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  1. Article ; Online: Transcriptome-wide association analyses identify an association between ARL14EP and polycystic ovary syndrome.

    Lyle, Sarah M / Ahmed, Samah / Elliott, Jason E / Stener-Victorin, Elisabet / Nachtigal, Mark W / Drögemöller, Britt I

    Journal of human genetics

    2023  Volume 68, Issue 5, Page(s) 347–353

    Abstract: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, which is accompanied by a variety of comorbidities including metabolic, reproductive, and psychiatric disorders. Genome-wide association studies have identified several genetic variants ... ...

    Abstract Polycystic ovary syndrome (PCOS) is a common endocrine disorder, which is accompanied by a variety of comorbidities including metabolic, reproductive, and psychiatric disorders. Genome-wide association studies have identified several genetic variants that are associated with PCOS. However, these variants often occur outside of coding regions and require further investigation to understand their contribution to PCOS. A transcriptome-wide association study (TWAS) was performed to uncover heritable gene expression profiles that are associated with PCOS in two independent cohorts. Causal gene prioritization was subsequently performed and expression of genes prioritized through these analyses was examined in 49 PCOS patients and 30 controls. TWAS analyses revealed that increased expression of ARL14EP was significantly associated with PCOS risk in the discovery (P = 1.6 × 10
    MeSH term(s) Female ; Humans ; Case-Control Studies ; Gene Expression Profiling ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Polycystic Ovary Syndrome/genetics ; Transcriptome
    Chemical Substances ARL14EP protein, human
    Language English
    Publishing date 2023-01-31
    Publishing country England
    Document type Journal Article
    ZDB-ID 1425192-9
    ISSN 1435-232X ; 1434-5161
    ISSN (online) 1435-232X
    ISSN 1434-5161
    DOI 10.1038/s10038-023-01120-w
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  2. Article ; Online: Current Perspectives on Data Sharing and Open Science in Pharmacogenomics.

    Miao, Deanne Nixie R / Ladha, Feryal / Lyle, Sarah M / Olivier, Daniel W / Ahmed, Samah / Drögemöller, Britt I

    Clinical pharmacology and therapeutics

    2023  Volume 115, Issue 3, Page(s) 408–411

    MeSH term(s) Humans ; Pharmacogenetics ; Information Dissemination
    Language English
    Publishing date 2023-12-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.3115
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  3. Article ; Online: Integrating disease and drug-related phenotypes for improved identification of pharmacogenomic variants.

    Ouellette, Tom W / Wright, Galen Eb / Drögemöller, Britt I / Ross, Colin Jd / Carleton, Bruce C

    Pharmacogenomics

    2021  Volume 22, Issue 5, Page(s) 251–261

    Abstract: Aim: ...

    Abstract Aim:
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; Allopurinol/therapeutic use ; Antihypertensive Agents/adverse effects ; Biological Specimen Banks ; Crohn Disease/chemically induced ; Crohn Disease/epidemiology ; Crohn Disease/genetics ; Diabetes Mellitus/chemically induced ; Diabetes Mellitus/epidemiology ; Diabetes Mellitus/genetics ; Genetic Pleiotropy ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Inflammatory Bowel Diseases/chemically induced ; Inflammatory Bowel Diseases/epidemiology ; Inflammatory Bowel Diseases/genetics ; Interleukin-18 Receptor beta Subunit/genetics ; Neoplasm Proteins/genetics ; Pharmacogenomic Variants/genetics ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics ; Sodium-Hydrogen Exchangers/genetics
    Chemical Substances ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Antihypertensive Agents ; IL18RAP protein, human ; Interleukin-18 Receptor beta Subunit ; Neoplasm Proteins ; SLC9A4 protein, human ; Sodium-Hydrogen Exchangers ; Allopurinol (63CZ7GJN5I)
    Language English
    Publishing date 2021-03-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2019513-8
    ISSN 1744-8042 ; 1462-2416
    ISSN (online) 1744-8042
    ISSN 1462-2416
    DOI 10.2217/pgs-2020-0130
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  4. Article ; Online: A Systematic Review and Analysis of the Use of Polygenic Scores in Pharmacogenomics.

    Johnson, Danielle / Wilke, MacKenzie A P / Lyle, Sarah M / Kowalec, Kaarina / Jorgensen, Andrea / Wright, Galen E B / Drögemöller, Britt I

    Clinical pharmacology and therapeutics

    2022  Volume 111, Issue 4, Page(s) 919–930

    Abstract: Polygenic scores (PGSs) have emerged as promising tools for complex trait risk prediction. The application of these scores to pharmacogenomics provides new opportunities to improve the prediction of treatment outcomes. To gain insight into this area of ... ...

