Browsing by Author "Karnes, Jason H."

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    Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension
    (American Association for the Advancement of Science, 2024) Tai, Yi-Yin; Yu, Qiujun; Tang, Ying; Sun, Wei; Kelly, Neil J.; Okawa, Satoshi; Zhao, Jingsi; Schwantes-An, Tae-Hwi; Lacoux, Caroline; Torrino, Stephanie; Al Aaraj, Yassmin; El Khoury, Wadih; Negi, Vinny; Liu, Mingjun; Corey, Catherine G.; Belmonte, Frances; Vargas, Sara O.; Schwartz, Brian; Bhat, Bal; Chau, B. Nelson; Karnes, Jason H.; Satoh, Taijyu; Barndt, Robert J.; Wu, Haodi; Parikh, Victoria N.; Wang, Jianrong; Zhang, Yingze; McNamara, Dennis; Li, Gang; Speyer, Gil; Wang, Bing; Shiva, Sruti; Kaufman, Brett; Kim, Seungchan; Gomez, Delphine; Mari, Bernard; Cho, Michael H.; Boueiz, Adel; Pauciulo, Michael W.; Southgate, Laura; Trembath, Richard C.; Sitbon, Olivier; Humbert, Marc; Graf, Stefan; Morrell, Nicholas W.; Rhodes, Christopher J.; Wilkins, Martin R.; Nouraie, Mehdi; Nichols, William C.; Desai, Ankit A.; Bertero, Thomas; Chan, Stephen Y.; Medicine, School of Medicine
    Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and histone lysine N-methyltransferase 2E (KMT2E). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.
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    Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update
    (Wiley, 2021) Karnes, Jason H.; Rettie, Allan E.; Somogyi, Andrew A.; Huddart, Rachel; Fohner, Alison E.; Formea, Christine M.; Lee, Ming Ta Michael; Llerena, Adrian; Whirl-Carrillo, Michelle; Klein, Teri E.; Phillips, Elizabeth J.; Mintzer, Scott; Gaedigk, Andrea; Caudle, Kelly E.; Callaghan, John T.; Medicine, School of Medicine
    Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (updates on cpicpgx.org).
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    Differential drug response in pulmonary arterial hypertension: The potential for precision medicine
    (Wiley, 2023-11-02) Miller, Elise; Sampson, Chinwuwanuju Ugo‐Obi; Desai, Ankit A.; Karnes, Jason H.; Medicine, School of Medicine
    Pulmonary arterial hypertension (PAH) is a rare, complex, and deadly cardiopulmonary disease. It is characterized by changes in endothelial cell function and smooth muscle cell proliferation in the pulmonary arteries, causing persistent vasoconstriction, resulting in right heart hypertrophy and failure. There are multiple drug classes specific to PAH treatment, but variation between patients may impact treatment response. A small subset of patients is responsive to pulmonary vasodilators and can be treated with calcium channel blockers, which would be deleterious if prescribed to a typical PAH patient. Little is known about the underlying cause of this important difference in vasoresponsive PAH patients. Sex, race/ethnicity, and pharmacogenomics may also factor into efficacy and safety of PAH-specific drugs. Research has indicated that endothelin receptor antagonists may be more effective in women and there have been some minor differences found in certain races and ethnicities, but these findings are muddled by the impact of socioeconomic factors and a lack of representation of non-White patients in clinical trials. Genetic variants in genes such as CYP3A5, CYP2C9, PTGIS, PTGIR, GNG2, CHST3, and CHST13 may influence the efficacy and safety of certain PAH-specific drugs. PAH research faces many challenges, but there is potential for new methodologies to glean new insights into PAH development and treatment.
