Modest effect of statins on fasting glucose in a longitudinal electronic health record based cohort.

BACKGROUND: Prior studies of the glycemic effect of statins have been inconsistent. Also, most studies have only considered a short duration of statin use; the effect of long-term statin use on fasting glucose (FG) has not been well examined. The aim of this work is to investigate the effect of long-term statin exposure on FG levels. METHODS: Using electronic health record (EHR) data from a large and diverse longitudinal cohort, we defined long-term statin exposure in two ways: the cumulative years of statin use (cumulative supply) and the years' supply-weighted sum of doses (cumulative dose). Simvastatin, lovastatin, atorvastatin and pravastatin were included in the analysis. The relationship between statin exposure and FG was examined using linear regression with mixed effects modeling, comparing statin users before and after initiating statins and statin never-users. RESULTS: We examined 593,130 FG measurements from 87,151 individuals over a median follow up of 20 years. Of these, 42,678 were never-users and 44,473 were statin users with a total of 730,031 statin prescriptions. FG was positively associated with cumulative supply of statin but not comulative dose when both measures were in the same model. While statistically significant, the annual increase in FG attributable to statin exposure was modest at only 0.14 mg/dl, with only slight and non-significant differences among statin types. CONCLUSIONS: Elevation in FG level is associated with statin exposure, but the effect is modest. The results suggest that the risk of a clinically significant increase in FG attributable to long-term statin use is small for most individuals.

Torsade de pointes: A nested case-control study in an integrated healthcare delivery system.

BACKGROUND: TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia. OBJECTIVE: Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real-world healthcare setting. METHODS: Case-control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow-up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018. RESULTS: A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non-white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in-hospital and 1-year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively. CONCLUSIONS: These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.

Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system.

OBJECTIVE: To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment. METHODS: A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response. RESULTS: Among 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin. CONCLUSION: CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.

Association between the EPHX2 p.Lys55Arg polymorphism and prognosis following an acute coronary syndrome.

Inhibition of soluble epoxide hydrolase (sEH, EPHX2) elicits potent cardiovascular protective effects in preclinical models of ischemic cardiovascular disease (CVD), and genetic polymorphisms in EPHX2 have been associated with developing ischemic CVD in humans. However, it remains unknown whether EPHX2 variants are associated with prognosis following an ischemic CVD event. We evaluated the association between EPHX2 p.Lys55Arg and p.Arg287Gln genotype with survival in 667 acute coronary syndrome (ACS) patients. No association with p.Arg287Gln genotype was observed (P = 0.598). Caucasian EPHX2 Arg55 carriers (Lys/Arg or Arg/Arg) had a significantly higher risk of 5-year mortality (adjusted hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.01-2.55, P = 0.045). In an independent population of 2712 ACS patients, this association was not replicated (adjusted HR 0.92, 95% CI 0.70-1.21, P = 0.559). In a secondary analysis, Caucasian homozygous Arg55 allele carriers (Arg/Arg) appeared to exhibit a higher risk of cardiovascular mortality (adjusted HR 2.60, 95% CI 1.09-6.17). These results demonstrate that EPHX2 p.Lys55Arg and p.Arg287Gln polymorphisms do not significantly modify survival after an ACS event. Investigation of other sEH metabolism biomarkers in ischemic CVD appears warranted.

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study.

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.

Epoxyeicosatrienoic acids and cardioprotection: the road to translation.

Cardiovascular disease, including acute myocardial infarction (AMI), is the leading cause of morbidity and mortality globally, despite well-established treatments. The discovery and development of novel therapeutics that prevent the progression of devastating consequences following AMI are thus important in reducing the global burden of this devastating disease. Scientific evidence for the protective effects of epoxyeicosatrienoic acids (EETs) in the cardiovascular system is rapidly emerging and suggests that promoting the effects of these cytochrome P450-derived epoxyeicosanoids is a potentially viable clinical therapeutic strategy. Through a translational lens, this review will provide insight into the potential clinical utility of this therapeutic strategy for AMI by 1) outlining the known cardioprotective effects of EETs and underlying mechanisms demonstrated in preclinical models of AMI with a particular focus on myocardial ischemia-reperfusion injury, 2) describing studies in human cohorts that demonstrate a relationship between EETs and associated pathways with coronary artery disease risk, and 3) discussing preclinical and clinical areas that require further investigation in order to increase the probability of successfully translating this rapidly emerging body of evidence into a clinically applicable therapeutic strategy for AMI.

X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction.

