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1. Meta-analysis of genome-wide association studies of stable warfarin dose in patients of African ancestry

Author

Asiimwe, Innocent G., Blockman, Marc, Cavallari, Larisa H., Cohen, Karen, Cupido, Clint, Dandara, Collet, Davis, Brittney H., Jacobson, Barry, Johnson, Julie A., Lamorde, Mohammed, Limdi, Nita A., Morgan, Jennie, Mouton, Johannes P., Muyambo, Sarudzai, Nakagaayi, Doreen, Ndadza, Arinao, Okello, Emmy, Perera, Minoli A., Schapkaitz, Elise, Sekaggya-Wiltshire, Christine, Semakula, Jerome R., Tatz, Gayle, Waitt, Catriona, Yang, Guang, Zhang, Eunice J., Jorgensen, Andrea L., and Pirmohamed, Munir

Published
2024
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3. Real world treatment of juvenile-onset systemic lupus erythematosus: Data from the UK JSLE cohort study

Author

Smith, Eve M.D., Egbivwie, Naomi, Jorgensen, Andrea L., Ciurtin, Coziana, Al-Abadi, Eslam, Armon, Kate, Bailey, Kathryn, Brennan, Mary, Gardner-Medwin, Janet, Haslam, Kirsty, Hawley, Daniel P., Leahy, Alice, Leone, Valentina, Malik, Gulshan, McLaren, Zoe, Pilkington, Clarissa, Ramanan, Athimalaipet V., Rangaraj, Satyapal, Ratcliffe, Annie, Riley, Phil, Sen, Ethan, Sridhar, Arani, Wilkinson, Nick, Wood, Fiona, Beresford, Michael W., and Hedrich, Christian M.

Published
2022
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4. Genetic Determinants of Thiazide‐Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances – A Genome‐Wide Evaluation of the UK Biobank.

Author

Asiimwe, Innocent G., Walker, Lauren, Sofat, Reecha, Jorgensen, Andrea L., and Pirmohamed, Munir

Subjects
LOCUS (Genetics), GENOTYPE-environment interaction, GENETIC variation, HYPERURICEMIA, HYPERGLYCEMIA, BLOOD sugar
Abstract

Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide‐use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self‐reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene–environment interaction (GEI) tests on the significant (P < 2.5 × 10−9) vQTLs, included a second UK Biobank cohort comprising 13,647 unrelated hypertensive White British participants (3,478 on thiazides other than bendroflumethiazide) and set significance at P = 0.05 divided by the number of vQTL SNPs tested for GEIs. The vQTL analysis identified eight statistically significant SNPs for blood glucose (5 SNPs) and serum urate (3 SNPs), with none being identified for the urinary biomarkers. Two of the SNPs (1 glucose SNP: CDKAL1 intron rs35612982, GEI P = 6.24 × 10−3; and 1 serum urate SNP: SLC2A9 intron rs938564, GEI P = 4.51 × 10−4) demonstrated significant GEI effects in the first, but not the second, cohort. Both genes are biologically plausible candidates, with the SLC2A9‐mediated interaction having been previously reported. In conclusion, we used a two‐stage approach to detect two biologically plausible genetic loci that can interact with thiazides to increase the risk of thiazide‐associated biochemical abnormalities. Understanding how environmental exposures (including medications such as thiazides) and genetics interact, is an important step toward precision medicine and improved patient outcomes. [ABSTRACT FROM AUTHOR]

Published
2024
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8. A “Bundle of Care” to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study

Author

Jorgensen, Andrea L, primary, Orrell, Catherine, additional, Waitt, Catriona, additional, Toh, Cheng-Hock, additional, Sekaggya-Wiltshire, Christine, additional, Hughes, Dyfrig A, additional, Allen, Elizabeth, additional, Okello, Emmy, additional, Tatz, Gayle, additional, Culeddu, Giovanna, additional, Asiimwe, Innocent G, additional, Semakula, Jerome Roy, additional, Mouton, Johannes P, additional, Cohen, Karen, additional, Blockman, Marc, additional, Lamorde, Mohammed, additional, and Pirmohamed, Munir, additional