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    Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension
    (American Thoracic Society, 2020-06-01) Karnes, Jason H.; Wiener, Howard W.; Schwantes-An, Tae-Hwi; Natarajan, Balaji; Sweatt, Andrew J.; Chaturvedi, Abhishek; Arora, Amit; Batai, Ken; Nair, Vineet; Steiner, Heidi E.; Giles, Jason B.; Yu, Jeffrey; Hosseini, Maryam; Pauciulo, Michael W.; Lutz, Katie A.; Coleman, Anna W.; Feldman, Jeremy; Vanderpool, Rebecca; Tang, Haiyang; Garcia, Joe G.N.; Yuan, Jason X.J; Kittles, Rick; de Jesus Perez, Vinicio; Zamanian, Roham T.; Rischard, Franz; Tiwari, Hemant K.; Nichols, William C.; Benza, Raymond L.; Desai, Ankit A.; Medicine, School of Medicine
    Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.
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    Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension
    (American Thoracic Society, 2022) Harbaum, Lars; Rhodes, Christopher J.; Wharton, John; Lawrie, Allan; Karnes, Jason H.; Desai, Ankit A.; Nichols, William C.; Humbert, Marc; Montani, David; Girerd, Barbara; Sitbon, Olivier; Boehm, Mario; Novoyatleva, Tatyana; Schermuly, Ralph T.; Ghofrani, H. Ardeschir; Toshner, Mark; Kiely, David G.; Howard, Luke S.; Swietlik, Emilia M.; Gräf, Stefan; Pietzner, Maik; Morrell, Nicholas W.; Wilkins, Martin R.; U.K. National Institute for Health Research BioResource Rare Diseases Consortium; U.K. Pulmonary Arterial Hypertension Cohort Study Consortium; U.S. Pulmonary Arterial Hypertension Biobank Consortium; Medical and Molecular Genetics, School of Medicine
    Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16–2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74–0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.
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    Reply to Non and Chang: Challenging the Role of Genetic Ancestry in Explaining Racial/Ethnic Health Disparities
    (American Thoracic Society, 2021) Karnes, Jason H.; Schwantes-An, Tae-Hwi; Kittles, Rick; Desai, Ankit A.; Medical and Molecular Genetics, School of Medicine
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    SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics
    (American Thoracic Society, 2023) Sangam, Shreya; Sun, Xutong; Schwantes-An, Tae-Hwi; Yegambaram, Manivannan; Lu, Qing; Shi, Yinan; Cook, Todd; Fisher, Amanda; Frump, Andrea L.; Coleman, Anna; Sun, Yanan; Liang, Shuxin; Crawford, Howard; Lutz, Katie A.; Maun, Avinash D.; Pauciulo, Michael W.; Karnes, Jason H.; Chaudhary, Ketul R.; Stewart, Duncan J.; Langlais, Paul R.; Jain, Mohit; Alotaibi, Mona; Lahm, Tim; Jin, Yan; Gu, Haiwei; Tang, Haiyang; Nichols, William C.; Black, Stephen M.; Desai, Ankit A.; Medical and Molecular Genetics, School of Medicine
    Rationale: Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk. Objectives: On the basis of pathological roles of estrogen and HIF2α (hypoxia-inducible factor 2α) signaling in pulmonary artery endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition. Methods: We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis. Measurements and Main Results: Sox17 expression was reduced in PAH tissues (rodent models and from patients). Chronic hypoxic pulmonary hypertension was exacerbated by mice with conditional Tie2-Sox17 (Sox17EC-/-) deletion and attenuated by transgenic Tie2-Sox17 overexpression (Sox17Tg). On the basis of untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found that HIF2α concentrations were increased in the lungs of Sox17EC-/- and reduced in those from Sox17Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2α overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16α-hydroxyestrone (16αOHE; a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16αOHE-mediated exacerbations of chronic hypoxic pulmonary hypertension. Finally, in adjusted analyses in patients with PAH, we report novel associations between a SOX17 risk variant, rs10103692, and reduced plasma citrate concentrations (n = 1,326). Conclusions: Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF2α. 16αOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.