scholarly journals UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1566
Author(s):  
Ryan S. Nelson ◽  
Nathan D. Seligson ◽  
Sal Bottiglieri ◽  
Estrella Carballido ◽  
Alex Del Cueto ◽  
...  
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Clinical Implementation ◽  
Drug Label ◽  
Genome Wide ◽  
Starting Dose ◽  
Therapeutic Decision Making ◽  
Meta Analyses ◽  
The Impact

Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.

scholarly journals Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Erika N. Scott ◽  
Galen E. B. Wright ◽  
Britt I. Drögemöller ◽  
Jafar S. Hasbullah ◽  
Erandika P. Gunaretnam ◽  
...  
Keyword(s):  
Association Study ◽  
Association Studies ◽  
Chemotherapeutic Agents ◽  
Genome Wide Association Studies ◽  
Gene Set Enrichment ◽  
Genome Wide ◽  
Pathway Analyses ◽  
The Impact ◽  
Identify Gene Expression

AbstractAnthracyclines are highly effective chemotherapeutic agents; however, their clinical utility is limited by severe anthracycline-induced cardiotoxicity (ACT). Genome-wide association studies (GWAS) have uncovered several genetic variants associated with ACT, but the impact of these findings requires further elucidation. We conducted a transcriptome-wide association study (TWAS) using our previous GWAS summary statistics (n = 280 patients) to identify gene expression-related associations with ACT. We identified a genetic association between decreased expression of GDF5 and ACT (Z-score = −4.30, P = 1.70 × 10−5), which was replicated in an independent cohort (n = 845 patients, P = 3.54 × 10−3). Additionally, cell viability of GDF5-silenced human cardiac myocytes was significantly decreased in response to anthracycline treatment. Subsequent gene set enrichment and pathway analyses of the TWAS data revealed that genes essential for survival, cardioprotection and response to anthracyclines, as well as genes involved in ribosomal, spliceosomal and cardiomyopathy pathways are important for the development of ACT.

scholarly journals The genetic basis of psoriasis

2016 ◽  
Vol 14 (2) ◽  
pp. 197-207
Author(s):  
Nguyễn Thị Kim Liên ◽  
Nguyễn Huy Hoàng
Keyword(s):  
Genetic Basis ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Chromosome 6 ◽  
Disease Manifestation ◽  
Genome Wide ◽  
Increasing Risk ◽  
The Impact ◽  
Main Influence

Psoriasis is a chronic dermatitis disease. Although the disease is not dangerous but it affects patients’s life in many aspects and involving a large number of people in the world. Besides that, psoriasis related to many other diseases such as metabolic disorder, diabetes, cardiovascular disease or can develop into servere arthritis and psoriasis arthritis leading to joint deformities. HLAC gene located on chromosome 6 (locus PSORS1) is known to have an important role in the susceptibility of disease. Besides, investigations showed that psoriasis is controlled by many loci and genes. By using traditional methods and genome wide association studies (GWAS) have been identified 13 loci and many genes involved of disease. However, the role of each locus and gene influence to the susceptibility of disease, presentation of disease, time onset and the links with other diseases have not yet been defined clearly. Among the relevant loci, the PSORS1 locus still considered the main influence on the susceptibility of disease. Noteworthy, the factors of age, gender and race have influences to the disease manifestation of different loci. The studies also provides evidences of the relation of proriasis and increasing risk cardiovascular, hypertension, diabetes and other diseases. So that, by understanding the genetic basis of the disease, the doctors and patients can get orientation in prevention, treatment and minimizing the impact of the disease. In this article, we give a clearer view of the genetic basis of psoriasis.

scholarly journals Tantalizing dilemma in risk prediction from disease scoring statistics

2019 ◽  
Vol 18 (4) ◽  
pp. 211-219 ◽  
Author(s):  
Denis Awany ◽  
Imane Allali ◽  
Emile R Chimusa
Keyword(s):  
Statistical Methods ◽  
Association Studies ◽  
Complex Trait ◽  
Genome Wide Association Studies ◽  
Causal Factors ◽  
Genome Wide ◽  
Host Genetic ◽  
The Impact ◽  
Disease Scoring

Abstract Over the past decade, human host genome-wide association studies (GWASs) have contributed greatly to our understanding of the impact of host genetics on phenotypes. Recently, the microbiome has been recognized as a complex trait in host genetic variation, leading to microbiome GWAS (mGWASs). For these, many different statistical methods and software tools have been developed for association mapping. Applications of these methods and tools have revealed several important findings; however, the establishment of causal factors and the direction of causality in the interactive role between human genetic polymorphisms, the microbiome and the host phenotypes are still a huge challenge. Here, we review disease scoring approaches in host and mGWAS and their underlying statistical methods and tools. We highlight the challenges in pinpointing the genetic-associated causal factors in host and mGWAS and discuss the role of multi-omic approach in disease scoring statistics that may provide a better understanding of human phenotypic variation by enabling further system biological experiment to establish causality.

scholarly journals Genetic Determinants of Paget’s Disease of Bone

2021 ◽  
Author(s):  
Navnit S. Makaram ◽  
Stuart H. Ralston
Keyword(s):  
Genetic Factors ◽  
Association Studies ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Genome Wide Association Studies ◽  
Paget's Disease Of Bone ◽  
Genome Wide ◽  
Family Based

Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

26-OR: Meta-analyses of Genome-Wide Association Studies for Proinsulin Provide Insight into Glycemic Trait Dysregulation

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 26-OR
Author(s):  
K. ALAINE BROADAWAY ◽  
XIANYONOG YIN ◽  
ALICE WILLIAMSON ◽  
EMMA WILSON ◽  
MAGIC INVESTIGATORS
Keyword(s):  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Meta Analyses ◽  
Insight Into

Stroke Genetics: Turning Discoveries into Clinical Applications

Stroke ◽  
2021 ◽  
Author(s):  
Martin Dichgans ◽  
Nathalie Beaufort ◽  
Stephanie Debette ◽  
Christopher D. Anderson
Keyword(s):  
Mendelian Randomization ◽  
Association Studies ◽  
Clinical Applications ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Neuroprotective Agents ◽  
Experimental Systems ◽  
Genome Wide ◽  
Rapid Pace

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

scholarly journals Current knowledge in hypertension genetics: mosaic theory, candidate genes and genome-wide association studies

2020 ◽  
Vol 26 (5) ◽  
pp. 490-500
Author(s):  
A. O. Konradi
Keyword(s):  
Candidate Genes ◽  
High Performance ◽  
New Technologies ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Modern Approach ◽  
Genome Wide

The article reviews monogenic forms of hypertension, data on the role of heredity of essential hypertension and candidate genes, as well as genome-wide association studies. Modern approach for the role of genetics is driven by implementation of new technologies and their productivity. High performance speed of new technologies like genome-wide association studies provide data for better knowledge of genetic markers of hypertension. The major goal nowadays for research is to reveal molecular pathways of blood pressure regulation, which can help to move from populational to individual level of understanding of pathogenesis and treatment targets.

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