Published
2023
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11. A “Bundle of Care” to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study (Preprint)

Author

Jorgensen, Andrea L, primary, Orrell, Catherine, additional, Waitt, Catriona, additional, Toh, Cheng-Hock, additional, Sekaggya-Wiltshire, Christine, additional, Hughes, Dyfrig A, additional, Allen, Elizabeth, additional, Okello, Emmy, additional, Tatz, Gayle, additional, Culeddu, Giovanna, additional, Asiimwe, Innocent G, additional, Semakula, Jerome Roy, additional, Mouton, Johannes P, additional, Cohen, Karen, additional, Blockman, Marc, additional, Lamorde, Mohammed, additional, and Pirmohamed, Munir, additional

Published
2023
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13. Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia

Author

Hurkmans, Evelien G. E., primary, Klumpers, Marije J., additional, Dello Russo, Cinzia, additional, De Witte, Ward, additional, Guchelaar, Henk-Jan, additional, Gelderblom, Hans, additional, Cleton-Jansen, Anne-Marie, additional, Vermeulen, Sita H., additional, Kaal, Suzanne, additional, van der Graaf, Winette T. A., additional, Flucke, Uta, additional, Gidding, Corrie E. M., additional, Schreuder, Hendrik W. B., additional, de Bont, Eveline S. J. M., additional, Caron, Huib N., additional, Gattuso, Giovanna, additional, Schiavello, Elisabetta, additional, Terenziani, Monica, additional, Massimino, Maura, additional, McCowage, Geoff, additional, Nagabushan, Sumanth, additional, Limaye, Anuja, additional, Rose, Victoria, additional, Catchpoole, Daniel, additional, Jorgensen, Andrea L., additional, Barton, Christopher, additional, Delaney, Lucy, additional, Hawcutt, Daniel B., additional, Pirmohamed, Munir, additional, Pizer, Barry, additional, Coenen, Marieke J. H., additional, and te Loo, D. Maroeska W. M., additional

Published
2023
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16. A genome-wide association study of plasma concentrations of warfarin enantiomers and metabolites in sub-Saharan black-African patients

Author

Asiimwe, Innocent G., primary, Blockman, Marc, additional, Cohen, Karen, additional, Cupido, Clint, additional, Hutchinson, Claire, additional, Jacobson, Barry, additional, Lamorde, Mohammed, additional, Morgan, Jennie, additional, Mouton, Johannes P., additional, Nakagaayi, Doreen, additional, Okello, Emmy, additional, Schapkaitz, Elise, additional, Sekaggya-Wiltshire, Christine, additional, Semakula, Jerome R., additional, Waitt, Catriona, additional, Zhang, Eunice J., additional, Jorgensen, Andrea L., additional, and Pirmohamed, Munir, additional

Published
2022
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18. Multi-ancestry genome-wide association study of asthma exacerbations