    Abstract Polygenic scores (PGSs) have emerged as promising tools for complex trait risk prediction. The application of these scores to pharmacogenomics provides new opportunities to improve the prediction of treatment outcomes. To gain insight into this area of research, we conducted a systematic review and accompanying analysis. This review uncovered 51 papers examining the use of PGSs for drug-related outcomes, with the majority of these papers focusing on the treatment of psychiatric disorders (n = 30). Due to difficulties in collecting large cohorts of uniformly treated patients, the majority of pharmacogenomic PGSs were derived from large-scale genome-wide association studies of disease phenotypes that were related to the pharmacogenomic phenotypes under investigation (e.g., schizophrenia-derived PGSs for antipsychotic response prediction). Examination of the research participants included in these studies revealed that the majority of cohort participants were of European descent (78.4%). These biases were also reflected in research affiliations, which were heavily weighted towards institutions located in Europe and North America, with no first or last authors originating from institutions in Africa or South Asia. There was also substantial variability in the methods used to develop PGSs, with between 3 and 6.6 million variants included in the PGSs. Finally, we observed significant inconsistencies in the reporting of PGS analyses and results, particularly in terms of risk model development and application, coupled with a lack of data transparency and availability, with only three pharmacogenomics PGSs deposited on the Polygenic Score Catalog. These findings highlight current gaps and key areas for future pharmacogenomic PGS research.
    MeSH term(s) Genome-Wide Association Study ; Humans ; Multifactorial Inheritance/genetics ; Pharmacogenetics ; Phenotype ; Schizophrenia
    Language English
    Publishing date 2022-01-17
    Publishing country United States
    Document type Journal Article ; Systematic Review
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.2520
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  5. Article ; Online: Association Between HLA-DPB1 and Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in Children.

    Gibson, Kristen M / Drögemöller, Britt I / Foell, Dirk / Benseler, Susanne M / Graham, Jinko / Hancock, Robert E W / Luqmani, Raashid A / Cabral, David A / Brown, Kelly L / Ross, Colin J

    Arthritis & rheumatology (Hoboken, N.J.)

    2023  Volume 75, Issue 6, Page(s) 1048–1057

    Abstract: Objective: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children, ... ...

    Abstract Objective: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children, with an annual prevalence of 0.5-6.4 cases per million children. The etiology of AAV remains largely unknown, and both environmental and genetic factors are likely involved. The present study was undertaken to explore the genetic susceptibility factors recently identified in adult patients, including HLA-DP and HLA-DQ, in pediatric patients.
    Methods: We performed a genome-wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population-matched controls).
    Results: We identified a significant genetic association between pediatric AAV and the HLA-DPB1*04:01 allele (P = 1.5 × 10
    Conclusion: The HLA-DPB1 locus showed an association with pediatric AAV, as similarly shown previously in adult AAV. Despite the difference in the age of onset, these findings suggest that childhood- and adult-onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies.
    MeSH term(s) Adult ; Humans ; Child ; Antibodies, Antineutrophil Cytoplasmic ; Genome-Wide Association Study ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/genetics ; HLA-DP beta-Chains/genetics ; Genetic Predisposition to Disease ; Peroxidase
    Chemical Substances Antibodies, Antineutrophil Cytoplasmic ; HLA-DPB1 antigen ; HLA-DP beta-Chains ; Peroxidase (EC 1.11.1.7)
    Language English
    Publishing date 2023-03-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2756371-6
    ISSN 2326-5205 ; 2326-5191
    ISSN (online) 2326-5205
    ISSN 2326-5191
    DOI 10.1002/art.42423
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  6. Article ; Online: Characterization of CYP2B6 and CYP2A6 Pharmacogenetic Variation in Sub-Saharan African Populations.

    Twesigomwe, David / Drögemöller, Britt I / Wright, Galen E B / Adebamowo, Clement / Agongo, Godfred / Boua, Palwendé R / Matshaba, Mogomotsi / Paximadis, Maria / Ramsay, Michèle / Simo, Gustave / Simuunza, Martin C / Tiemessen, Caroline T / Lombard, Zané / Hazelhurst, Scott

    Clinical pharmacology and therapeutics

    2023  Volume 115, Issue 3, Page(s) 576–594

    Abstract: Genetic variation in CYP2B6 and CYP2A6 is known to impact interindividual response to antiretrovirals, nicotine, and bupropion, among other drugs. However, the full catalogue of clinically relevant pharmacogenetic variants in these genes is yet to be ... ...

