Genome-wide association study of warfarin maintenance dose in a Brazilian sample

Parra, Esteban J.; Botton, Mariana Rodrigues; Perini, Jamila Alessandra; Krithika, S.; Bourgeois, Stéphane; Johnson, Todd A.; Tsunoda, Tatsuhiko; Pirmohamed, Munir; Wadelius, Mia; Limdi, Nita A.; Cavallari, Larisa H.; Burmester, James K.; Rettie, Allan E.; Klein, Teri E.; Johnson, Julie A.; Hutz, Mara H.; Suarez‐Kurtz, Guilherme

doi:10.2217/pgs.15.73

Cited by 34 publications

(37 citation statements)

References 40 publications

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“…These associations were also confirmed by several genome-wide studies [Takeuchi et al, 2009;Perera et al, 2013;Parra et al, 2015].…”

Section: B23 Combination Of Polymorphisms That Influence Pharmacoksupporting

confidence: 69%

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

et al. 2017

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“…These associations were also confirmed by several genome-wide studies [Takeuchi et al, 2009;Perera et al, 2013;Parra et al, 2015].…”

Section: B23 Combination Of Polymorphisms That Influence Pharmacoksupporting

confidence: 69%

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

et al. 2017

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“…Furthermore, a GWAS with larger sample-size (Takeuchi et al, 2009) also discovered an additional locus with relatively small-effect ( CYP4F2 = 1.1%); this CYP4F2 polymorphism, however, has not been included in most dosing algorithms (Johnson et al, 2011; Pirmohamed, Kamali, Daly, & Wadelius, 2015). GWAS have also identified similar genetic determinants involving other coumarin anticoagulants (Teichert et al, 2009), as well as in several different ethnic groups (Cha et al,2010; Parra et al, 2015; Perera et al, 2013). …”

Section: Genetic Studies Of Pgx Traitsmentioning

confidence: 91%

Personalized medicine: Genetic risk prediction of drug response

Zhang

Nebert

2017

Pharmacology & Therapeutics

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Pharmacogenomics (PGx), a substantial component of “personalized medicine”, seeks to understand each individual's genetic composition to optimize drug therapy reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants. [b] Predominantly oligogenic traits represent variation largely influenced by a small number of major pharmacokinetic or pharmacodynamic genes. [c] Complex PGx traits resemble most multifactorial quantitative traits –– influenced by numerous small-effect variants, together with epigenetic effects and environmental factors. Prediction of monogenic drug responses is relatively simple, involving detection of underlying mutations; due to rarity of these events and incomplete penetrance, however, prospective tests based on genotype will have high false-positive rates, plus pharmacoeconomics will require justification. Prediction of predominantly oligogenic traits is slowly improving. Although a substantial fraction of variation can be explained by limited numbers of large-effect genetic variants, uncertainty in successful predictions and overall cost-benefit ratios will make such tests elusive for everyday clinical use. Prediction of complex PGx traits is almost impossible in the foreseeable future. Genome-wide association studies of large cohorts will continue to discover relevant genetic variants; however, these small-effect variants, combined, explain only a small fraction of phenotypic variance –– thus having limited predictive power and clinical utility.

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“…Conversely, rs2860905 is a strong genetic predictor of warfarin dose requirements that is relevant for all Puerto Ricans, independently of their ancestral contributions. These haplotypes contain other variants identified by ClinVar as drug-response alleles ( CYP2C9 * 8 and rs4917639) based on sustained evidence that showed their association with warfarin response (Scott et al, 2009; Parra et al, 2015; Landrum et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

“…GWAS conducted in Brazilians and Europeans have identified two other variants in CYP2C9 associated with warfarin dose requirements that are in LD with rs2860905. The top genome-wide signals were CYP2C9 rs9332238 and rs4917639 in the warfarin-treated Brazilians and Europeans cohorts respectively (Takeuchi et al, 2009; Parra et al, 2015). Therefore, these variants reflected a combined CYP2C9 * 2 and * 3 effect in the cited Brazilian and European studies.…”

Section: Discussionmentioning

confidence: 99%

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study

Claudio‐Campos

Labastida²,

Ramos

et al. 2017

Front. Pharmacol.

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Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.

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Genome-wide association study of warfarin maintenance dose in a Brazilian sample

Cited by 34 publications

References 40 publications

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

Personalized medicine: Genetic risk prediction of drug response

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study

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