Effect of CYP2C19 genetic variants on bleeding and major adverse cardiovascular events in a cohort of Arab patients undergoing percutaneous coronary intervention and stent implantation.

INTRODUCTION: One-third of patients have clopidogrel resistance that may lead to major adverse cardiac events (MACEs). By contrast, it was found that some clopidogrel-treated patients have hyperresponsive platelets that are associated with higher bleeding risk. Several studies have shown that polymorphisms in the gene encoding the CYP2C19 contribute to the variability in response to clopidogrel. Data on genetic and nongenetic factors affecting clopidogrel response in the Arab population are scarce. In this prospective cohort study, we sought to assess the association between the increased function allele (CYP2C19*17) and bleeding events, and validate the effect of the CYP2C19 genetic variants and nongenetic factors on the incidence of MACEs. METHODS: Blood samples were collected from patients that were undergoing percutaneous coronary intervention and receiving clopidogrel at the Heart Hospital, a specialist tertiary hospital in Doha, Qatar. Patients were followed for 12 months. Genotyping was performed for CYP2C19*2, *3, and *17 using TaqMan assays. RESULTS: In 254 patients, the minor allele frequencies were 0.13, 0.004, and 0.21 for *2, *3, and *17, respectively. Over a 12-month follow-up period, there were 21 bleeding events (8.5 events/100 patient-year). CYP2C19*17 carriers were found to be associated with increased risk of bleeding (OR, 21.6; 95% CI, 4.8-96.8; P < 0.0001). CYP2C19*2 or *3 carriers were found to be associated with increased risk of baseline and incident MACE combined (OR, 8.4; 95% CI, 3.2-23.9; P < 0.0001). CONCLUSION: This study showed a significant association between CYP2C19*17 allele and the increased risk of bleeding, and CYP2C19*2 or *3 with MACE outcomes.

The effect of genetic and nongenetic factors on warfarin dose variability in Qatari population.

The objective of this study is to estimate the prevalence of VKORC1, CYP2C9, and CYP4F2 genetic variants and their contribution to warfarin dose variability in Qataris. One hundred and fifty warfarin-treated Qatari patients on a stable dose and with a therapeutic INR for at least three consecutive clinic visits were recruited. Saliva samples were collected using Oragene DNA self-collection kit, followed by DNA purification and genotyping via TaqMan Real-Time-PCR assay. The population was stratified into derivation and validation cohorts for the dosing model. The minor allele frequency (MAF) of VKORC1 (-1639G>A) was A (0.47), while the MAF's for the CYP2C9*2 and *3 and CYP4F2*3 were T (0.12), C (0.04) and T (0.43), respectively. Carriers of at least one CYP2C9 decreased function allele (*2 or *3) required lower median (IQR) warfarin doses compared to noncarriers [24.5 (14.5) mg/week vs. 35 (21) mg/week, p < 0.001]. Similarly, carriers of each additional copy of (A) variant in VKORC1 (-1639G>A) led to reduction in warfarin dose requirement compared to noncarriers [21(7.5) vs. 31.5(18.7) vs. 43.7(15), p < 0.0001]. CYP4F2*3 polymorphism on the other hand was not associated with warfarin dose. Multivariate analysis on the derivation cohort (n = 104) showed that a dosing model consisting of hypertension (HTN), heart failure (HF), VKORC1 (-1639G>A), CYP2C9*2 & *3, and smoking could explain 39.2% of warfarin dose variability in Qataris (P < 0.001). In the validation cohort (n = 45), correlation between predicted and actual warfarin doses was moderate (Spearman's rho correlation coefficient = 0.711, p < 0.001). This study concluded that VKORC1 (-1639G>A), CYP2C9*2 & *3 are the most significant predictors of warfarin dose along with HTN, HF and smoking.

Pharmacogenetic and clinical predictors of response to clopidogrel plus aspirin after acute coronary syndrome in Egyptians.

