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- Fangwen Rao
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Lian Zhang
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Jennifer Wessel
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Kuixing Zhang
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Gen Wen
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Brian P. Kennedy
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Brinda K. Rana
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Madhusudan Das
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Juan L. Rodriguez-Flores
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Douglas W. Smith
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Peter E. Cadman
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Rany M. Salem
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Sushil K. Mahata
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Nicholas J. Schork
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Laurent Taupenot
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Michael G. Ziegler
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
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- Daniel T. O’Connor
- From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.
書誌事項
- タイトル別名
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- Discovery of Common Human Genetic Variants Governing Transcription, Autonomic Activity, and Blood Pressure In Vivo
抄録
<jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human <jats:italic>TH</jats:italic> alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the <jats:italic>TH</jats:italic> locus and then tested variants for contributions to sympathetic function and blood pressure. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> We resequenced 80 ethnically diverse individuals across the <jats:italic>TH</jats:italic> locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production, reflex control of the circulation, and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human <jats:italic>TH</jats:italic> promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single-nucleotide polymorphisms were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned 4 common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable (h <jats:sup>2</jats:sup> ), as were stress-induced blood pressure changes. In the <jats:italic>TH</jats:italic> promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. <jats:italic>TH</jats:italic> promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. Coalescent simulations suggest that <jats:italic>TH</jats:italic> haplotype 2 likely arose ≈380 000 years ago. In hypertension, 2 independent case-control studies (1266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, <jats:italic>TH</jats:italic> . The results suggest novel pathophysiological links between a key adrenergic locus, catecholamine metabolism, and blood pressure and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension. </jats:p>
収録刊行物
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- Circulation
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Circulation 116 (9), 993-1006, 2007-08-28
Ovid Technologies (Wolters Kluwer Health)