    Abstract Genetic variation in CYP2B6 and CYP2A6 is known to impact interindividual response to antiretrovirals, nicotine, and bupropion, among other drugs. However, the full catalogue of clinically relevant pharmacogenetic variants in these genes is yet to be established, especially across African populations. This study therefore aimed to characterize the star allele (haplotype) distribution in CYP2B6 and CYP2A6 across diverse and understudied sub-Saharan African (SSA) populations. We called star alleles from 961 high-depth full genomes using StellarPGx, Aldy, and PyPGx. In addition, we performed CYP2B6 and CYP2A6 star allele frequency comparisons between SSA and other global biogeographical groups represented in the new 1000 Genomes Project high-coverage dataset (n = 2,000). This study presents frequency information for star alleles in CYP2B6 (e.g., *6 and *18; frequency of 21-47% and 2-19%, respectively) and CYP2A6 (e.g., *4, *9, and *17; frequency of 0-6%, 3-10%, and 6-20%, respectively), and predicted phenotypes (for CYP2B6), across various African populations. In addition, 50 potentially novel African-ancestry star alleles were computationally predicted by StellarPGx in CYP2B6 and CYP2A6 combined. For each of these genes, over 4% of the study participants had predicted novel star alleles. Three novel star alleles in CYP2A6 (*54, *55, and *56) and CYP2B6 apiece, and several suballeles were further validated via targeted Single-Molecule Real-Time resequencing. Our findings are important for informing the design of comprehensive pharmacogenetic testing platforms, and are highly relevant for personalized medicine strategies, especially relating to antiretroviral medication and smoking cessation treatment in Africa and the African diaspora. More broadly, this study highlights the importance of sampling diverse African ethnolinguistic groups for accurate characterization of the pharmacogene variation landscape across the continent.
    MeSH term(s) Humans ; Cytochrome P-450 CYP2B6/genetics ; Pharmacogenetics ; Cytochrome P-450 CYP2A6/genetics ; Nicotine ; Gene Frequency ; Africa South of the Sahara ; Genotype ; Alleles
    Chemical Substances Cytochrome P-450 CYP2B6 (EC 1.14.14.1) ; Cytochrome P-450 CYP2A6 (EC 1.14.14.1) ; Nicotine (6M3C89ZY6R) ; CYP2B6 protein, human (EC 1.14.14.1) ; CYP2A6 protein, human (EC 1.14.14.1)
    Language English
    Publishing date 2023-12-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.3124
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  7. Article ; Online: StellarPGx: A Nextflow Pipeline for Calling Star Alleles in Cytochrome P450 Genes.

    Twesigomwe, David / Drögemöller, Britt I / Wright, Galen E B / Siddiqui, Azra / da Rocha, Jorge / Lombard, Zané / Hazelhurst, Scott

    Clinical pharmacology and therapeutics

    2021  Volume 110, Issue 3, Page(s) 741–749

    Abstract: Bioinformatics pipelines for calling star alleles (haplotypes) in cytochrome P450 (CYP) genes are important for the implementation of precision medicine. Genotyping CYP genes using high throughput sequencing data is complicated, e.g., by being highly ... ...

    Abstract Bioinformatics pipelines for calling star alleles (haplotypes) in cytochrome P450 (CYP) genes are important for the implementation of precision medicine. Genotyping CYP genes using high throughput sequencing data is complicated, e.g., by being highly polymorphic, not to mention the structural variations especially in CYP2D6, CYP2A6, and CYP2B6. Genome graph-based variant detection approaches have been shown to be reliable for genotyping HLA alleles. However, their application to enhancing star allele calling in CYP genes has not been extensively explored. We present StellarPGx, a Nextflow pipeline for accurately genotyping CYP genes by combining genome graph-based variant detection, read coverage information from the original reference-based alignments, and combinatorial diplotype assignments. The implementation of StellarPGx using Nextflow facilitates its portability, reproducibility, and scalability on various user platforms. StellarPGx is currently able to genotype 12 important pharmacogenes belonging to the CYP1, 2, and 3 families. For purposes of validation, we use CYP2D6 as a model gene owing to its high degree of polymorphisms (over 130 star alleles defined to date, including complex structural variants) and clinical importance. We applied StellarPGx and three existing callers to 109 whole genome sequenced samples for which the Genetic Testing Reference Material Coordination Program (GeT-RM) has recently provided consensus truth CYP2D6 diplotypes. StellarPGx had the highest CYP2D6 diplotype concordance (99%) with GeT-RM compared with Cyrius (98%), Aldy (82%), and Stargazer (84%). This exemplifies the high accuracy of StellarPGx and highlights its importance for both research and clinical pharmacogenomics applications. The StellarPGx pipeline is open-source and available from https://github.com/SBIMB/StellarPGx.
    MeSH term(s) Alleles ; Computational Biology/methods ; Cytochrome P-450 Enzyme System/genetics ; Genotype ; Haplotypes/genetics ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Pharmacogenetics/methods ; Polymorphism, Genetic/genetics ; Reproducibility of Results ; Sequence Analysis, DNA/methods ; Whole Genome Sequencing/methods
    Chemical Substances Cytochrome P-450 Enzyme System (9035-51-2)
    Language English
    Publishing date 2021-02-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.2173
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  8. Article ; Online: Genome-Wide Association Studies of Drug-Induced Liver Injury Make Progress Beyond the HLA Region.

