Pharmacogenomics: current status and future perspectives

Pirmohamed, Munir

doi:10.1038/s41576-022-00572-8

Cited by 130 publications

(79 citation statements)

References 157 publications

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“…Such methods have been successfully leveraged to prioritize therapeutic targets, including OAS1 for COVID-19 9,17 and IL6R for both COVID-19 18,19 and CAD 20 , and ANGPTL3 for CAD 21 . As drug discovery is costly and prone to failure 22 , proteo-genomicsbased MR could play an important role since such studies could provide causal targets, which can be measured, thereby providing proximal read-out of drug target engagement, but also providing biomarkers for recruitment into clinical trials. Indeed, drugs with human genetics evidence are more likely to be successful in Phase II and III trials, and two-thirds of FDA-approved drugs in 2021 were supported by human genetics evidence 23,24 .…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

“…Lastly, we evaluated whether reducing COL6A3-derived endotrophin is associated with any 430 adverse health outcomes using a phenome-wide association analysis in the UK Biobank, FinnGen, 431 and the GWAS catalog. We did this because clinical trials for some drug candidates have been 432 terminated due to unexpected adverse events in later stages of the trials 22,56 ; thus, understanding 433 the potential effects of perturbing the target on a phenome-wide level may to anticipate possible 434 adverse events. Therefore, we assessed whether reducing COL6A3-derived endotrophin levels 435 may have any implications on other traits.…”

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confidence: 99%

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COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

Yoshiji

Butler‐Laporte

et al. 2023

Preprint

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Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity has broad effects on circulating protein levels, we investigated circulating proteins that mediate the effects of obesity on coronary artery disease (CAD), stroke, and type 2 diabetes—since doing so may prioritize targets for therapeutic intervention. By integrating proteome-wide Mendelian randomization (MR) screening 4,907 plasma proteins, colocalization, and mediation analyses, we identified seven plasma proteins, including collagen type VI α3 (COL6A3). COL6A3 was strongly increased by body mass index (BMI) (β = 0.32, 95% CI: 0.26–0.38, P = 3.7 × 10-8per s.d. increase in BMI) and increased the risk of CAD (OR = 1.47, 95% CI:1.26–1.70, P = 4.5 × 10-7per s.d. increase in COL6A3). Notably, COL6A3 is cleaved at its C-terminus to produce endotrophin, which was found to mediate this effect on CAD. In single-cell RNA sequencing of adipose tissues and coronary arteries, COL6A3 was highly expressed in cell types involved in metabolic dysfunction and fibrosis. Finally, we found that body fat reduction can reduce plasma levels of COL6A3-derived endotrophin, thereby highlighting a tractable way to modify endotrophin levels. In summary, we provide actionable insights into how circulating proteins mediate the effect of obesity on cardiometabolic diseases and prioritize endotrophin as a potential therapeutic target.

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Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

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confidence: 99%

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

Yoshiji

Butler‐Laporte

et al. 2023

Preprint

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“…There is an unprecedented abundance of heterogenous data available at the clinical (electronic health records) and molecular (-omic databases) level, but occasionally phenotypic information is incomplete to assist interpretation of high through-put data (Haendel et al, 2018). The interrogation of DNA has been under investigation as a diagnostic modality for a few decades with increasing translation into clinical care (Pirmohamed, 2023) and measurement of protein products is common practice. For instance, a combination of gene markers and a panel of proteins in CancerSEEK (Cohen et al, 2018) and methylation of circulating tumour DNA (Jin et al, 2021) are breakthroughs in early detection of solid tumours and colorectal cancer, respectively.…”

Section: Introductionmentioning

confidence: 99%

Leveraging transcriptomics for precision diagnosis: Lessons learned from cancer and sepsis

Tsakiroglou

Evans²,

Pirmohamed³

2023

Front. Genet.

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Diagnostics require precision and predictive ability to be clinically useful. Integration of multi-omic with clinical data is crucial to our understanding of disease pathogenesis and diagnosis. However, interpretation of overwhelming amounts of information at the individual level requires sophisticated computational tools for extraction of clinically meaningful outputs. Moreover, evolution of technical and analytical methods often outpaces standardisation strategies. RNA is the most dynamic component of all -omics technologies carrying an abundance of regulatory information that is least harnessed for use in clinical diagnostics. Gene expression-based tests capture genetic and non-genetic heterogeneity and have been implemented in certain diseases. For example patients with early breast cancer are spared toxic unnecessary treatments with scores based on the expression of a set of genes (e.g., Oncotype DX). The ability of transcriptomics to portray the transcriptional status at a moment in time has also been used in diagnosis of dynamic diseases such as sepsis. Gene expression profiles identify endotypes in sepsis patients with prognostic value and a potential to discriminate between viral and bacterial infection. The application of transcriptomics for patient stratification in clinical environments and clinical trials thus holds promise. In this review, we discuss the current clinical application in the fields of cancer and infection. We use these paradigms to highlight the impediments in identifying useful diagnostic and prognostic biomarkers and propose approaches to overcome them and aid efforts towards clinical implementation.

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“…Beyond socio-demographic factors, genetics might play a role in drug adherence. Pharmacogenomic studies have identified several genetic variants relevant to drug response that can increase an individual’s risk for adverse drug reactions 13 and a recent randomized trial suggested that a pre-emptive testing with a 12-gene pharmacogenetic panel can significantly reduce the incidence of clinically relevant adverse drug reactions 14 . Because an adverse drug reaction decreases the likelihood of a patient continuing to take a medication, genetics might impact adherence via this mechanism.…”

Section: Introductionmentioning

confidence: 99%

Socio-demographic and genetic risk factors for drug adherence and persistence: a retrospective nationwide and biobank study across 5 medication classes and 1 845 665 individuals

Cordioli,

Corbetta,

Kariis

et al. 2023

Preprint

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Low drug adherence is a major obstacle to the benefits of pharmacotherapies, and it is therefore important to identify factors associated with discontinuing or being poorly adherent to a prescribed treatment regimen. Using high-quality nationwide health registry data and genome-wide genotyping, we evaluate the impact of socio-demographic and genetic risk factors on adherence and persistence for 5 common medication classes that require long-term, regular therapy (N = 1 814 591 individuals, 185 931 with genetic data).Need for social assistance and immigration status showed a notable negative effect on persistence and adherence across the examined medications (odd ratios between 0.48 and 0.82 for persistence and between 1.1% to 4.3% decrease in adherence) while demographic (age and sex), health (comorbidity status), and genetic factors showed comparably modest or inconsistent effects. Some pharmacogenes were modestly associated with persistence, but not with adherence. We observed significant genetic correlations between medication adherence and participation in research studies. Overall, our findings suggest that socio-economically disadvantaged groups would benefit from targeted interventions to improve the dispensing and uptake of pharmacological treatments.

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Pharmacogenomics: current status and future perspectives

Cited by 130 publications

References 157 publications

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

Leveraging transcriptomics for precision diagnosis: Lessons learned from cancer and sepsis

Socio-demographic and genetic risk factors for drug adherence and persistence: a retrospective nationwide and biobank study across 5 medication classes and 1 845 665 individuals

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