Author

Herrera Luis, Esther, Ortega, Victor E., Ampleford, Elizabeth J., Sio, Yang Yie, Granell, Raquel, de Roos, Emmely, Terzikhan, Natalie, Elorduy Vergara, Ernesto, Hernández Pacheco, Natalia, Pérez García, Javier, Martín González, Elena, Lorenzo Díaz, Fabián, Hashimoto, Simone, Brinkman, Paul, U-BIOPRED Study Group, Jorgensen, Andrea L., Yan, Qi, Forno, Erick, Vijverberg, Susanne J., Lethem, Ryan, Espuela Ortiz, Antonio, Gorenjak, Mario, Eng, Celeste, González Pérez, Ruperto, Hernández Pérez, José M., Poza Guedes, Paloma, Sardón Prado, Olaia, Corcuera Elosegui, Paula, Hawkins, Greg A., Marsico, Annalisa, Bahmer, Thomas, Rabe, Klaus F., Hansen, Gesine, Kopp, Matthias Volkmar, Rios, Raimon, Cruz Carmona, María Jesús, González Barcala, Francisco Javier, Olaguibel, José María, Plaza, Vicente, Quirce, Santiago, Canino, Glorisa, Cloutier, Michelle, Del Pozo, Victoria, Rodríguez Santana, José R., Korta Murua, José Javier, Villar, Jesús, Potočnik, Uroš, Figueiredo, Camila, Kabesch, Michael, Mukhopadhyay, Somnath, Pirmohamed, Munir, Hawcutt, Daniel B., Melén, Erik, Palmer, Colin N., Turner, Steven, Maitland-van der Zee, Anke H., von Mutius, Erika, Celedón, Juan C., Brusselle, Guy, Chew, Fook Tim, Bleecker, Eugene, Meyers, Deborah, Burchard, Esteban G., Pino Yanes, María, European Commission, Epidemiology, Pulmonary Medicine, Institut Català de la Salut, [Herrera-Luis E] Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), San Cristóbal de La Laguna, Tenerife, Spain. [Ortega VE] Division of Respiratory Medicine, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA. [Ampleford EJ] Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. [Sio YY] Department of Biological Sciences, National University of Singapore, Singapore City, Singapore. [Granell R] MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. [de Roos E] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. [Cruz MJ] CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain. Servei de Pneumologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Pulmonology, Paediatric Pulmonology, AII - Inflammatory diseases, and APH - Personalized Medicine

Subjects
Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Immunology, EFFICIENT, 610 Medicine & health, ADHESION, Polymorphism, Single Nucleotide, Article, fenómenos genéticos::variación genética::polimorfismo genético::polimorfismo de nucleótido único [FENÓMENOS Y PROCESOS], Extl2, Pank1, Gwas, Asthma Exacerbations, Single-nucleotide Polymorphism, SDG 3 - Good Health and Well-being, Medicine and Health Sciences, Other subheadings::Other subheadings::/genetics [Other subheadings], TOOL, Humans, Immunology and Allergy, GWAS, Genetic Predisposition to Disease, EXTL2, Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [PHENOMENA AND PROCESSES], Asma - Aspectes genètics, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Polimorfisme genètic, Hispanic or Latino, Respiratory Tract Diseases::Bronchial Diseases::Asthma [DISEASES], single-nucleotide polymorphism, ALSPAC, Asthma, PANK1, Genòmica, asthma exacerbations, Pediatrics, Perinatology and Child Health, Quality of Life, técnicas de investigación::métodos epidemiológicos::diseño de la investigación epidemiológica::estudio de asociación genómica completa [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], enfermedades respiratorias::enfermedades bronquiales::asma [ENFERMEDADES], Genome-Wide Association Study
Abstract