OBJECTIVES: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the risk for recurrent cardiovascular events after acute coronary syndrome (ACS). However, there is significant variation in response to DAPT that may be influenced by both genetic and nongenetic factors. This study aimed to assess the effect of genetic polymorphisms in PON-1, PEAR-1, P2Y12, CES1, and CYP2C19, along with clinical, demographic, and social factors, on variation in response to DAPT in Egyptians. PARTICIPANTS AND METHODS: This study included 230 Egyptians treated with clopidogrel 75 mg/day and aspirin 81 mg/day for at least 12 months following their first ACS. Simple and multivariable logistic regression analyses were carried out to identify factors associated with major adverse cardiovascular events (MACE), defined as the occurrence of recurrent ACS, ischemic stroke, stent-related revascularization, or death, in clopidogrel-treated participants. RESULTS: Using multivariable logistic regression analysis, the CYP2C19*2 polymorphism was the only genetic predictor of MACE [odds ratio (OR): 2.23, 95% confidence interval (CI): 1.15-4.33, P=0.01]. In addition, proton pump inhibitor use (OR: 4.77, 95% CI: 1.47-15.54, P=0.009) and diabetes (OR: 1.83, 95% CI: 1.03-3.26, P=0.03) were associated with higher cardiovascular risk, whereas statin use was associated with lower risk (OR: 0.43, 95% CI: 0.25-0.76, P=0.003). The contribution of these four genetic and nongenetic factors explained 19% of the variability in risk for MACE in Egyptians treated with DAPT. CONCLUSION: These results highlight that CYP2C19*2, along with diabetes, and use of proton pump inhibitor and statin are important factors jointly associated with variability in clinical response to DAPT following ACS in Egyptians.

Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide.

Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, ß=-1.60, ΔDBP: P=0.023, ß=-1.08) and GERA (ΔSBP: P=0.028, ß=-1.95, ΔDBP: P=0.032, ß=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.

Matrix Metalloproteinase Polymorphisms in Patients with Floppy Mitral Valve/Mitral Valve Prolapse (FMV/MVP) and FMV/MVP Syndrome.

BACKGROUND: It has been suggested that collagen abnormalities of the mitral valve are present in patients with floppy mitral valve (FMV)/mitral valve prolapse (MVP). Genetic factors determining collagen synthesis and degradation have not been well defined in these patients. This study was undertaken to determine whether selective polymorphisms of matrix metalloproteinase-2 (MMP2) or transforming growth factor-ß (TGFß), with known or putative effects on collagen turnover, are more frequent in FMV/MVP. METHODS: Single nucleotide polymorphisms (SNPs) in select genes related to collagen turnover, including MMP2 rs2285053, MMP2 rs243865, TGFß1 rs1800469, and TGFß2 rs900, were determined in 98 patients with FMV/MVP who had severe mitral regurgitation and compared to 99 controls. RESULTS: MMP2 rs243865 was the only SNP significantly associated with FMV/MVP as compared to the control (odds ratio 2.07, 95% CI 1.23-3.50, p = 0.006). MMP2 rs228503 was the only SNP significantly associated with the FMV/MVP syndrome as compared to patients with FMV/MVP without the syndrome (odds ratio 2.41, 95% CI 1.08-5.40, p = 0.032). CONCLUSION: The frequency of certain MMP2 polymorphisms is higher in patients with the FMV/MVP syndrome and patients with FMV/MVP without the syndrome. The data suggest that a genetic predisposition that alters collagen turnover may play a role in the pathogenesis and development of FMV/MVP.

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study.

BACKGROUND: VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. METHODS: We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10(-8) in the discovery cohort and p<0·0038 in the replication cohort. FINDINGS: The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10(-8)). This association was confirmed in the replication cohort (p=5·04×10(-5)); analysis of the two cohorts together produced a p value of 4·5×10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). INTERPRETATION: A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. FUNDING: National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.

Artificial Intelligence: From Buzzword to Useful Tool in Clinical Pharmacology.

The advent of artificial intelligence (AI) in clinical pharmacology and drug development is akin to the dawning of a new era. Previously dismissed as merely technological hype, these approaches have emerged as promising tools in different domains, including health care, demonstrating their potential to empower clinical pharmacology decision making, revolutionize the drug development landscape, and advance patient care. Although challenges remain, the remarkable progress already made signals that the leap from hype to reality is well underway, and AI promises to offer clinical pharmacology new tools and possibilities for optimizing patient care is gradually coming to fruition. This review dives into the burgeoning world of AI and machine learning (ML), showcasing different applications of AI in clinical pharmacology and the impact of successful AI/ML implementation on drug development and/or regulatory decisions. This review also highlights recommendations for areas of opportunity in clinical pharmacology, including data analysis (e.g., handling large data sets, screening to identify important covariates, and optimizing patient population) and efficiencies (e.g., automation, translation, literature curation, and training). Realizing the benefits of AI in drug development and understanding its value will lead to the successful integration of AI tools in our clinical pharmacology and pharmacometrics armamentarium.