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

Dual modulation of cyclooxygenase and CYP epoxygenase metabolism and acute vascular inflammation in mice.

Cyclooxygenase (COX)-derived prostaglandins and cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids are important regulators of inflammation; however, functional interactions between these pathways in the regulation of vascular inflammation in vivo have not been studied. We investigated the relative and additive effects of endothelial CYP2J2 overexpression (Tie2-CYP2J2-Tr), global sEH disruption (Ephx2(-/-)), and pharmacologic COX inhibition with indomethacin on the acute vascular inflammatory response to endotoxin in mice. Compared to vehicle-treated wild-type C57BL/6 controls, induction of myeloperoxidase (MPO) activity in lung and liver was similarly attenuated in Tie2-CYP2J2-Tr mice, Ephx2(-/-) mice and wild-type mice treated with moderate dose indomethacin. Dual modulation of both pathways, however, did not produce an additive anti-inflammatory effect. These findings demonstrate that both COX and CYP epoxygenase-mediated eicosanoid metabolism are important regulators of the acute vascular inflammatory response in vivo, and suggest that the anti-inflammatory effects of modulating each pathway may be mediated, at least in part, by overlapping mechanisms.

Advancing CYP2D6 Pharmacogenetics through a Pharmacoequity Lens.

Over 20% of US Food and Drug Administration (FDA)-approved drugs in the United States are metabolized by the hepatic enzyme cytochrome P450 2D6 (CYP2D6). The gene encoding CYP2D6 is highly polymorphic and genetic variation has been shown to impact drug response for many commonly dispensed drugs including opioids and antidepressants. Thus, it is important to understand an individual's CYP2D6 metabolizer status to optimize treatment outcomes for patients taking medications that are metabolized by this enzyme. Consequently, clinical CYP2D6 pharmacogenetic testing is being implemented by a growing number of health centers. Furthermore, clinical guidelines currently recommend adapting therapeutic regimens based on CYP2D6 genotype-informed phenotype. However, CYP2D6 genetic variation varies considerably across global populations and many allelic variants, or star alleles, are predominantly found in certain ancestral populations. Although CYP2D6 genetic variation has been extensively studied, there is still a paucity of information for many non-European populations. As has been shown for other pharmacogenes in randomized controlled trials, results from European populations cannot simply be extrapolated to other groups and, in some cases, even has the potential to cause harm. Therefore, enhanced inclusion in pharmacogenetic studies is urgently needed to increase ancestral representation, determine the extent of global CYP2D6 genetic variation (e.g., ancestry-specific variants), and determine the clinical impact of this variation on clinical treatment outcome. This review highlights knowledge gaps, challenges, and future directions in CYP2D6 pharmacogenomics through a unique pharmacoequity lens to address health inequities that hamper our ability to optimize drug therapy for improved pharmacological outcomes in diverse populations globally.

Development and application of an algorithm for statin-induced myopathy based on electronic health record-derived structured elements.

Objective: Considering the non-specific nature of muscle symptoms, studies of statin-induced myopathy (SIM) in electronic health records require accurate algortihms that can reliably identify true statin-related cases. However, prior algorithms have been constructed in study populations that preclude broad applicability. Here we developed and validated an algorithm that accurately defines SIM from electronic health records using structured data elements and conducted a study of determinants of SIM after applying the algorithm. Materials and Methods: We used electronic records from an integrated health care delivery system (including comprehensive pharmacy dispensing records) and defined SIM as elevated creatine kinase (CK) ≥4 x upper limit of normal. A diverse cohort of participants receiving a variety of statin regimens met the criteria for study inclusion. Results: We identified multiple conditions strongly associated with elevated CK independent of statin use. A 2-step algorithm was developed using these all-cause conditions as secondary causes (step 1) along with evidence of a statin regimen change (step 2). We identified 1,262 algorithm-derived statin-induced elevated CK cases. Gold standard SIM cases determined from manual chart reviews on a random subset of the all-cause elevated CK cases were used to validate the algorithm, which had a 76% sensitivity and 77% specificity for detecting the most certain cases. Pravastatin use was associated with a 2.18 odds (95% confidence interval 1.39-3.40, P=0.0007) for statin-induced CK elevation compared to lovastatin use after adjusting for dose and other factors. Conclusions: We have produced an efficient, easy-to-apply methodological tool that can improve the quality of future research on statin-induced myopathy.

SLCO1B1 functional variants and statin-induced myopathy in people with recent genealogical ancestors from Africa: a population-based real-world study.

