/pharmacogenomic education. Eight schools had content relating to undergraduate medical genomic competencies. Of those which had pharmacogenomic-related learning objectives, the majority (65%) were categorized in Bloom's Taxonomy's lower levels (Remember and Understand) and 15% were deemed to be at the level of 'Clinical Implementation.'

Conclusion: The majority of Australian medical schools have incorporated pharmacogenomics in their current curriculum; however, learning objectives addressing application and clinical implementation are required. Doctors have a unique role to play in implementing pharmacogenomics into clinical practice. Comprehensiveness of course curricula across all learning domains would support uptake of pharmacogenomics into routine practice.

Aims: Clopidogrel exhibits substantial variability in therapeutic response, largely contributed by genetic factors. The pharmacogenomic variants data on clopidogrel metabolism in South Asians have been sparsely studied. This study explores the impact of CYP2C19 and CES1 gene variants on clopidogrel metabolism in Sri Lankans, revealing significant pharmacogenomic insights with broader implications for South Asians.

Materials & methods: Genotype data were filtered out from an anonymized database of 690 Sri Lankans, and minor allele frequencies (MAFs) were calculated. Five variants of CYP2C19 and one variant of CES1 gene were studied.

Results: Among the five CYP2C19 variants studied, rs12769205 (A>G) and rs4244285 (G>A) had the highest MAF of 42.1% and 42.0%, respectively. The CES1 variant rs71647871 (C>T) showed a MAF of 0.2%. Sri Lankans exhibited significantly higher MAFs for key variants compared to populations such as Europeans, African Americans, and East Asians (p < 0.05).

Conclusion: Given that South Asians share genetic similarities, these findings suggest that a substantial proportion of the region's population may also be poor responders to clopidogrel, increasing the risk of adverse outcomes. This highlights the importance of genotype-guided antiplatelet therapy, which could improve clinical outcomes across South Asia amidst rising cardiovascular disease rates.

Aim: To explore the effect of CYP2D6*10 (100C > T) and ADRB1 1165 G > C polymorphisms on heart rate of post-PCI (percutaneous coronary intervention) patients treated with metoprolol succinate sustained-release tablets. Methods: A total of 756 inpatients with metoprolol succinate sustained-release tablets were selected and the genotypes of CYP2D6*10 and ADRB1 1165G > C were detected in 319 patients using gene chip detection. The target heart rate was defined as a resting heart rate < 70 beats/min. Clinical data were collected. Results: A total of 319 inpatients were enrolled in the study. The mutant allele frequencies of CYP2D6 and ADRB1 were 57.21 and 69.44%, respectively. Whatever the dose of metoprolol, the heart rates were lower in patients with homozygous mutation of CYP2D6 than those with heterozygous mutation and wild-type (p < 0.05). Nevertheless, this effect was not seen between different genotypes of ADRB1. Logistic regression analysis showed that the dose of metoprolol and the genotypes of CYP2D6 were predictors of heart rate <70 beats/min in these patients. Further multivariate analysis indicated that patients with homozygous mutation had better control of heart rates compared with those with wild-type and heterozygous mutation of CYP2D6*10 genotypes (all: p < 0.001). Conclusion:CYP2D6*10 polymorphisms were associated with the heart rate of post-PCI patients treated with metoprolol succinate sustained-release tablets.

This study shows that the distribution of CYP3A5 alleles (*1, *3, *6 and *7) and genotype-predicted CYP3A5 phenotypes vary significantly across Latin American cohorts (Brazilians and the One Thousand Genomes Admixed American superpopulation), as well as among subcohorts comprising individuals with the highest proportions of Native, European or sub-Saharan African ancestry. Differences in biogeographical ancestry across the study groups are the likely explanation for these results. The differential distribution of CYP3A5 phenotypes has major pharmacogenomic implications, affecting the proportion of individuals carrying high risk CYP3A5 phenotypes for the immunosuppressant tacrolimus and the number of patients that would need to be genotyped to prevent acute rejection in kidney transplant recipients under tacrolimus treatment.

Objective: This work was designed to describe the knowledge and perceptions of pharmacogenomics (PGx) among pharmacists in the Canadian province of Manitoba. Methods: A 40-item, web-based survey was distributed to pharmacists in Manitoba. Results: Of 74 participants, one third had some education or training in PGx, and 12.2% had used PGx test results in their practice. Participants' self-rated knowledge of PGx testing and common PGx resources (e.g., Pharmacogenomics Knowledge Base, Clinical Pharmacogenetics Implementation Consortium) was low. Most pharmacists surveyed believe that PGx can improve medication efficacy (82.4%) or prevent adverse drug reactions (81.1%). Most (91%) desired more education on PGx. Conclusion: Manitoba pharmacists reported positive perceptions toward PGx. However, they are currently underprepared to implement PGx into practice.

Whole-exome sequencing (WES) is widely used in clinical settings; however, the exploration of its use in pharmacogenomic analysis remains limited. Our study compared the variant callings for 28 core absorption, distribution, metabolism and elimination genes by WES and array-based technology using clinical trials samples. The results revealed that WES had a positive predictive value of 0.71-0.92 and a sensitivity of single-nucleotide variants between 0.68 and 0.95, compared with array-based technology, for the variants in the commonly targeted regions of the WES and PhamacoScan™ assay. Besides the common variants detected by both assays, WES identified 200-300 exclusive variants per sample, totalling 55 annotated exclusive variants, including important modulators of metabolism such as rs2032582 (ABCB1) and rs72547527 (SULT1A1). This study highlights the potential clinical advantages of using WES to identify a wider range of genetic variations and enabling precision medicine.

Aim: The study aim was to determine caregiver interest and planned utilization of pharmacogenomic (PGx) results for their child with Prader-Willi syndrome. Methods: Caregivers consented to PGx testing for their child and completed a survey before receiving results. Results: Of all caregivers (n = 48), 93.8% were highly interested in their child's upcoming PGx results. Most (97.9%) planned to share results with their child's medical providers. However, only 47.9% of caregivers were confident providers would utilize the PGx results. Conclusion: Caregivers are interested in utilizing PGx but are uncertain providers will use these results in their child's care. More information about provider comfort with PGx utilization is needed to understand how PGx education would benefit providers and ultimately patients with PGx results.