Artificial Intelligence for Quantitative Modeling in Drug Discovery and Development: An Innovation and Quality Consortium Perspective on Use Cases and Best Practices.

Recent breakthroughs in artificial intelligence (AI) and machine learning (ML) have ushered in a new era of possibilities across various scientific domains. One area where these advancements hold significant promise is model-informed drug discovery and development (MID3). To foster a wider adoption and acceptance of these advanced algorithms, the Innovation and Quality (IQ) Consortium initiated the AI/ML working group in 2021 with the aim of promoting their acceptance among the broader scientific community as well as by regulatory agencies. By drawing insights from workshops organized by the working group and attended by key stakeholders across the biopharma industry, academia, and regulatory agencies, this white paper provides a perspective from the IQ Consortium. The range of applications covered in this white paper encompass the following thematic topics: (i) AI/ML-enabled Analytics for Pharmacometrics and Quantitative Systems Pharmacology (QSP) Workflows; (ii) Explainable Artificial Intelligence and its Applications in Disease Progression Modeling; (iii) Natural Language Processing (NLP) in Quantitative Pharmacology Modeling; and (iv) AI/ML Utilization in Drug Discovery. Additionally, the paper offers a set of best practices to ensure an effective and responsible use of AI, including considering the context of use, explainability and generalizability of models, and having human-in-the-loop. We believe that embracing the transformative power of AI in quantitative modeling while adopting a set of good practices can unlock new opportunities for innovation, increase efficiency, and ultimately bring benefits to patients.

Clopidogrel and warfarin pharmacogenetic tests: what is the evidence for use in clinical practice?

PURPOSE OF REVIEW: To review the most promising genetic markers associated with the variability in the safety or efficacy of warfarin and clopidogrel and highlight the verification and validation initiatives for translating clopidogrel and warfarin pharmacogenetic tests to clinical practice. RECENT FINDINGS: Rapid advances in pharmacogenetics, continuous decrease in genotyping cost, development of point-of-care devices and the newly established clinical genotyping programs at several institutions hold the promise of individualizing clopidogrel and warfarin based on genotype. Guidelines have been established to assist clinicians in prescribing clopidogrel or warfarin dose based on genotype. However, the clinical utility of clopidogrel and warfarin is still limited. Accordingly, large randomized clinical trials are underway to define the role of clopidogrel and warfarin pharmacogenetics in clinical practice. SUMMARY: Pharmacogenetics has offered compelling evidence toward the individualization of clopidogrel and warfarin therapies. The rapid advances in technology make the clinical implementation of clopidogrel and warfarin pharmacogenetics possible. The clinical genotyping programs and the ongoing clinical trials will help in overcoming some of the barriers facing the clinical implementation of clopidogrel and warfarin pharmacogenetics.

Fesoterodine treatment of pediatric patients with neurogenic detrusor overactivity: A 24-week, randomized, open-label, phase 3 study.

BACKGROUND: Neurogenic detrusor overactivity (NDO) can damage the upper urinary tract leading to chronic renal impairment. Antimuscarinic therapy is used to improve urinary incontinence and protect the upper urinary tract in patients with NDO. OBJECTIVE: This study investigated safety and efficacy of fesoterodine, a muscarinic receptor antagonist, in 6‒<18-year-old patients with NDO (NCT01557244). STUDY DESIGN: This open-label phase 3 study included 2 pediatric cohorts. Patients in Cohort 1 (bodyweight >25 kg) were randomized to fesoterodine 4 or 8 mg extended-release tablets or oxybutynin XL tablets administered over the 12-week active comparator-controlled phase. The safety extension phase evaluated fesoterodine 4 and 8 mg for a further 12 weeks, with patients in the oxybutynin arm allocated to fesoterodine 4 or 8 mg. Patients in Cohort 2 (bodyweight ≤25 kg) were randomized to fesoterodine 2 or 4 mg extended-release beads-in-capsule (BIC) administered over a 12-week efficacy phase and 12-week safety extension phase. Patients with stable neurologic disease and clinically or urodynamically proven NDO were included. The primary endpoint was change from baseline to Week 12 in maximum cystometric bladder capacity (MCC). Secondary efficacy endpoints included detrusor pressure at maximum bladder capacity, bladder volume at first involuntary detrusor contraction, bladder compliance, and incontinence episodes. Safety endpoints included adverse event incidence, and specific assessments of cognition, behavior and vision. The pharmacokinetics of 5-hydroxymethyl tolterodine (5-HMT; fesoterodine's active metabolite) was determined using population-pharmacokinetic analysis. RESULTS: In Cohort 1 (n = 124), fesoterodine 4 and 8 mg treatment resulted in significant increases from baseline in the primary endpoint of MCC at Week 12. In Cohort 2 (n = 57), fesoterodine 2 and 4 mg BIC treatment resulted in improvements in MCC from baseline. Fesoterodine 4 and 8 mg and fesoterodine 4 mg BIC led to improvements in some secondary efficacy endpoints. The most common treatment-related adverse reactions were gastrointestinal effects, such as dry mouth, which occurred more frequently with oxybutynin than fesoterodine. No detrimental effects on visual accommodation or acuity, or on cognitive function or behavior were observed. DISCUSSION: These safety and efficacy results are consistent with limited published data on fesoterodine treatment in pediatric populations with overactive bladder or NDO. Study limitations include the lack of placebo control and the small sample size, which limits the ability to make formal efficacy comparisons and detect rare adverse reactions. CONCLUSION: Fesoterodine has a favorable benefit-risk profile in 6‒<18-year-old patients with NDO and may represent an additional option for pediatric NDO treatment.