Background: Clinical pharmacogenetic implementation guidelines for statin therapy are derived from evidence of primarily Eurocentric study populations. Functional SLCO1B1 variants that are rare in these study populations have not been investigated as a determinant of statin myotoxicity and are thus missing from guideline inclusion. Objective: Determine the relationship between candidate functional SLCO1B1 variants and statin-induced myopathy in people with recent genealogical ancestors from Africa. Design: Population-based pharmacogenetic study using real-world evidence from electronic health record-linked biobanks. Setting: Various health care settings. Participants: Self-identified white and Black statin users with genome-wide genotyping data available. Measurements: Primarily, the odds of statin-induced myopathy + rhabdomyolysis. Secondarily, total bilirubin levels. Thirdly, cell-based functional assay results. Results: Meta-analyses results demonstrated an increased risk of statin-induced myopathy + rhabdomyolysis with c.481+1G>T (odds ratio [OR] = 3.27, 95% confidence interval [CI] 1.43-7.46, P =.005) and c.1463G>C (OR = 2.45, 95% CI 1.04-5.78, P =.04) for Black participants. For White participants, c.521T>C was also significantly associated with increased risk of statin-induced myopathy + rhabdomyolysis (OR = 1.41, 95% CI 1.20-1.67, P =5.4x10 -5 ). This effect size for c.521T>C was similar in the Black participants, but did not meet the level of statistical significance (OR = 1.47, 95% CI 0.58-3.73, P =0.41). Supporting evidence using total bilirubin as an endogenous biomarker of SLCO1B1 function as well as from cell-based functional studies corroborated these findings. Limitations: Data limited to severe statin myotoxicity events. Conclusion: Our findings implicate Afrocentric SLCO1B1 variants on preemptive pharmacogenetic testing panels, which could have an instant impact on reducing the risk of statin-associated myotoxicity in historically excluded groups. Primary Funding Source: National Institutes of Health, Office of the Director - All of Us (OD-AoURP).

Diversity in Clinical Pharmacology: A Call to Action.

Prioritization of diversity, equity, and inclusion in all facets of our work is long overdue for the clinical pharmacology community. Increasing diversity in clinical research will deepen our understanding of nuanced patient populations and help improve all patient outcomes. Fostering an inclusive and diverse workforce will lead to broader perspectives that can better inform critical decisions and create work environments where everyone can thrive. In this call to action, we invite you to join us.

Preferences and Perspectives of Black Male Barbershop Patrons on Receiving Health Care in Nontraditional Settings.

Introduction: Non-Hispanic Black men experience a disproportionate rate of morbidity and mortality from hypertension, cardiovascular disease, and other chronic conditions in the United States. Studies have demonstrated the efficacy of community-based health outreach in settings not traditionally utilized for health care. Understanding how potential future participants view health care services in nontraditional settings is a necessary step to ascertain the success of these interventions in the real world. Our study objective was to explore the preferences of Black male barbershop patrons regarding health care-provided services in these nontraditional settings. Methods: We recruited patrons of a Black-owned barbershop in the San Francisco Bay Area. Study participants were asked to complete a survey assessing individual attitudes and preferences toward the idea of receiving health care services in traditional and nontraditional settings. Results: Among non-Hispanic Black males (n=17), 81% agreed or strongly agreed that they would prefer to receive health care in traditional clinics. Receiving care at the pharmacy (56% agreed or strongly agreed) and the patient's own home (53% agreed or strongly agreed) were the next most preferred locations. A minority of participants agreed or strongly agreed that they preferred to receive health care in nontraditional settings: 47% for barbershops, 19% for churches, and 6% for grocery stores. Discussion: Participants expressed preference for traditional over nontraditional settings, despite listing barriers that may be addressed, in part, by nontraditional settings. One potential reason for this is simply a lack of familiarity. Establishing and normalizing nontraditional clinical settings may allow for enhanced acceptance within Black communities, ultimately increasing health care access.

An Introductory Tutorial on Cardiovascular Pharmacogenetics for Healthcare Providers.

Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of cardiovascular diseases. One of the major barriers to the clinical implementation of cardiovascular pharmacogenetics is limited education on this field for current healthcare providers and students. The abundance of pharmacogenetic literature underscores its promise, but it can also be challenging to learn such a wealth of information. Moreover, current clinical recommendations for cardiovascular pharmacogenetics can be confusing because they are outdated, incomplete, or inconsistent. A myriad of misconceptions about the promise and feasibility of cardiovascular pharmacogenetics among healthcare providers also has halted clinical implementation. Therefore, the main goal of this tutorial is to provide introductory education on the use of cardiovascular pharmacogenetics in clinical practice. The target audience is any healthcare provider (or student) with patients that use or have indications for cardiovascular drugs. This tutorial is organized into the following 6 steps: (1) understand basic concepts in pharmacogenetics; (2) gain foundational knowledge of cardiovascular pharmacogenetics; (3) learn the different organizations that release cardiovascular pharmacogenetic guidelines and recommendations; (4) know the current cardiovascular drugs/drug classes to focus on clinically and the supporting evidence; (5) discuss an example patient case of cardiovascular pharmacogenetics; and (6) develop an appreciation for emerging areas in cardiovascular pharmacogenetics. Ultimately, improved education among healthcare providers on cardiovascular pharmacogenetics will lead to a greater understanding for its potential in improving outcomes for a leading cause of morbidity and mortality.

Metformin Cessation and Dementia Incidence.

Importance: Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends. Cessation of metformin therapy in people with diabetes typically occurs due to signs of kidney dysfunction but sometimes is due to less serious adverse effects associated with metformin. Objective: To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence. Design, Setting, and Participants: This cohort study was conducted at Kaiser Permanente Northern California, a large integrated health care delivery system, among a cohort of metformin users born prior to 1955 without history of diagnosed kidney disease at metformin initiation. Dementia follow-up began with the implementation of electronic health records in 1996 and continued to 2020. Data were analyzed from November 2021 through September 2023. Exposures: A total of 12 220 early terminators, individuals who stopped metformin with normal estimated glomerular filtration rate (eGFR), were compared with routine metformin users, who had not yet terminated metformin treatment or had terminated (with or without restarting) after their first abnormal eGFR measurement. Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration. Main outcomes and measures: The outcome of interest was all-cause incident dementia. Follow-up for early terminators and their matched routine users was started at age of termination for the early terminator. Survival models adjusted for sociodemographic characteristics and comorbidities at the time of metformin termination (or matched age). Mediation models with HbA1c level and insulin usage 1 and 5 years after termination tested whether changes in blood glucose or insulin usage explained associations between early termination of metformin and dementia incidence. Results: The final analytic sample consisted of 12 220 early terminators (5640 women [46.2%]; mean [SD] age at start of first metformin prescription, 59.4 [9.0] years) and 29 126 routine users (13 582 women [46.6%]; mean [SD] age at start of first metformin prescription, 61.1 [8.9] years). Early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users (hazard ratio, 1.21; 95% CI, 1.12 to 1.30). In mediation analysis, contributions to this association by changes in HbA1c level or insulin use ranged from no contribution (0.00 years; 95% CI, -0.02 to 0.02 years) for insulin use at 5 years after termination to 0.07 years (95% CI, 0.02 to 0.13 years) for HbA1c level at 1 year after termination, suggesting that the association was largely independent of changes in HbA1c level and insulin usage. Conclusions and Relevance: In this study, terminating metformin treatment was associated with increased dementia incidence. This finding may have important implications for clinical treatment of adults with diabetes and provides additional evidence that metformin is associated with reduced dementia risk.

Low- and High-Density Lipoprotein Cholesterol and Dementia Risk Over 17 Years of Follow-up Among Members of a Large Health Care Plan.

BACKGROUND AND OBJECTIVES: The associations of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) with dementia risk in later life may be complex, and few studies have sufficient data to model nonlinearities or adequately adjust for statin use. We evaluated the observational associations of HDL-C and LDL-C with incident dementia in a large and well-characterized cohort with linked survey and electronic health record (EHR) data. METHODS: Kaiser Permanente Northern California health plan members aged 55 years and older who completed a health behavior survey between 2002 and 2007, had no history of dementia before the survey, and had laboratory measurements of cholesterol within 2 years after survey completion were followed up through December 2020 for incident dementia (Alzheimer disease-related dementia [ADRD]; Alzheimer disease, vascular dementia, and/or nonspecific dementia) based on ICD-9 or ICD-10 codes in EHRs. We used Cox models for incident dementia with follow-up time beginning 2 years postsurvey (after cholesterol measurement) and censoring at end of membership, death, or end of study period. We evaluated nonlinearities using B-splines, adjusted for demographic, clinical, and survey confounders, and tested for effect modification by baseline age or prior statin use. RESULTS: A total of 184,367 participants [mean age at survey = 69.5 years, mean HDL-C = 53.7 mg/dL (SD = 15.0), mean LDL-C = 108 mg/dL (SD = 30.6)] were included. Higher and lower HDL-C values were associated with elevated ADRD risk compared with the middle quantile: HDL-C in the lowest quintile was associated with an HR of 1.07 (95% CI 1.03-1.11), and HDL-C in the highest quintile was associated with an HR of 1.15 (95% CI 1.11-1.20). LDL-C was not associated with dementia risk overall, but statin use qualitatively modified the association. Higher LDL-C was associated with a slightly greater risk of ADRD for statin users (53% of the sample, HR per 10 mg/dL increase = 1.01, 95% CI 1.01-1.02) and a lower risk for nonusers (HR per 10 mg/dL increase = 0.98; 95% CI 0.97-0.99). There was evidence for effect modification by age with linear HDL-C (p = 0.003) but not LDL-C (p = 0.59). DISCUSSION: Both low and high levels of HDL-C were associated with elevated dementia risk. The association between LDL-C and dementia risk was modest.