Background: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p

Published
2022

21. Multi-ancestry genome-wide association study of asthma exacerbations

Author

Pediatría, Pediatria, Herrera Luis, Esther, Ortega, Victor E., Ampleford, Elizabeth J., Sio, Yang Yie, Granell, Raquel, de Roos, Emmely, Terzikhan, Natalie, Elorduy Vergara, Ernesto, Hernández Pacheco, Natalia, Pérez García, Javier, Martín González, Elena, Lorenzo Díaz, Fabián, Hashimoto, Simone, Brinkman, Paul, U-BIOPRED Study Group, Jorgensen, Andrea L., Yan, Qi, Forno, Erick, Vijverberg, Susanne J., Lethem, Ryan, Espuela Ortiz, Antonio, Gorenjak, Mario, Eng, Celeste, González Pérez, Ruperto, Hernández Pérez, José M., Poza Guedes, Paloma, Sardón Prado, Olaia, Corcuera Elosegui, Paula, Hawkins, Greg A., Marsico, Annalisa, Bahmer, Thomas, Rabe, Klaus F., Hansen, Gesine, Kopp, Matthias Volkmar, Rios, Raimon, Cruz Carmona, María Jesús, González Barcala, Francisco Javier, Olaguibel, José María, Plaza, Vicente, Quirce, Santiago, Canino, Glorisa, Cloutier, Michelle, Del Pozo, Victoria, Rodríguez Santana, José R., Korta Murua, José Javier, Villar, Jesús, Potočnik, Uroš, Figueiredo, Camila, Kabesch, Michael, Mukhopadhyay, Somnath, Pirmohamed, Munir, Hawcutt, Daniel B., Melén, Erik, Palmer, Colin N., Turner, Steven, Maitland-van der Zee, Anke H., von Mutius, Erika, Celedón, Juan C., Brusselle, Guy, Chew, Fook Tim, Bleecker, Eugene, Meyers, Deborah, Burchard, Esteban G., Pino Yanes, María, Pediatría, Pediatria, Herrera Luis, Esther, Ortega, Victor E., Ampleford, Elizabeth J., Sio, Yang Yie, Granell, Raquel, de Roos, Emmely, Terzikhan, Natalie, Elorduy Vergara, Ernesto, Hernández Pacheco, Natalia, Pérez García, Javier, Martín González, Elena, Lorenzo Díaz, Fabián, Hashimoto, Simone, Brinkman, Paul, U-BIOPRED Study Group, Jorgensen, Andrea L., Yan, Qi, Forno, Erick, Vijverberg, Susanne J., Lethem, Ryan, Espuela Ortiz, Antonio, Gorenjak, Mario, Eng, Celeste, González Pérez, Ruperto, Hernández Pérez, José M., Poza Guedes, Paloma, Sardón Prado, Olaia, Corcuera Elosegui, Paula, Hawkins, Greg A., Marsico, Annalisa, Bahmer, Thomas, Rabe, Klaus F., Hansen, Gesine, Kopp, Matthias Volkmar, Rios, Raimon, Cruz Carmona, María Jesús, González Barcala, Francisco Javier, Olaguibel, José María, Plaza, Vicente, Quirce, Santiago, Canino, Glorisa, Cloutier, Michelle, Del Pozo, Victoria, Rodríguez Santana, José R., Korta Murua, José Javier, Villar, Jesús, Potočnik, Uroš, Figueiredo, Camila, Kabesch, Michael, Mukhopadhyay, Somnath, Pirmohamed, Munir, Hawcutt, Daniel B., Melén, Erik, Palmer, Colin N., Turner, Steven, Maitland-van der Zee, Anke H., von Mutius, Erika, Celedón, Juan C., Brusselle, Guy, Chew, Fook Tim, Bleecker, Eugene, Meyers, Deborah, Burchard, Esteban G., and Pino Yanes, María

Abstract

Background: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p <= 5 x 10(-5)) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. Results: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele) = 0.82, p = 9.05 x 10(-6) and replication: ORT allele = 0.89, p = 5.35 x 10(-3)) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 x 10(-5) and replication: ORC allele = 0.89, p = 1.30 x 10(-2)). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

