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Article ; Online: Warfarin dosing algorithms: A systematic review.

Asiimwe, Innocent G / Zhang, Eunice J / Osanlou, Rostam / Jorgensen, Andrea L / Pirmohamed, Munir

British journal of clinical pharmacology

2020 Volume 87, Issue 4, Page(s) 1717–1729

Abstract: Aims: Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms.: Methods: We ... ...

Abstract	Aims: Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms. Methods: We systematically searched MEDLINE up to 20 May 2020 and selected studies describing the development, external validation or clinical utility of a multivariable warfarin dosing algorithm. Two investigators conducted data extraction and quality assessment. Results: Of 10 035 screened records, 266 articles were included in the review, describing the development of 433 dosing algorithms, 481 external validations and 52 clinical utility assessments. Most developed algorithms were for dose initiation (86%), developed by multiple linear regression (65%) and mostly applicable to Asians (49%) or Whites (43%). The most common demographic/clinical/environmental covariates were age (included in 401 algorithms), concomitant medications (270 algorithms) and weight (229 algorithms) while CYP2C9 (329 algorithms), VKORC1 (319 algorithms) and CYP4F2 (92 algorithms) variants were the most common genetic covariates. Only 26% and 7% algorithms were externally validated and evaluated for clinical utility, respectively, with <2% of algorithm developments and external validations being rated as having a low risk of bias. Conclusion: Most warfarin dosing algorithms have been developed in Asians and Whites and may not be applicable to under-served populations. Few algorithms have been externally validated, assessed for clinical utility, and/or have a low risk of bias which makes them unreliable for clinical use. Algorithm development and assessment should follow current methodological recommendations to improve reliability and applicability, and under-represented populations should be prioritized.
MeSH term(s)	Algorithms ; Anticoagulants/adverse effects ; Cytochrome P-450 CYP2C9/genetics ; Dose-Response Relationship, Drug ; Genotype ; Humans ; Pharmacogenetics ; Reproducibility of Results ; Vitamin K Epoxide Reductases/genetics ; Warfarin/adverse effects
Chemical Substances	Anticoagulants ; Warfarin (5Q7ZVV76EI) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; VKORC1 protein, human (EC 1.17.4.4) ; Vitamin K Epoxide Reductases (EC 1.17.4.4)
Language	English
Publishing date	2020-11-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review ; Systematic Review
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.14608
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Article: A genome-wide association study of plasma concentrations of warfarin enantiomers and metabolites in sub-Saharan black-African patients.

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 / Pirmohamed, Munir

Frontiers in pharmacology

2022 Volume 13, Page(s) 967082

Abstract: Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic ... ...

Abstract	Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained.
Language	English
Publishing date	2022-09-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2022.967082
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Article ; Online: Developing and Validating a Clinical Warfarin Dose-Initiation Model for Black-African Patients in South Africa and Uganda.

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

Clinical pharmacology and therapeutics

2020 Volume 109, Issue 6, Page(s) 1564–1574

Abstract: Warfarin remains the oral anticoagulant of choice in sub-Saharan Africa. However, dosing is challenging due to a highly variable clinical response for a given dose. This study aimed to develop and validate a clinical warfarin dose-initiation model in sub- ...

