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School of Medicine
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Genomic control of platelet function
(1) Gene and protein expression in megakaryocytes derived from pluripotent stem cells in familes with early onset coronary disease
(2) Gene expression in platelets and relation to in vitro platelet function
Aggregation of blood platelets initiates clotting in coronary arteries, the main cause of heart attacks. Our laboratory conducts experiments to understand how genes control platelet function. Through funding by the National Heart Lung and Blood Institute, we have performed candidate gene analysis, linkage studies, whole genome association studies, and now whole genome sequencing in about 2000 healthy subjects from families with early onset coronary artery disease. The subjects are siblings or offspring of an individual identified with coronary artery disease before age 60 in the GeneSTAR Research Program (Genetic Studies of Atherosclerosis Risk). We have identified a large number of common and rare genetic variants associated with platelet aggregation, and although some variants are located in genes known to be important in the biology of platelet function, most are in non-protein coding regions of genes (introns) or in intergenic regions of the genome. To understand better how these variants influence platelet function, we created pluripotent stem cells from blood mononuclear cells in 257 genotyped GeneSTAR subjects and then transformed the stem cells to megakaryocytes, the source of platelets in the bone marrow. We have determined the entire transcriptome of these megakaryocytes to measure gene expression levels in an effort to functionally link genetic variation with platelet function. We are also interested in epigenetic effects which regulate the amount of gene transcription and resulting protein formation. We have done similar transcriptomic and proteomic studies in blood platelets as we have in stem cell-derived megakaryocytes.
Our goal is to identify new therapeutic targets for drug development to control excessive platelet aggregation and reduce the risk of heart attack in susceptible individuals. We also hope to use the genetic information to predict who is at greatest risk for platelet aggregation or bleeding, and tailor treatment to effectively apply individualized precision medicine.
The Becker laboratory also extends its cardiovascular work well beyond platelet function, as noted on the GeneSTAR Research Program website.
- SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a).Yang X, Sethi A, Yanek LR, Knapper C, Nordestgaard BG, Tybjærg-Hansen A, Becker DM, Mathias RA, Remaley AT, Becker LC. Circulation. Cardiovascular genetics. 2016; 9(5):408-418. PubMed [journal]PMID: 27651445
- Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. Eicher JD, Chami N, Kacprowski T, Nomura A, Chen MH, Yanek LR, Tajuddin SM, Schick UM, Slater AJ, Pankratz N, Polfus L, Schurmann C, Giri A, Brody JA, Lange LA, Manichaikul A, Hill WD, Pazoki R, Elliot P, Evangelou E, Tzoulaki I, Gao H, Vergnaud AC, Mathias RA, Becker DM, Becker LC, Burt A, Crosslin DR, Lyytikäinen LP, Nikus K, Hernesniemi J, Kähönen M, Raitoharju E, Mononen N, Raitakari OT, Lehtimäki T, Cushman M, Zakai NA, Nickerson DA, Raffield LM, Quarells R, Willer CJ, Peloso GM, Abecasis GR, Liu DJ, Deloukas P, Samani NJ, Schunkert H, Erdmann J, Fornage M, Richard M, Tardif JC, Rioux JD, Dube MP, de Denus S, Lu Y, Bottinger EP, Loos RJ, Smith AV, Harris TB, Launer LJ, Gudnason V, Velez Edwards DR, Torstenson ES, Liu Y, Tracy RP, Rotter JI, Rich SS, Highland HM, Boerwinkle E, Li J, Lange E, Wilson JG, Mihailov E, Mägi R, Hirschhorn J, Metspalu A, Esko T, Vacchi-Suzzi C, Nalls MA, Zonderman AB, Evans MK, Engström G, Orho-Melander M, Melander O, O'Donoghue ML, Waterworth DM, Wallentin L, White HD, Floyd JS, Bartz TM, Rice KM, Psaty BM, Starr JM, Liewald DC, Hayward C, Deary IJ, Greinacher A, Völker U, Thiele T, Völzke H, van Rooij FJ, Uitterlinden AG, Franco OH, Dehghan A, Edwards TL, Ganesh SK, Kathiresan S, Faraday N, Auer PL, Reiner AP, Lettre G, Johnson AD. American journal of human genetics. 2016; 99(1):40-55. PubMed [journal]PMID: 27346686 PMCID: PMC5005441
- Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. Liu CT, Raghavan S, Maruthur N, Kabagambe EK, Hong J, Ng MC, Hivert MF, Lu Y, An P, Bentley AR, Drolet AM, Gaulton KJ, Guo X, Armstrong LL, Irvin MR, Li M, Lipovich L, Rybin DV, Taylor KD, Agyemang C, Palmer ND, Cade BE, Chen WM, Dauriz M, Delaney JA, Edwards TL, Evans DS, Evans MK, Lange LA, Leong A, Liu J, Liu Y, Nayak U, Patel SR, Porneala BC, Rasmussen-Torvik LJ, Snijder MB, Stallings SC, Tanaka T, Yanek LR, Zhao W, Becker DM, Bielak LF, Biggs ML, Bottinger EP, Bowden DW, Chen G, Correa A, Couper DJ, Crawford DC, Cushman M, Eicher JD, Fornage M, Franceschini N, Fu YP, Goodarzi MO, Gottesman O, Hara K, Harris TB, Jensen RA, Johnson AD, Jhun MA, Karter AJ, Keller MF, Kho AN, Kizer JR, Krauss RM, Langefeld CD, Li X, Liang J, Liu S, Lowe WL Jr, Mosley TH, North KE, Pacheco JA, Peyser PA, Patrick AL, Rice KM, Selvin E, Sims M, Smith JA, Tajuddin SM, Vaidya D, Wren MP, Yao J, Zhu X, Ziegler JT, Zmuda JM, Zonderman AB, Zwinderman AH, Adeyemo A, Boerwinkle E, Ferrucci L, Hayes MG, Kardia SL, Miljkovic I, Pankow JS, Rotimi CN, Sale MM, Wagenknecht LE, Arnett DK, Chen YD, Nalls MA, Province MA, Kao WH, Siscovick DS, Psaty BM, Wilson JG, Loos RJ, Dupuis J, Rich SS, Florez JC, Rotter JI, Morris AP, Meigs JB. American journal of human genetics. 2016; 99(1):56-75. PubMed [journal]PMID: 27321945 PMCID: PMC5005440
- Development of hematopoietic stem and progenitor cells from human pluripotent stem cells.Chen T, Wang F, Wu M, Wang ZZ. Journal of cellular biochemistry. 2015; 116(7):1179-89. NIHMSID: NIHMS686012 PubMed [journal]PMID: 25740540 PMCID: PMC4452944
- Effect of white matter lesions on manual dexterity in healthy middle-aged persons.Nyquist PA, Yanek LR, Bilgel M, Cuzzocreo JL, Becker LC, Chevalier-Davis K, Yousem D, Prince J, Kral BG, Vaidya D, Becker DM. Neurology. 2015; 84(19):1920-6. PubMed [journal]PMID: 25862800 PMCID: PMC4433457