Prevalence of predicted gene-drug interactions for antidepressants in the treatment of major depressive disorder in the Precision Medicine in Mental Health Care Study.

BACKGROUND: Pharmacogenetic (PGx) testing is a potentially important, but understudied approach to precision medicine that could improve prescribing practices for antidepressants (ADs) in patients with Major Depressive Disorder (MDD). Thus, it is important to understand the scope of its potential impact and to identify patients who may benefit most from PGx-guided care. METHODS: Participants were treatment-seeking US veterans (N=1149) with MDD enrolled in the Precision Medicine in Mental Health Care study, a pragmatic multi-site, randomized, controlled trial that examines the utility of PGx testing in the context of pharmacotherapy for MDD. We report the prevalence of ADs with predicted moderate and clinically significant gene-drug interaction potential based on next-intended treatment. We also examined demographic and treatment history characteristics as predictors of the gene-drug interaction potential of participants' next-intended treatment. RESULTS: Prevalence of the next-intended AD with moderate or clinically significant gene-drug interaction was 45.1% and19.3%. Previous treatment with an AD in the past two years was associated with a 1.59 increased likelihood of having a next-intended AD treatment with predicted clinically significant gene-drug interaction (95% CI: 1.08-2.35). LIMITATIONS: The gene-drug interaction potential of ADs is specific to the PGx test panel used in this study and may not generalize to other PGx test panels. CONCLUSIONS: PGx testing could benefit one in five patients prescribed ADs with clinically significant gene-drug interaction potential. Patients with prior AD treatment are more likely to have an AD with significant gene-drug interaction potential as their next-intended treatment and therefore may benefit most from PGx testing.

Gene and microRNA transcriptional signatures of angiotensin II in endothelial cells.

Growth of atherosclerotic plaque requires neovascularization (angiogenesis). To elucidate the involvement of angiotensin II (Ang II) in angiogenesis, we performed gene microarray and microRNA (miRNA) polymerase chain reaction array analyses on human coronary artery endothelial cells exposed to moderate concentration of Ang II for 2 and 12 hours. At 12, but not 2, hours, cultures treated with Ang II exhibited shifts in transcriptional activity involving 267 genes (>1.5-fold difference; P < 0.05). Resulting transcriptome was most significantly enriched for genes associated with blood vessel development, angiogenesis, and regulation of proliferation. Majority of upregulated genes implicated in angiogenesis shared a commonality of being either regulators (HES1, IL-18, and CXCR4) or targets (ADM, ANPEP, HES1, KIT, NOTCH4, PGF, and SOX18) of STAT3. In line with these findings, STAT3 inhibition attenuated Ang II-dependent stimulation of tube formation in Matrigel assay. Expression analysis of miRNAs transcripts revealed that the pattern of differential expression for miRNAs was largely consistent with proangiogenic response with a prominent theme of upregulation of miRs targeting PTEN (miR-19b-3p, miR-21-5p, 23b-3p, and 24-3p), many of which are directly or indirectly STAT3 dependent. We conclude that STAT3 signaling may be an intrinsic part of Ang II-mediated proangiogenic response in human endothelial cells.