Abstract	Warfarin remains the oral anticoagulant of choice in sub-Saharan Africa. However, dosing is challenging due to a highly variable clinical response for a given dose. This study aimed to develop and validate a clinical warfarin dose-initiation model in sub-Saharan Black-African patients. For the development cohort, we used data from 364 patients who were recruited from 8 outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was undertaken using the International Warfarin Pharmacogenetics Consortium (IWPC) dataset (690 black patients). Four predictors (age, weight, target International Normalized Ratio range, and HIV status) were included in the final model, which achieved mean absolute errors (MAEs; mean of absolute differences between true dose and dose predicted by the model) of 11.6 (95% confidence interval (CI) 10.4-12.8) and 12.5 (95% CI 11.6-13.4) mg/week in the development and validation cohorts, respectively. Two other clinical models, IWPC and Gage, respectively, obtained MAEs of 12.5 (95% CI 11.3-13.7) and 12.7 (95% CI 11.5-13.8) mg/week in the development cohort, and 12.1 (95% CI 11.2-13.0) and 12.2 (95% CI 11.4-13.1) mg/week in the validation cohort. Compared with fixed dose-initiation, our model decreased the percentage of patients at high risk of suboptimal anticoagulation by 7.5% (1.5-13.7%) and 11.9% (7.1-16.8%) in the development and validation cohorts, respectively. The clinical utility of this model will be tested in a prospective study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ☑ Warfarin dosing remains challenging due to a highly variable clinical response for a given dose. WHAT QUESTION DID THIS STUDY ADDRESS? ☑ Can a clinical dose-initiation model be developed and validated for sub-Saharan Black-African patients? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ☑ We have developed the first warfarin dose-initiation clinical model for Black-African patients in Uganda and South Africa. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ☑ We will be implementing and validating this model in a prospective cohort to inform future large-scale implementation. More optimized dosing should improve the quality of warfarin anticoagulation in these two developing countries.
MeSH term(s)	Adolescent ; Adult ; African Continental Ancestry Group ; Age Factors ; Aged ; Aged, 80 and over ; Body Weight ; Child ; Cohort Studies ; Dose-Response Relationship, Drug ; Female ; HIV Seropositivity ; Humans ; International Normalized Ratio ; Male ; Middle Aged ; Predictive Value of Tests ; Prospective Studies ; Reproducibility of Results ; Sensitivity and Specificity ; South Africa ; Treatment Outcome ; Uganda ; Warfarin/administration & dosage ; Warfarin/adverse effects ; Warfarin/therapeutic use ; Young Adult
Chemical Substances	Warfarin (5Q7ZVV76EI)
Language	English
Publishing date	2020-12-28
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.2128
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Article ; Online: Stable warfarin dose prediction in sub-Saharan African patients: A machine-learning approach and external validation of a clinical dose-initiation algorithm.

CPT: pharmacometrics & systems pharmacology

2021 Volume 11, Issue 1, Page(s) 20–29

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 ... ...

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.
MeSH term(s)	Adult ; Africa South of the Sahara ; Age Factors ; Algorithms ; Anticoagulants/administration & dosage ; Body Weight ; Drug Dosage Calculations ; Female ; HIV Infections/epidemiology ; Humans ; International Normalized Ratio ; Machine Learning ; Male ; Middle Aged ; Models, Biological ; Reproducibility of Results ; Sex Factors ; Simvastatin/administration & dosage ; Warfarin/administration & dosage
Chemical Substances	Anticoagulants ; Warfarin (5Q7ZVV76EI) ; Simvastatin (AGG2FN16EV)
Language	English
Publishing date	2021-12-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12740
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Article ; Online: Genetic associations with clozapine-induced myocarditis in patients with schizophrenia.

Lacaze, Paul / Ronaldson, Kathlyn J / Zhang, Eunice J / Alfirevic, Ana / Shah, Hardik / Newman, Leah / Strahl, Maya / Smith, Melissa / Bousman, Chad / Francis, Ben / Morris, Andrew P / Wilson, Trevor / Rossello, Fernando / Powell, David / Vasic, Vivien / Sebra, Robert / McNeil, John J / Pirmohamed, Munir

Translational psychiatry

2020 Volume 10, Issue 1, Page(s) 37

Abstract: Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced ... ...

Abstract	Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10
MeSH term(s)	Agranulocytosis/drug therapy ; Antipsychotic Agents/adverse effects ; Clozapine/adverse effects ; Genome-Wide Association Study ; Humans ; Myocarditis/chemically induced ; Myocarditis/drug therapy ; Myocarditis/genetics ; Schizophrenia/drug therapy ; Schizophrenia/genetics
Chemical Substances	Antipsychotic Agents ; Clozapine (J60AR2IKIC)
Language	English
Publishing date	2020-01-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-020-0722-0
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Article ; Online: Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis.

