1.
Gottlieb, Assaf, et al.
(författare)
Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans
2017
Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 9:1
Tidskriftsartikel (refereegranskat) abstract
Background: Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects. Methods: Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals. Results: We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Conclusions: Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions. MATLAB code is available at https://github.com/assafgo/warfarin-cohort.
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3.
Eriksson, Niclas, et al.
(författare)
Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range : a RE-LY genomics substudy
2016
Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 17:13, s. 1425-1439
Tidskriftsartikel (refereegranskat) abstract
Aims: We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding. Materials & methods: In total, 982 warfarin-treated patients from the RE-LY trial were studied. Results: After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R-2 by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding. Conclusions: We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.
4.
Hallberg, Pär, et al.
(författare)
Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough
2017
Ingår i: The Annals of Pharmacotherapy. - Thousand Oaks, USA : Sage Publications. - 1060-0280 .- 1542-6270. ; 51:4, s. 293-300
Tidskriftsartikel (refereegranskat) abstract
Background: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema.Objective: We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events.Methods: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons.Results: Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10(-5), and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10(-5) Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10(-4)) and had longer time to onset and higher doses than those with cough (P = 3.2 × 10(-10) and P = 2.6 × 10(-4)). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups.Conclusion: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.
5.
Hallberg, Pär, et al.
(författare)
Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough : a genome-wide association study in a Swedish population
2017
Ingår i: Pharmacogenomics (London). - : FUTURE MEDICINE LTD. - 1462-2416 .- 1744-8042. ; 18:3, s. 201-213
Tidskriftsartikel (refereegranskat) abstract
Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 x 10(-8). Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 x 10(-8)). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.
6.
Parra, Esteban J., et al.
(författare)
Genome-wide association study of warfarin maintenance dose in a Brazilian sample
2015
Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 16:11, s. 1253-1263
Tidskriftsartikel (refereegranskat) abstract
Aim: Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians. Methods: Patients receiving low (<= 20 mg/week; n = 180) or high stable warfarin doses (>= 42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom (R) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project. Results: Genome-wide signals (p <= 5 x 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 x 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 x 10(-13)) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study. Conclusion: We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose.
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