Genomewide association analysis of warfarin dose requirements in Middle Eastern and North African populations.

To date, there has been no genomewide association study (GWAS) from the Middle East and North African (MENA) region to identify genetic variants associated with warfarin dose variability using this approach. In this study, we aimed to conduct the first GWAS of warfarin dose requirements in patients from the MENA region. A total of 132 Qatari (discovery) and 50 Egyptians (replication) were genotyped using Illumina Multi-Ethnic Global BeadChip Array. A GWAS was performed on log-transformed weekly warfarin dose in the studied population, adjusting for clinical characteristics and ancestry. The genomewide signals from the discovery cohort were tested in the Egyptian cohort. A GWAS meta-analysis, including the Qatari and Egyptian cohorts, was also performed and the output from this analysis was used in a gene-based analysis. The discovery analysis in Qatari identified five genomewide single-nucleotide polymorphisms (SNPs) in chromosome 16. These signals were replicated in the Egyptian cohort. Combining the two data through a GWAS meta-analysis strengthened the association in chromosome 16 with VKORC1 rs9934438 being the lead genomewide signal (ß = -0.17, 6 × 10-15 ). Other SNPs were identified in chromosome 10 at a p value less than 1 × 10-5 . The genetic variants within VKORC1 rs9934438 and CYP2C9 rs4086116 explained 39% and 27% of the variability in the weekly warfarin dose requirement in the Qatari and Egyptians, respectively. This is the first GWAS of warfarin dose variability in the MENA region. It confirms the importance of VKORC1 and CYP2C9 variants in warfarin dose variability among patients from the MENA region.

Implications of Polymorphisms in the BCKDK and GATA-4 Gene Regions on Stable Warfarin Dose in African Americans.

VKORC1 and CYP2C9 genotypes explain less variability in warfarin dose requirements in African Americans compared with Europeans. Variants in BCKDK and GATA-4 gene regions, purported to regulate VKORC1 and CYP2C9 expression, have been shown to play an important role in warfarin dose requirements in Europeans and Asians, respectively. We sought to determine whether rs56314408 near BCKDK or GATA-4 rs2645400 influence warfarin dose requirements in 200 African Americans. Unlike the strong linkage disequilibrium (LD) between rs56314408 and VKORC1 rs9923231 in Europeans, they were not in LD in African Americans. No associations were found on univariate analysis. On multivariable analysis, rs56314408 was associated (P = 0.027) with dose in a regression model excluding VKORC1 rs9923231, and GATA-4 rs2645400 was associated (P = 0.032) with dose in a model excluding CYP2C (CYP2C9*2, *3, *5, *6, *8, and *11, CYP2C rs12777823) variants. Neither variant contributed to dose in the model that included both VKORC1 rs9923231 and CYP2C variants. Our results do not support contributions of the studied variants to warfarin dose requirements in African Americans. However, they illustrate the value of studies in African descent populations, who have low LD in their genome, in teasing out genetic variation underlying drug response associations. They also emphasize the importance of confirming associations in persons of African ancestry.

Open Data Revolution in Clinical Research: Opportunities and Challenges.

