Browsing by Subject "Genomic medicine"

Now showing 1 - 3 of 3
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    Analysis of the Combined Effect of rs699 and rs5051 on Angiotensinogen Expression and Hypertension
    (bioRxiv, 2023-04-08) Powell, Nicholas R.; Shugg, Tyler; Leighty, Jacob; Martin, Matthew; Kreutz, Rolf P.; Eadon, Michael T.; Lai, Dongbing; Lu, Tao; Skaar, Todd C.; Medicine, School of Medicine
    Hypertension (HTN) involves genetic variability in the renin-angiotensin system and characterizing this variability will help advance precision antihypertensive treatments. We previously reported that angiotensinogen (AGT) mRNA is endogenously bound by mir-122-5p and that rs699 A>G significantly decreases reporter mRNA in the functional mirSNP assay PASSPORT-seq. The AGT promoter variant rs5051 C>T is in linkage disequilibrium (LD) with rs699 A>G and increases AGT transcription. We hypothesized that the increased AGT by rs5051 C>T counterbalances AGT decrease by rs699 A>G, and when these variants occur independently, would translate to HTN-related phenotypes. The independent effect of each of these variants is understudied due to their LD, therefore, we used in silico, in vitro, in vivo, and retrospective clinical and biobank analyses to assess HTN and AGT expression phenotypes where rs699 A>G occurs independently from rs5051 C>T. In silico, rs699 A>G is predicted to increase mir-122-5p binding strength by 3%. Mir-eCLIP assay results show that rs699 is 40-45 nucleotides from the strongest microRNA binding site in the AGT mRNA. Unexpectedly, rs699 A>G increases AGT mRNA in a plasmid cDNA HepG2 expression model. GTEx and UK Biobank analyses demonstrate that liver AGT expression and HTN phenotypes were not different when rs699 A>G occurs independently from rs5051 C>T, allowing us to reject the original hypothesis. However, both GTEx and our in vitro experiments suggest rs699 A>G confers cell-type specific effects on AGT mRNA abundance. We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a 4-fold larger effect than in White participants. Further studies are warranted to determine if the altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.
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    Defining the clinical validity of genes reported to cause pulmonary arterial hypertension
    (Elsevier, 2023) Welch, Carrie L.; Aldred, Micheala A.; Balachandar, Srimmitha; Dooijes, Dennis; Eichstaedt, Christina A.; Gräf, Stefan; Houweling, Arjan C.; Machado, Rajiv D.; Pandya, Divya; Prapa, Matina; Shaukat, Memoona; Southgate, Laura; Tenorio-Castano, Jair; ClinGen PH VCEP; Chung, Wendy K.; International Consortium for Genetic Studies in Pulmonary Arterial Hypertension (PAH-ICON) at the Pulmonary Vascular Research Institute (PVRI); Medicine, School of Medicine
    Purpose: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing. Methods: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence. Results: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time. Conclusion: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.
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    Strategies to Integrate Genomic Medicine into Clinical Care: Evidence from the IGNITE Network
    (MDPI, 2021-07-08) Sperber, Nina R.; Dong, Olivia M.; Roberts, Megan C.; Dexter, Paul; Elsey, Amanda R.; Ginsburg, Geoffrey S.; Horowitz, Carol R.; Johnson, Julie A.; Levy, Kenneth D.; Ong, Henry; Peterson, Josh F.; Pollin, Toni I.; Rakhra-Burris, Tejinder; Ramos, Michelle A.; Skaar, Todd C.; Orlando, Lori A.; Medicine, School of Medicine
    The complexity of genomic medicine can be streamlined by implementing some form of clinical decision support (CDS) to guide clinicians in how to use and interpret personalized data; however, it is not yet clear which strategies are best suited for this purpose. In this study, we used implementation science to identify common strategies for applying provider-based CDS interventions across six genomic medicine clinical research projects funded by an NIH consortium. Each project’s strategies were elicited via a structured survey derived from a typology of implementation strategies, the Expert Recommendations for Implementing Change (ERIC), and follow-up interviews guided by both implementation strategy reporting criteria and a planning framework, RE-AIM, to obtain more detail about implementation strategies and desired outcomes. We found that, on average, the three pharmacogenomics implementation projects used more strategies than the disease-focused projects. Overall, projects had four implementation strategies in common; however, operationalization of each differed in accordance with each study’s implementation outcomes. These four common strategies may be important for precision medicine program implementation, and pharmacogenomics may require more integration into clinical care. Understanding how and why these strategies were successfully employed could be useful for others implementing genomic or precision medicine programs in different contexts.