Clinical pharmacology and therapeutics

2020 Volume 107, Issue 6, Page(s) 1420–1433

Abstract: Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in ... ...

Abstract	Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C92), rs1057910 (CYP2C93), rs28371686 (CYP2C95), rs9332131 (CYP2C96), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.
MeSH term(s)	Anticoagulants/administration & dosage ; Black People/genetics ; Cytochrome P-450 CYP2C9/genetics ; Dose-Response Relationship, Drug ; Humans ; Polymorphism, Single Nucleotide ; Vitamin K Epoxide Reductases/genetics ; Warfarin/administration & dosage
Chemical Substances	Anticoagulants ; Warfarin (5Q7ZVV76EI) ; CYP2C9 protein, human (EC 1.14.13.-) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; VKORC1 protein, human (EC 1.17.4.4) ; Vitamin K Epoxide Reductases (EC 1.17.4.4)
Language	English
Publishing date	2020-01-28
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Systematic Review
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.1755
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Article ; Online: A multi-factorial analysis of response to warfarin in a UK prospective cohort.

Bourgeois, Stephane / Jorgensen, Andrea / Zhang, Eunice J / Hanson, Anita / Gillman, Matthew S / Bumpstead, Suzannah / Toh, Cheng Hock / Williamson, Paula / Daly, Ann K / Kamali, Farhad / Deloukas, Panos / Pirmohamed, Munir

Genome medicine

2016 Volume 8, Issue 1, Page(s) 2

Abstract: Background: Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors ... ...

Abstract	Background: Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. Methods: A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. Results: VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C93, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. Conclusion:* Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Anticoagulants/administration & dosage ; Cytochrome P-450 CYP2C9/genetics ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P450 Family 4 ; Dose-Response Relationship, Drug ; Female ; Follow-Up Studies ; Genotype ; Humans ; International Normalized Ratio ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Prospective Studies ; Risk Factors ; United Kingdom ; Vitamin K Epoxide Reductases/genetics ; Warfarin/administration & dosage ; Young Adult
Chemical Substances	Anticoagulants ; Warfarin (5Q7ZVV76EI) ; Cytochrome P-450 Enzyme System (9035-51-2) ; CYP2C9 protein, human (EC 1.14.13.-) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; Cytochrome P450 Family 4 (EC 1.14.14.1) ; CYP4F2 protein, human (EC 1.14.14.78) ; VKORC1 protein, human (EC 1.17.4.4) ; Vitamin K Epoxide Reductases (EC 1.17.4.4)
Language	English
Publishing date	2016-01-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-015-0255-y
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Article ; Online: Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study.

Hawcutt, Daniel B / Francis, Ben / Carr, Daniel F / Jorgensen, Andrea L / Yin, Peng / Wallin, Naomi / O'Hara, Natalie / Zhang, Eunice J / Bloch, Katarzyna M / Ganguli, Amitava / Thompson, Ben / McEvoy, Laurence / Peak, Matthew / Crawford, Andrew A / Walker, Brian R / Blair, Joanne C / Couriel, Jonathan / Smyth, Rosalind L / Pirmohamed, Munir

The Lancet. Respiratory medicine

2018 Volume 6, Issue 6, Page(s) 442–450

Abstract: Background: A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression.: Methods: We enrolled children with asthma who ... ...