Efforts for sharing individual clinical data are gaining momentum due to a heightened recognition that integrated data sets can catalyze biomedical discoveries and drug development. Among the benefits are the fact that data sharing can help generate and investigate new research hypothesis beyond those explored in the original study. Despite several accomplishments establishing public systems and guidance for data sharing in clinical trials, this practice is not the norm. Among the reasons are ethical challenges, such as privacy of individuals, data ownership, and control. This paper creates awareness of the potential benefits and challenges of sharing individual clinical data, how to overcome these challenges, and how as a clinical pharmacology community we can shape future directions in this field.

Effect of Genetic and Nongenetic Factors on the Clinical Response to Mineralocorticoid Receptor Antagonist Therapy in Egyptians with Heart Failure.

This prospective cohort study evaluated the association between the renin angiotensin aldosterone system genotypes and response to spironolactone in 155 Egyptian patients with heart failure with reduced ejection fraction (HFrEF). Genotype frequencies for AGT rs699 were: CC = 16%, CT = 48%, and TT = 36%. Frequencies for CYP11B2 rs1799998 were: TT = 33%, TC = 50%, and CC = 17%. After 6 months of spironolactone treatment, change in the left ventricular ejection fraction (LVEF) differed by AGT rs699 (CC, 14.6%; TC, 7.9%; TT, 2.7%; P = 2.1E-26), and CYP11B2 rs1799998 (TT, 9.1%; TC, 8.7%; CC, 1.4%; P = 0.0006) genotypes. Multivariate linear regression showed that the AGT rs699 and CYP11B2 rs1799998 polymorphisms plus baseline serum potassium explained 71% of variability in LVEF improvement (P = 0.001), 63% of variability in serum potassium increase (P = 2.25E-08), and 39% of the variability in improvement in quality of life (P = 2.3E-04) with spironolactone therapy. These data suggest that AGT and CYP11B2 genotypes as well as baseline serum K are predictors of spironolactone response in HFrEF.

ß2 -Adrenergic Receptor Gene Affects the Heart Rate Response of ß-Blockers: Evidence From 3 Clinical Studies.

ß-Blockers' heart rate (HR)-lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among ß-blocker-treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to ß-blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single-nucleotide polymorphisms (SNPs) previously associated with the HR response to ß-blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following ß-blocker used in the PEAR (n = 757), PEAR-2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR-2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both ß-blockers in whites (rs1042714 C-allele carriers, meta-analysis ß = -0.95 beats per minute [bpm], meta-analysis P = 3×10-4 ; rs1042713 A-allele carriers, meta-analysis ß = -1.15 bpm, meta-analysis P = 2×10-3 ). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective ß-blockade in hypertensive patient cohorts.

Effect of plasma MicroRNA on antihypertensive response to beta blockers in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies.

ß-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to ß-blockers. Expression of 22 ß-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery). Logistic regression was performed to identify miRNAs significantly associated with metoprolol response. Those miRNAs were profiled in baseline plasma samples from 25 responders and 25 non-responders to atenolol from the PEAR study (validation). In discovery, miR-101, miR-27a, miR-22, miR-19a, and let-7e were significantly associated with metoprolol response (P = 0.01, 0.017, 0.025, 0.025, and 0.04, respectively). In validation, miR-19a was significantly associated with atenolol response (P = 0.038). Meta-analysis between PEAR-2 and PEAR revealed significant association between miR-19a (P = 0.004), miR-101 (P = 0.006), and let-7e (P = 0.012) and ß-blocker response. Hence, miR-19a, miR-101, and let-7e, which regulate ß1-adrenergic receptor and other ß-blocker pharmacodynamics-related genes, may be biomarkers for antihypertensive response to ß-blockers.

Metabolomic association between venous thromboembolism in critically ill trauma patients and kynurenine pathway of tryptophan metabolism.

