calcium homeostasis; malignant hyperthermia; myopathy; rhabdomyolysis; ryanodine receptor; RYR1; statin; succinylcholine; volatile anesthetics
Abacavir; allopurinol; carbamazepine; HLA-B; HLA-B*15:02; HLA-B*57:01; HLA-B*58:01; pharmacogenetics; PharmGKB; phenytoin
hepatitis C; IFNL3; IL28B; pathway; peginterferon-α; pharmacodynamics; pharmacogenetics; pharmacogenomics
Acetaminophen; paracetamol; NSAIDs; cyclooxygenase; glucuronidation; UGT1A9; UGT1A6; sulfation; oxidation; CYP2E1; GSTP1; drug-induced liver injury; NAPQI; hepatotoxicity; pharmacogenomics; pharmacometabolomics
warfarin; vitamin K; phylloquinone; menaquinone; MK-4; vitamin E; α-tocopherol; arachidonic acid; eicosanoids; pharmacogenomics
Although the field of pharmacogenetics has existed for decades, the implementation of, pharmacogenetic testing in clinical care has been slow. There are numerous publications, describing the barriers to clinical implementation of pharmacogenetics. Recently, several freely, available resources have been developed to help address these barriers. In this review we, discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of, patients. Array-based preemptive testing includes a large number of relevant pharmacogenes, that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to, be available prior to any prescribing decision so that genomic variation may be considered as, an inherent patient characteristic in the planning of therapy. This review describes the common, elements among programs that have implemented preemptive genotyping and highlights key, processes for implementation, including clinical decision support.
Pharmacogenomics; Precision medicine; Individualized medicine; Personalized medicine; Clinical decision support
anesthesia; neuromuscular blocking agents; succinylcholine; prolonged apnea; BCHE deficiency; malignant hyperthermia; hyperkalemia; calcium homeostasis
analgesic; CYP2D6; OCT1; opioids; OPRM1; pathway; pharmacogenomics; pharmacokinetics; tramadol
Efavirenz; CYP2B6; pharmacokinetics; pharmacogenetics
drug transport; OCT1; pharmacogenetics; pharmacogenomics; SLC22A1
drug response; genetic variants; pharmacogenomics; vitamin D receptor
CYP2D6; pharmacogenetics; pharmacogenomics; PharmGKB; polymorphism; variant
cyclooxygenase; CYP2C8; CYP2C9; ibuprofen; nonsteroidal anti-inflammatory drugs; pathway; pharmacogenomics; prostaglandins
CFTR; cystic fibrosis; pharmacogenetics; pharmacodynamics; ivacaftor; potentiator; corrector; modulator
immunosuppressive agents; inosine monophosphate dehydrogenase; mycophenolate mofetil; mycophenolic acid; pharmacogenetics; pharmacogenomics
CYP2C19; CYP2D6; pharmacogenetics; serotonin–norepinephrine reuptake inhibitor; venlafaxine
African Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population‐specific genetic factors influencing the higher VTE rate are not well characterized.
We performed a candidate gene analysis on an exome‐sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP).
In the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case–control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51–15.20; allele frequencies – cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26–4.10).
We found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case–control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population‐specific genetic risk factor for VTE in African Americans.
African American; hypercoagulability; pulmonary embolism; venous thromboembolism
CYP2C8; CYP2C8*3; metabolism; pharmacogenetics; pharmacogenomics; pharmGKB
Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians.
Patients receiving low (≤20 mg/week; n = 180) or high stable warfarin doses (≥42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom® Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project.
Genome-wide signals (p ≤5 × 10−8) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10−33) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 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.
We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose.
1000 Genomes Project; Brazilians; CYP2C9; extreme discordant phenotypes; genome-wide association study; VKORC1; warfarin
breast cancer; pathway; pharmacogenomics; tamoxifen
Gemcitabine; deoxycytidine analogs; pancreatic cancer; non-small cell lung cancer; breast cancer; pharmacogenomics
To comprehensively assess the pharmacogenomic evidence of routinely-used drugs for clinical utility.
From January 2, 2011 to May 31, 2013, we assessed 71 drugs by identifying all drug/genetic variant combinations with published clinical pharmacogenomic evidence. Literature supporting each drug/variant pair was assessed for study design and methodology, outcomes, statistical significance, and clinical relevance. Proposed clinical summaries were formally scored using a modified AGREE (Appraisal of Guidelines for Research and Evaluation) II instrument, including recommendation for or against guideline implementation.
Positive pharmacogenomic findings were identified for 51 of 71 cardiovascular drugs (71.8%) representing 884 unique drug/variant pairs from 597 publications. After analysis for quality and clinical relevance, 92 drug/variant pairs were proposed for translation into clinical summaries, encompassing 23 drugs (32.4% of drugs reviewed). All were found recommended for clinical implementation using AGREE, with average overall quality scores of 5.18 (out of 7.0; range 3.67 to 7.0; SD 0.91). Drug guidelines had highest scores in AGREE domain 1 (Scope) (average 91.9 out of 100; SD 6.1), and moderate but still robust scores in domain 3 (Rigour) (average 73.1; SD 11.1), domain 4 (Clarity) (average 67.8; SD 12.5), and domain 5 (Applicability) (average 65.8; SD 10). The drugs clopidogrel (CYP2C19), metoprolol (CYP2D6), simvastatin (rs4149056), dabigatran (rs2244613), hydralazine (rs1799983, rs1799998), and warfarin (CYP2C9/VKORC1) were distinguished by the highest scores. Eight of the 10 most commonly-prescribed drugs warranted translation guidelines summarizing clinical pharmacogenomic information.
Considerable clinically actionable pharmacogenomic information for cardiovascular drugs exists, supporting the idea that consideration of such information when prescribing is warranted.
etoposide; pathway; pharmacogenetics; pharmacogenomics; pharmGKB
anticancer; drug response; pathway; pharmacogenomics; platinum
Adverse drug reactions; allopurinol; rasburicase; uric acid; uricosurics; pharmacodynamics; pharmacogenetics