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BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

Original citation: J Clin Invest. 2024; 134(10):e173278. https://doi.org/10.1172/JCI173278. Citation for this corrigendum: J Clin Invest. 2024;134(16):e185290. https://doi.org/10.1172/JCI185290 During the preparation of this manuscript, Daniel Duprez's information was inadvertently omitted from [...]

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype‐guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6‐months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient‐Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ‐8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug–drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow‐up will be complete in April of 2024. [ABSTRACT FROM AUTHOR]

BACKGROUND. Preclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) -- suggestive of cellular cholesterol accumulation -- were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation. METHODS. Monocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples. RESULTS. During a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes -- ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) -- and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D. CONCLUSION. These data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis. FUNDING. The MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962. [ABSTRACT FROM AUTHOR]

Aim: To survey Veterans Health Administration providers who prescribed tramadol or codeine to patients with known genotyping for cytochrome 2D6 ( CYP2D6 ) to ascertain awareness of their patient's pharmacogenetic (PGx) test status, whether these results influenced prescribing, perceived benefit of PGx testing, and resources needed to obtain and deliver PGx testing information. Materials & methods: A provider survey was conducted of those who prescribed tramadol or codeine in a patient genotyped for CYP2D6 . Results: Of 876 eligible providers, 220 completed the survey. Ten percent were aware that their patient received a PGx test, 64% had not ordered any PGx test related to any medication in the prior year, 55% strongly agreed or agreed that PGx testing is or will be valuable to guide pain medication prescriptions, 29% felt that the evidence base for PGx testing is very strong or moderately strong, 22% responded likely or extremely likely to order a future PGx test, and 51% felt that it would be either very important or fairly important to have a local subject matter expert as a resource for PGx testing. Conclusion: There are modifiable factors that the Veterans Health Administration could address to optimize PGx testing for pain management.

Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5-5.1, p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 -0.94, n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 -0.79, n = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07-3.36; p = 0.027, n = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction., (© 2024. The Author(s).)

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoter to yield isoforms RUNX1 B and C, respectively. The roles of these isoforms in RUNX1 autoregulation and downstream-gene regulation in megakaryocytes and platelets are unknown., Objectives: To understand the regulation of RUNX1 and its target genes by RUNX1 isoforms., Methods: We performed studies on RUNX1 isoforms in megakaryocytic HEL cells and HeLa cells (lack endogenous RUNX1), in platelets from 85 healthy volunteers administered aspirin or ticagrelor, and on the association of RUNX1 target genes with acute events in 587 patients with cardiovascular disease (CVD)., Results: In chromatin immunoprecipitation and luciferase promoter assays, RUNX1 isoforms B and C bound and regulated P1 and P2 promoters. In HeLa cells RUNX1B decreased and RUNX1C increased P1 and P2 activities, respectively. In HEL cells, RUNX1B overexpression decreased RUNX1C and RUNX1A expression; RUNX1C increased RUNX1B and RUNX1A. RUNX1B and RUNX1C regulated target genes ( MYL9, F13A1, PCTP, PDE5A and others) differentially in HEL cells. In platelets RUNX1B transcripts (by RNAseq) correlated negatively with RUNX1C and RUNX1A; RUNX1C correlated positively with RUNX1A. RUNX1B correlated positively with F13A1, PCTP, PDE5A, RAB1B , and others, and negatively with MYL9 . In our previous studies, RUNX1C transcripts in whole blood were protective against acute events in CVD patients. We found that higher expression of RUNX1 targets F13A1 and RAB31 associated with acute events., Conclusions: RUNX1 isoforms B and C autoregulate RUNX1 and regulate downstream genes in a differential manner and this associates with acute events in CVD., Competing Interests: Conflict of Interest Disclosures The authors have no conflicts of interest to declare with respect to this manuscript.

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)