OBJECTIVE: Incidence of venous thromboembolism (VTE) in critically ill patients remains unacceptably high despite widespread use of thromboprophylaxis. A systems biology approach may be useful in understanding disease pathology and predicting response to treatment. Metabolite profile under specific environmental conditions provides the closest link to phenotype, but the relationship between metabolomics and risk of VTE in critically ill patients is unknown. In this study, metabolomics signatures are compared in patients with and without VTE. DESIGN: Multicenter case-control study using prospectively collected data from the Inflammation and Host Response to Injury program, with pathway and in silico gene expression analyses. SETTING: Eight level 1 US trauma centers. PATIENTS: Critically ill adults with blunt trauma who developed VTE within the first 28 days of hospitalization compared to patients without VTE (N-VTE). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients included in the study (n = 20 VTE, n = 20 N-VTE) were mean age of 34 years, injury severity score of 35, and VTE diagnosed a median of 10.5 days after admission. Global metabolomics revealed two kynurenine metabolites, N-formylkynurenine (AUC = 0.77; 95% CI: 0.59-0.89) and 5-hydroxy-N-formylkynurenine (AUC = 0.80; 95% CI:0.63-0.90) significantly discriminated VTE and N-VTE; ratio between N-formylkynurenine/5-hydroxy-N-formylkynurenine improved predictive power (AUC = 0.87; 95% CI: 0.74-0.95). In the pathway analysis, tryptophan was the only significant metabolic pathway including N-formylkynurenine and 5-hydroxy-N-formylkynurenine (p < 0.001), and 8 proteins directly or indirectly interacted with these metabolites in the interaction network analysis. Of the 8 genes tested in the in silico gene expression analyses, KYNU (p < 0.001), CCBL1 (p < 0.001), and CCBL2 (p = 0.001) were significantly different between VTE and N-VTE, controlling for age and sex. CONCLUSIONS: Two novel kynurenine metabolites in the tryptophan pathway associated with hospital-acquired VTE, and 3 candidate genes were identified via pathway and interaction network analyses. Future studies are warranted to validate these findings in diverse populations using a multi-omics approach.

Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to ß-Blockers.

BACKGROUND: For many indications, the negative chronotropic effect of ß-blockers is important to their efficacy, yet the heart rate (HR) response to ß-blockers varies. Herein, we sought to use a genome-wide association approach to identify novel single nucleotide polymorphisms (SNPs) associated with HR response to ß-blockers. METHODS AND RESULTS: We first performed 4 genome-wide association analyses for HR response to atenolol (a ß1-adrenergic receptor blocker) as: (1) monotherapy or (2) add-on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta-analysis was then performed between the genome-wide association analysis performed in PEAR atenolol monotherapy and add-on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNPs associated with HR response to atenolol at a P<1E-05 were tested for replication in whites (n=200) and blacks (n=168) treated with metoprolol (a ß1-adrenergic receptor blocker). From the genome-wide association meta-analyses, SNP rs17117817 near olfactory receptor family10 subfamily-p-member1 (OR10P1), and SNP rs2364349 in sorting nexin-9 (SNX9) replicated in blacks. The combined studies meta-analysis P values for the rs17117817 and rs2364349 reached genome-wide significance (rs17117817G-allele; Meta-ß=5.53 beats per minute, Meta-P=2E-09 and rs2364349 A-allele; Meta-ß=3.5 beats per minute, Meta-P=1E-08). Additionally, SNPs in the OR10P1 and SNX9 gene regions were also associated with HR response in whites. CONCLUSIONS: This study highlights OR10P1 and SNX9 as novel genes associated with changes in HR in response to ß-blockers. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519.

Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies.

BACKGROUND: Recently, 34 genes had been associated with differential expression relative to blood pressure (BP)/ hypertension (HTN). We hypothesize that some of the genes associated with BP/HTN are also associated with BP response to antihypertensive treatment with thiazide diuretics. METHODS: We assessed these 34 genes for association with differential expression to BP response to thiazide diuretics with RNA sequencing in whole blood samples from 150 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. PEAR white and PEAR-2 white and black participants (n = 50 for each group) were selected based on the upper and lower quartile of BP response to hydrochlorothiazide (HCTZ) and to chlorthalidone. RESULTS: FOS, DUSP1 and PPP1R15A were differentially expressed across all cohorts (meta-analysis p-value < 2.0 × 10- 6), and responders to HCTZ or chlorthalidone presented up-regulated transcripts. Rs11065987 in chromosome 12, a trans-eQTL for expression of FOS, PPP1R15A and other genes, is also associated with BP response to HCTZ in PEAR whites (SBP: ß = - 2.1; p = 1.7 × 10- 3; DBP: ß = - 1.4; p = 2.9 × 10- 3). CONCLUSIONS: These findings suggest FOS, DUSP1 and PPP1R15A as potential molecular determinants of antihypertensive response to thiazide diuretics. TRIAL REGISTRATION: NCT00246519 , NCT01203852 www.clinicaltrials.gov.