    Wright, Galen E B / Drögemöller, Britt I / Ross, Colin J D / Carleton, Bruce C

    Gastroenterology

    2019  Volume 157, Issue 4, Page(s) 1167–1168

    MeSH term(s) Chemical and Drug Induced Liver Injury ; Genome-Wide Association Study ; Humans ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; Risk Factors
    Chemical Substances PTPN22 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 (EC 3.1.3.48)
    Language English
    Publishing date 2019-07-23
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 80112-4
    ISSN 1528-0012 ; 0016-5085
    ISSN (online) 1528-0012
    ISSN 0016-5085
    DOI 10.1053/j.gastro.2019.03.076
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  9. Article ; Online: Characterization of CYP2D6 Pharmacogenetic Variation in Sub-Saharan African Populations.

    Twesigomwe, David / Drögemöller, Britt I / Wright, Galen E B / Adebamowo, Clement / Agongo, Godfred / Boua, Palwendé R / Matshaba, Mogomotsi / Paximadis, Maria / Ramsay, Michèle / Simo, Gustave / Simuunza, Martin C / Tiemessen, Caroline T / Lombard, Zané / Hazelhurst, Scott

    Clinical pharmacology and therapeutics

    2022  Volume 113, Issue 3, Page(s) 643–659

    Abstract: Cytochrome P450 2D6 (CYP2D6) is a key enzyme in drug response owing to its involvement in the metabolism of ~ 25% of clinically prescribed medications. The encoding CYP2D6 gene is highly polymorphic, and many pharmacogenetics studies have been performed ... ...

    Abstract Cytochrome P450 2D6 (CYP2D6) is a key enzyme in drug response owing to its involvement in the metabolism of ~ 25% of clinically prescribed medications. The encoding CYP2D6 gene is highly polymorphic, and many pharmacogenetics studies have been performed worldwide to investigate the distribution of CYP2D6 star alleles (haplotypes); however, African populations have been relatively understudied to date. In this study, the distributions of CYP2D6 star alleles and predicted drug metabolizer phenotypes-derived from activity scores-were examined across multiple sub-Saharan African populations based on bioinformatics analysis of 961 high-depth whole genome sequences. This was followed by characterization of novel star alleles and suballeles in a subset of the participants via targeted high-fidelity Single-Molecule Real-Time resequencing (Pacific Biosciences). This study revealed varying frequencies of known CYP2D6 alleles and predicted phenotypes across different African ethnolinguistic groups. Twenty-seven novel CYP2D6 star alleles were predicted computationally and two of them were further validated. This study highlights the importance of studying variation in key pharmacogenes such as CYP2D6 in the African context to better understand population-specific allele frequencies. This will aid in the development of better genotyping panels and star allele detection approaches with a view toward supporting effective implementation of precision medicine strategies in Africa and across the African diaspora.
    MeSH term(s) Humans ; Cytochrome P-450 CYP2D6/genetics ; Cytochrome P-450 CYP2D6/metabolism ; Pharmacogenetics ; Gene Frequency ; Haplotypes ; Phenotype ; Alleles ; Africa South of the Sahara ; Genotype
    Chemical Substances Cytochrome P-450 CYP2D6 (EC 1.14.14.1)
    Language English
    Publishing date 2022-10-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.2749
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  10. Article ; Online: A systematic comparison of pharmacogene star allele calling bioinformatics algorithms: a focus on

    Twesigomwe, David / Wright, Galen E B / Drögemöller, Britt I / da Rocha, Jorge / Lombard, Zané / Hazelhurst, Scott

    NPJ genomic medicine

    2020  Volume 5, Page(s) 30

    Abstract: Genetic variation in genes encoding ... ...

    Abstract Genetic variation in genes encoding cytochrome
    Language English
    Publishing date 2020-08-03
    Publishing country England
    Document type Journal Article
    ZDB-ID 2813848-X
    ISSN 2056-7944 ; 2056-7944
    ISSN (online) 2056-7944
    ISSN 2056-7944
    DOI 10.1038/s41525-020-0135-2
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