Published
2022

22. Multi-ancestry genome-wide association study of asthma exacerbations

Author

Herrera-Luis, Esther, Ortega, Victor E., Ampleford, Elizabeth J., Sio, Yang Yie, Granell, Raquel, de Roos, Emmely, Terzikhan, Natalie, Vergara, Ernesto Elorduy, Hernandez-Pacheco, Natalia, Perez-Garcia, Javier, Martin-Gonzalez, Elena, Lorenzo-Diaz, Fabian, Hashimoto, Simone, Brinkman, Paul, Jorgensen, Andrea L., Yan, Qi, Forno, Erick, Vijverberg, Susanne J., Lethem, Ryan, Espuela-Ortiz, Antonio, Gorenjak, Mario, Eng, Celeste, González-Pérez, Ruperto, Hernández-Pérez, José M., Poza-Guedes, Paloma, Sardón, Olaia, Corcuera, Paula, Hawkins, Greg A, Marsico, Annalisa, Bahmer, Thomas, Rabe, Klaus F., Hansen, Gesine, Kopp, Matthias Volkmar, Rios, Raimon, Cruz, Maria Jesus, González-Barcala, Francisco Javier, Olaguibel, José María, Plaza, Vicente, Quirce, Santiago, Canino, Glorisa, Cloutier, Michelle, del Pozo, Victoria, Rodriguez-Santana, Jose R., Korta-Murua, Javier, Villar, Jesús, Potočnik, Uroš, Figueiredo, Camila, Kabesch, Michael, Mukhopadhyay, Somnath, Brusselle, Guy, Burchard, Esteban G., Pino-Yanes, Maria, Herrera-Luis, Esther, Ortega, Victor E., Ampleford, Elizabeth J., Sio, Yang Yie, Granell, Raquel, de Roos, Emmely, Terzikhan, Natalie, Vergara, Ernesto Elorduy, Hernandez-Pacheco, Natalia, Perez-Garcia, Javier, Martin-Gonzalez, Elena, Lorenzo-Diaz, Fabian, Hashimoto, Simone, Brinkman, Paul, Jorgensen, Andrea L., Yan, Qi, Forno, Erick, Vijverberg, Susanne J., Lethem, Ryan, Espuela-Ortiz, Antonio, Gorenjak, Mario, Eng, Celeste, González-Pérez, Ruperto, Hernández-Pérez, José M., Poza-Guedes, Paloma, Sardón, Olaia, Corcuera, Paula, Hawkins, Greg A, Marsico, Annalisa, Bahmer, Thomas, Rabe, Klaus F., Hansen, Gesine, Kopp, Matthias Volkmar, Rios, Raimon, Cruz, Maria Jesus, González-Barcala, Francisco Javier, Olaguibel, José María, Plaza, Vicente, Quirce, Santiago, Canino, Glorisa, Cloutier, Michelle, del Pozo, Victoria, Rodriguez-Santana, Jose R., Korta-Murua, Javier, Villar, Jesús, Potočnik, Uroš, Figueiredo, Camila, Kabesch, Michael, Mukhopadhyay, Somnath, Brusselle, Guy, Burchard, Esteban G., and Pino-Yanes, Maria

Abstract

Background: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10−5) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. Results: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele) = 0.82, p = 9.05 × 10−6 and replication: ORT allele = 0.89, p = 5.35 × 10−3) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10−5 and replication: ORC allele = 0.89, p = 1.30 × 10−2). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located

Published
2022

27. Stable warfarin dose prediction in sub‐Saharan African patients: A machine‐learning approach and external validation of a clinical dose–initiation algorithm

Author

Asiimwe, Innocent G., primary, Blockman, Marc, additional, Cohen, Karen, additional, Cupido, Clint, additional, Hutchinson, Claire, additional, Jacobson, Barry, additional, Lamorde, Mohammed, additional, Morgan, Jennie, additional, Mouton, Johannes P., additional, Nakagaayi, Doreen, additional, Okello, Emmy, additional, Schapkaitz, Elise, additional, Sekaggya‐Wiltshire, Christine, additional, Semakula, Jerome R., additional, Waitt, Catriona, additional, Zhang, Eunice J., additional, Jorgensen, Andrea L., additional, and Pirmohamed, Munir, additional

Published
2021
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28. Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration

Author

Bourgeois, Stephane, primary, Carr, Daniel F., additional, Musumba, Crispin O., additional, Penrose, Alexander, additional, Esume, Celestine, additional, Morris, Andrew P., additional, Jorgensen, Andrea L., additional, Zhang, J. Eunice, additional, Pritchard, D. Mark, additional, Deloukas, Panos, additional, and Pirmohamed, Munir, additional

Published
2021
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34. Genome-wide association studies of exacerbations in children using long-acting beta2-agonists

