Browsing by Author "Shuldiner, Alan R."

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    Genome sequencing unveils a regulatory landscape of platelet reactivity
    (Springer Nature, 2021-06-15) Keramati, Ali R.; Chen, Ming-Huei; Rodriguez, Benjamin A. T.; Yanek, Lisa R.; Bhan, Arunoday; Gaynor, Brady J.; Ryan, Kathleen; Brody, Jennifer A.; Zhong, Xue; Wei, Qiang; NHLBI Trans-Omics for Precision (TOPMed) Consortium; Kammers, Kai; Kanchan, Kanika; Iyer, Kruthika; Kowalski, Madeline H.; Pitsillides, Achilleas N.; Cupples, L. Adrienne; Li, Bingshan; Schlaeger, Thorsten M.; Shuldiner, Alan R.; O’Connell, Jeffrey R.; Ruczinski, Ingo; Mitchell, Braxton D.; Faraday, Nauder; Taub, Margaret A.; Becker, Lewis C.; Lewis, Joshua P.; Mathias, Rasika A.; Johnson, Andrew D.; Medicine, School of Medicine
    Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.
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    Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention
    (Elsevier, 2018-01-22) Cavallari, Larisa H.; Lee, Craig R.; Beitelshees, Amber L.; Cooper-DeHoff, Rhonda M.; Duarte, Julio D.; Voora, Deepak; Kimmel, Stephen E.; McDonough, Caitrin W.; Gong, Yan; Dave, Chintan V.; Pratt, Victoria M.; Alestock, Tameka D.; Anderson, R. David; Alsip, Jorge; Ardati, Amer K.; Brott, Brigitta C.; Brown, Lawrence; Chumnumwat, Supatat; Clare-Salzler, Michael J.; Coons, James C.; Denny, Joshua C.; Dillon, Chrisly; Elsey, Amanda R.; Hamadeh, Issam; Harada, Shuko; Hillegass, William B.; Hines, Lindsay; Horenstein, Richard B.; Howell, Lucius A.; Jeng, Linda J.B.; Kelemen, Mark D.; Lee, Y.M.; Magvanjav, Oyunbileg; Montasser, May; Nelson, David R.; Nutescu, Edith A.; Nwaba, Devon C.; Pakyz, Ruth E.; Palmer, Kathleen; Peterson, Josh F.; Pollin, Toni I.; Quinn, Alison H.; Robinson, Shawn W.; Schub, Jamie; Skaar, Todd C.; Smith, Donald M.; Sriramoju, Vindhya B.; Starostik, Petr; Stys, Tomasz P.; Stevenson, James M.; Varunok, Nicholas; Vesely, Mark R.; Wake, Dyson T.; Weck, Karen E.; Weitzel, Kristin W.; Wilke, Russell A.; Willig, James; Zhao, Richard Y.; Kreutz, Rolf P.; Stouffer, George A.; Empey, Philip E.; Limdi, Nita A.; Shuldiner, Alan R.; Winterstein, Almut G.; Johnson, Julie A.; Medical and Molecular Genetics, School of Medicine
    OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.
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    Whole Genome Sequence Association Analysis of Fasting Glucose and Fasting Insulin Levels in Diverse Cohorts from the NHLBI TOPMed Program
    (Springer Nature, 2022-07-28) DiCorpo, Daniel; Gaynor, Sheila M.; Russell, Emily M.; Westerman, Kenneth E.; Raffield, Laura M.; Majarian, Timothy D.; Wu, Peitao; Sarnowski, Chloé; Highland, Heather M.; Jackson, Anne; Hasbani, Natalie R.; de Vries, Paul S.; Brody, Jennifer A.; Hidalgo, Bertha; Guo, Xiuqing; Perry, James A.; O’Connell, Jeffrey R.; Lent, Samantha; Montasser, May E.; Cade, Brian E.; Jain, Deepti; Wang, Heming; D’Oliveira Albanus, Ricardo; Varshney, Arushi; Yanek, Lisa R.; Lange, Leslie; Palmer, Nicholette D.; Almeida, Marcio; Peralta, Juan M.; Aslibekyan, Stella; Baldridge, Abigail S.; Bertoni, Alain G.; Bielak, Lawrence F.; Chen, Chung-Shiuan; Chen, Yii-Der Ida; Choi, Won Jung; Goodarzi, Mark O.; Floyd, James S.; Irvin, Marguerite R.; Kalyani, Rita R.; Kelly, Tanika N.; Lee, Seonwook; Liu, Ching-Ti; Loesch, Douglas; Manson, JoAnn E.; Minster, Ryan L.; Naseri, Take; Pankow, James S.; Rasmussen-Torvik, Laura J.; Reiner, Alexander P.; Reupena, Muagututi’a Sefuiva; Selvin, Elizabeth; Smith, Jennifer A.; Weeks, Daniel E.; Xu, Huichun; Yao, Jie; Zhao, Wei; Parker, Stephen; Alonso, Alvaro; Arnett, Donna K.; Blangero, John; Boerwinkle, Eric; Correa, Adolfo; Cupples, L. Adrienne; Curran, Joanne E.; Duggirala, Ravindranath; He, Jiang; Heckbert, Susan R.; Kardia, Sharon L.R.; Kim, Ryan W.; Kooperberg, Charles; Liu, Simin; Mathias, Rasika A.; McGarvey, Stephen T.; Mitchell, Braxton D.; Morrison, Alanna C.; Peyser, Patricia A.; Psaty, Bruce M.; Redline, Susan; Shuldiner, Alan R.; Taylor, Kent D.; Vasan, Ramachandran S.; Viaud-Martinez, Karine A.; Florez, Jose C.; Wilson, James G.; Sladek, Robert; Rich, Stephen S.; Rotter, Jerome I.; Lin, Xihong; Dupuis, Josée; Meigs, James B.; Wessel, Jennifer; Manning, Alisa K.; Epidemiology, School of Public Health
    The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.