Gene expression in African Americans, Puerto Ricans and Mexican Americans reveals ancestry-specific patterns of genetic architecture.

We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities.

Enalapril reverses high-fat diet-induced alterations in cytochrome P450-mediated eicosanoid metabolism.

Metabolism of arachidonic acid by cytochrome P450 (CYP) to biologically active eicosanoids has been recognized increasingly as an integral mediator in the pathogenesis of cardiovascular and metabolic disease. CYP epoxygenase-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET + DHET) and CYP ω-hydroxylase-derived 20-hydroxyeicosatetraenoic acid (20-HETE) exhibit divergent effects in the regulation of vascular tone and inflammation; thus, alterations in the functional balance between these parallel pathways in liver and kidney may contribute to the pathogenesis and progression of metabolic syndrome. However, the impact of metabolic dysfunction on CYP-mediated formation of endogenous eicosanoids has not been well characterized. Therefore, we evaluated CYP epoxygenase (EET + DHET) and ω-hydroxylase (20-HETE) metabolic activity in liver and kidney in apoE(-/-) and wild-type mice fed a high-fat diet, which promoted weight gain and increased plasma insulin levels significantly. Hepatic CYP epoxygenase metabolic activity was significantly suppressed, whereas renal CYP ω-hydroxylase metabolic activity was induced significantly in high-fat diet-fed mice regardless of genotype, resulting in a significantly higher 20-HETE/EET + DHET formation rate ratio in both tissues. Treatment with enalapril, but not metformin or losartan, reversed the suppression of hepatic CYP epoxygenase metabolic activity and induction of renal CYP ω-hydroxylase metabolic activity, thereby restoring the functional balance between the pathways. Collectively, these findings suggest that the kinin-kallikrein system and angiotensin II type 2 receptor are key regulators of hepatic and renal CYP-mediated eicosanoid metabolism in the presence of metabolic syndrome. Future studies delineating the underlying mechanisms and evaluating the therapeutic potential of modulating CYP-derived EETs and 20-HETE in metabolic diseases are warranted.

A large genome-wide association study of QT interval length utilizing electronic health records.

QT interval length is an important risk factor for adverse cardiovascular outcomes; however, the genetic architecture of QT interval remains incompletely understood. We conducted a genome-wide association study of 76,995 ancestrally diverse Kaiser Permanente Northern California members enrolled in the Genetic Epidemiology Research on Adult Health and Aging cohort using 448,517 longitudinal QT interval measurements, uncovering 9 novel variants, most replicating in 40,537 individuals in the UK Biobank and Population Architecture using Genomics and Epidemiology studies. A meta-analysis of all 3 cohorts (n = 117,532) uncovered an additional 19 novel variants. Conditional analysis identified 15 additional variants, 3 of which were novel. Little, if any, difference was seen when adjusting for putative QT interval lengthening medications genome-wide. Using multiple measurements in Genetic Epidemiology Research on Adult Health and Aging increased variance explained by 163%, and we show that the ≈6 measurements in Genetic Epidemiology Research on Adult Health and Aging was equivalent to a 2.4× increase in sample size of a design with a single measurement. The array heritability was estimated at ≈17%, approximately half of our estimate of 36% from family correlations. Heritability enrichment was estimated highest and most significant in cardiovascular tissue (enrichment 7.2, 95% CI = 5.7-8.7, P = 2.1e-10), and many of the novel variants included expression quantitative trait loci in heart and other relevant tissues. Comparing our results to other cardiac function traits, it appears that QT interval has a multifactorial genetic etiology.