Author

Slob, Elise M.A., Richards, Levi B., Vijverberg, Susanne J.H., Longo, Cristina, Koppelman, Gerard H., Pijnenburg, Mariëlle W.H., Bel, Elisabeth H.D., Neerincx, Anne H., Herrera Luis, Esther, Perez-Garcia, Javier, Tim Chew, Fook, Yie Sio, Yang, Andiappan, Anand K., Turner, Steve W., Mukhopadhyay, Somnath, Palmer, Colin N.A., Hawcutt, Daniel, Jorgensen, Andrea L., Burchard, Esteban G., Hernandez-Pacheco, Natalia, Pino-Yanes, Maria, Maitland-van der Zee, Anke H., Slob, Elise M.A., Richards, Levi B., Vijverberg, Susanne J.H., Longo, Cristina, Koppelman, Gerard H., Pijnenburg, Mariëlle W.H., Bel, Elisabeth H.D., Neerincx, Anne H., Herrera Luis, Esther, Perez-Garcia, Javier, Tim Chew, Fook, Yie Sio, Yang, Andiappan, Anand K., Turner, Steve W., Mukhopadhyay, Somnath, Palmer, Colin N.A., Hawcutt, Daniel, Jorgensen, Andrea L., Burchard, Esteban G., Hernandez-Pacheco, Natalia, Pino-Yanes, Maria, and Maitland-van der Zee, Anke H.

Abstract

Background: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. Methods: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. Results: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10−6) associated with exacerbations despite LABA use. Conclusion: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

Published
2021

35. Genome‐wide association studies of exacerbations in children using long‐acting beta2‐agonists

Author

Slob, Elise M. A., primary, Richards, Levi B., additional, Vijverberg, Susanne J. H., additional, Longo, Cristina, additional, Koppelman, Gerard H., additional, Pijnenburg, Mariëlle W. H., additional, Bel, Elisabeth H. D., additional, Neerincx, Anne H., additional, Herrera Luis, Esther, additional, Perez‐Garcia, Javier, additional, Tim Chew, Fook, additional, Yie Sio, Yang, additional, Andiappan, Anand K., additional, Turner, Steve W., additional, Mukhopadhyay, Somnath, additional, Palmer, Colin N. A., additional, Hawcutt, Daniel, additional, Jorgensen, Andrea L., additional, Burchard, Esteban G., additional, Hernandez‐Pacheco, Natalia, additional, Pino‐Yanes, Maria, additional, and Maitland‐van der Zee, Anke H., additional

Published
2021
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36. A Randomized Trial of Genotype-Guided Dosing of Warfarin

Author

Pirmohamed, Munir, Burnside, Girvan, Eriksson, Niclas, Jorgensen, Andrea L., Toh, Cheng Hock, Nicholson, Toby, Kesteven, Patrick, Christersson, Christina, Wahlström, Bengt, Stafberg, Christina, Zhang, Eunice J., Leathart, Julian B., Kohnke, Hugo, Maitland-van der Zee, Anke H., Williamson, Paula R., Daly, Ann K., Avery, Peter, Kamali, Farhad, and Wadelius, Mia

Published
2013
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37. Developing and Validating a Clinical Warfarin Dose‐Initiation Model for Black‐African Patients in South Africa and Uganda

Author

Asiimwe, Innocent G., primary, Waitt, Catriona, additional, Sekaggya‐Wiltshire, Christine, additional, Hutchinson, Claire, additional, Okello, Emmy, additional, Zhang, Eunice J., additional, Semakula, Jerome R., additional, Mouton, Johannes P., additional, Cohen, Karen, additional, Blockman, Marc, additional, Lamorde, Mohammed, additional, Jorgensen, Andrea L., additional, and Pirmohamed, Munir, additional

Published
2020
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45. Genetic Factors Influencing Warfarin Dose in Black‐African Patients: A Systematic Review and Meta‐Analysis

Author

Asiimwe, Innocent G., primary, Zhang, Eunice J., additional, Osanlou, Rostam, additional, Krause, Amanda, additional, Dillon, Chrisly, additional, Suarez‐Kurtz, Guilherme, additional, Zhang, Honghong, additional, Perini, Jamila A., additional, Renta, Jessicca Y., additional, Duconge, Jorge, additional, Cavallari, Larisa H., additional, Marcatto, Leiliane R., additional, Beasly, Mark T., additional, Perera, Minoli A., additional, Limdi, Nita A., additional, Santos, Paulo C.J.L., additional, Kimmel, Stephen E., additional, Lubitz, Steven A., additional, Scott, Stuart A., additional, Kawai, Vivian K., additional, Jorgensen, Andrea L., additional, and Pirmohamed, Munir, additional

Published
2020
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47. Stable warfarin dose prediction in sub‐Saharan African patients: A machine‐learning approach and external validation of a clinical dose–initiation algorithm.