Abstract	Background: A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression. Methods: We enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a random-effects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing. Findings: Between November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p<1 × 10 Interpretation: Our findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively. Funding: Department of Health Chair in Pharmacogenetics.
MeSH term(s)	Adolescent ; Adrenal Cortex Hormones/administration & dosage ; Adrenal Cortex Hormones/adverse effects ; Adrenal Insufficiency/chemically induced ; Adrenal Insufficiency/genetics ; Adult ; Aged ; Anti-Asthmatic Agents/administration & dosage ; Anti-Asthmatic Agents/adverse effects ; Asthma/drug therapy ; Asthma/genetics ; Case-Control Studies ; Child ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Hydrocortisone/analysis ; Lymphokines/drug effects ; Lymphokines/genetics ; Male ; Middle Aged ; Pharmacogenomic Variants ; Platelet-Derived Growth Factor/drug effects ; Platelet-Derived Growth Factor/genetics ; Polymorphism, Single Nucleotide ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Pulmonary Disease, Chronic Obstructive/genetics ; Young Adult
Chemical Substances	Adrenal Cortex Hormones ; Anti-Asthmatic Agents ; Lymphokines ; PDGFD protein, human ; Platelet-Derived Growth Factor ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2018-03-15
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2686754-0
ISSN	2213-2619 ; 2213-2600
ISSN (online)	2213-2619
ISSN	2213-2600
DOI	10.1016/S2213-2600(18)30058-4
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Article ; Online: Genetic variation in

McCormack, Mark / Gui, Hongsheng / Ingason, Andrés / Speed, Doug / Wright, Galen E B / Zhang, Eunice J / Secolin, Rodrigo / Yasuda, Clarissa / Kwok, Maxwell / Wolking, Stefan / Becker, Felicitas / Rau, Sarah / Avbersek, Andreja / Heggeli, Kristin / Leu, Costin / Depondt, Chantal / Sills, Graeme J / Marson, Anthony G / Auce, Pauls /

Brodie, Martin J / Francis, Ben / Johnson, Michael R / Koeleman, Bobby P C / Striano, Pasquale / Coppola, Antonietta / Zara, Federico / Kunz, Wolfram S / Sander, Josemir W / Lerche, Holger / Klein, Karl Martin / Weckhuysen, Sarah / Krenn, Martin / Gudmundsson, Lárus J / Stefánsson, Kári / Krause, Roland / Shear, Neil / Ross, Colin J D / Delanty, Norman / Pirmohamed, Munir / Carleton, Bruce C / Cendes, Fernando / Lopes-Cendes, Iscia / Liao, Wei-Ping / O'Brien, Terence J / Sisodiya, Sanjay M / Cherny, Stacey / Kwan, Patrick / Baum, Larry / Cavalleri, Gianpiero L

Neurology

2017 Volume 90, Issue 4, Page(s) e332–e341

Abstract: Objective: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs.: Methods: We conducted a case-control genome-wide ... ...

Abstract	Objective: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results: We report an association between a rare variant in the complement factor H-related 4 ( Conclusions: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.
MeSH term(s)	Humans ; Anticonvulsants/adverse effects ; Anticonvulsants/therapeutic use ; Apolipoproteins/genetics ; Asian People/genetics ; Carbamazepine/adverse effects ; Carbamazepine/therapeutic use ; Case-Control Studies ; Complement Factor H/genetics ; Drug Eruptions/ethnology ; Drug Eruptions/etiology ; Drug Eruptions/genetics ; Epilepsy/drug therapy ; Epilepsy/genetics ; Genetic Variation ; Genome-Wide Association Study ; HLA-A Antigens/genetics ; Linkage Disequilibrium ; Mutation, Missense ; Pharmacogenomic Variants ; Phenytoin/adverse effects ; Phenytoin/therapeutic use ; Retrospective Studies ; White People/genetics
Chemical Substances	Anticonvulsants ; Apolipoproteins ; Carbamazepine (33CM23913M) ; CFH protein, human ; CFHR4 protein, human ; Complement Factor H (80295-65-4) ; HLA-A Antigens ; HLA-A*31:01 antigen ; Phenytoin (6158TKW0C5)
Language	English
Publishing date	2017-12-29
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000004853
Database	MEDical Literature Analysis and Retrieval System OnLINE

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