Author

Asiimwe, Innocent G., Blockman, Marc, Cohen, Karen, Cupido, Clint, Hutchinson, Claire, Jacobson, Barry, Lamorde, Mohammed, Morgan, Jennie, Mouton, Johannes P., Nakagaayi, Doreen, Okello, Emmy, Schapkaitz, Elise, Sekaggya‐Wiltshire, Christine, Semakula, Jerome R., Waitt, Catriona, Zhang, Eunice J., Jorgensen, Andrea L., and Pirmohamed, Munir

Subjects
MEDICAL protocols, AFRICANS, WARFARIN, RANDOM forest algorithms, ANTICOAGULANTS, CONFIDENCE intervals, FORECASTING
Abstract

Warfarin remains the most widely prescribed oral anticoagulant in sub‐Saharan Africa. However, because of its narrow therapeutic index, dosing can be challenging. We have therefore (a) evaluated and compared the performance of 21 machine‐learning techniques in predicting stable warfarin dose in sub‐Saharan Black‐African patients and (b) externally validated a previously developed Warfarin Anticoagulation in Patients in Sub‐Saharan Africa (War‐PATH) clinical dose–initiation algorithm. The development cohort included 364 patients recruited from eight outpatient clinics and hospital departments in Uganda and South Africa (June 2018–July 2019). Validation was conducted using an external validation cohort (270 patients recruited from August 2019 to March 2020 in 12 outpatient clinics and hospital departments). Based on the mean absolute error (MAE; mean of absolute differences between the actual and predicted doses), random forest regression (12.07 mg/week; 95% confidence interval [CI], 10.39–13.76) was the best performing machine‐learning technique in the external validation cohort, whereas the worst performing technique was model trees (17.59 mg/week; 95% CI, 15.75–19.43). By comparison, the simple, commonly used regression technique (ordinary least squares) performed similarly to more complex supervised machine‐learning techniques and achieved an MAE of 13.01 mg/week (95% CI, 11.45–14.58). In summary, we have demonstrated that simpler regression techniques perform similarly to more complex supervised machine‐learning techniques. We have also externally validated our previously developed clinical dose–initiation algorithm, which is being prospectively tested for clinical utility. [ABSTRACT FROM AUTHOR]

Published
2022
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50. ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta‐analysis.

Author

Karimi, Leila, Vijverberg, Susanne J., Engelkes, Marjolein, Hernandez‐Pacheco, Natalia, Farzan, Niloufar, Soares, Patricia, Pino‐Yanes, Maria, Jorgensen, Andrea L., Eng, Celeste, Mukhopadhyay, Somnath, Schieck, Maximilian, Kabesch, Michael, Burchard, Esteban G., Chew, Fook Tim, Sio, Yang Yie, Potočnik, Uroš, Gorenjak, Mario, Hawcutt, Daniel B., Palmer, Colin N., and Turner, Steve

Subjects
ASTHMA in children, YOUNG adults, HAPLOTYPES, TREATMENT effectiveness, ASTHMA
Abstract

Background: The polymorphism Arg16 in β2‐adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long‐acting β2‐agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. Methods: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi‐ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma‐related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta‐analysed using the inverse variance weighting method assuming random‐effects. Results: In subjects treated with ICS and LABA (n = 832, age: 3–21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05–1.87, I2 = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05–1.94, I2 = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71–1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as‐required short‐acting β2‐agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). Conclusion and clinical relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype‐guided treatment which might improve clinical outcomes in asthmatic patients. [ABSTRACT FROM AUTHOR]

Published
2021
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