The specific aim of this Core is to use the power of twin and sibling pairs, coupled with SNP and microsatellite genotyping at candidate loci, to establish the significance or effect of such loci, in particular to understand whether allelic variation at such loci influences autonomic function in either the sympathetic or parasympathetic branches. The autonomic nervous system is the key second-to-second regulator of the circulation, and hence of blood pressure. Autonomic activity is deranged not only in patients with established hypertension, but also in their still-normotensive offspring; thus, autonomic traits are valuable as ?intermediate phenotypes? (O?Connor et al, 2000; Dao et al, 1998; Kailasam et al, 1996, 2000; Lacy et al, 1998; Brinton et al, 1996; Song et al, 2000) in hypertension, a common disease with non-Mendelian (complex) inheritance (Schork and Lander, 1994). Since Human phenotyping plays a role that is largely hypothesis generating (rather than hypothesis testing), and since the materials from Human phenotyping (biological samples, DNA, phenotypes, genotypes) now flow systematically to all Projects and Cores (see Diagram), the previous Project on Human phenotyping has been retooled to form new Core C, ?Human phenotyping? (O?Connor and Ziegler). The previous leader of pedigree phenotyping has now moved on to a new series of additional clinical duties in nephrology (wards, consultations, and clinics) at the San Diego VA Medical Center. This change should facilitate interactions among all Projects and Cores. Core C utilizes the San Diego Twin Project , which has already recruited n=245 nuclear families based on human MZ and DZ twin pairs (also ascertaining available sibs and parents), phenotyped and genotyped as outlined below, as well as an additional n=69 nuclear families based on sib trios. These nuclear families already give rise to n=573 sib pairs. Twin pairs allow estimation of heritability (h2), which in turn allows us to determine the tractability of any human trait (biochemical or physiological) to genetic investigation. Parental DNA is available on these twinships and sibships (from approximately 45% of parents). The previous phenotyping Project also ascertained n=69 nuclear families based on probands with essential hypertension (first degree relatives studied; average sibship size 3 [offspring of the hypertensive patient]). Genomic DNAs from these sibling pairs, and parents, have already been subjected to a n=777 microsatellite (approximately 5 cM) genome scan, performed by James L. Weber at the NHLBI?s Mammalian Genotyping Service at Marshfield Clinic. This genome scan was completed in April of 2004. Major results emerging from studies employing the human subjects (especially twin pairs) studied by Core C are presented in the overall Preamble to the HL58120 renewal application.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL058120-07
Application #
7312489
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
7
Fiscal Year
2006
Total Cost
$190,318
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Benyamin, Beben; Maihofer, Adam X; Schork, Andrew J et al. (2017) Identification of novel loci affecting circulating chromogranins and related peptides. Hum Mol Genet 26:233-242
Hook, Vivian; Bandeira, Nuno (2015) Neuropeptidomics Mass Spectrometry Reveals Signaling Networks Generated by Distinct Protease Pathways in Human Systems. J Am Soc Mass Spectrom 26:1970-80
Podvin, Sonia; Bundey, Richard; Toneff, Thomas et al. (2015) Profiles of secreted neuropeptides and catecholamines illustrate similarities and differences in response to stimulation by distinct secretagogues. Mol Cell Neurosci 68:177-85
Rao, Fangwen; Schork, Andrew J; Maihofer, Adam X et al. (2015) Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study. Arterioscler Thromb Vasc Biol 35:1704-11
Zhang, Kuixing; Huentelman, Matthew J; Rao, Fangwen et al. (2014) Genetic implication of a novel thiamine transporter in human hypertension. J Am Coll Cardiol 63:1542-55
Zhang, Kuixing; Biswas, Nilima; Gayen, Jiaur R et al. (2014) Chromogranin B: intra- and extra-cellular mechanisms to regulate catecholamine storage and release, in catecholaminergic cells and organisms. J Neurochem 129:48-59
Austin, Anthony W; Patterson, Stephen M; Ziegler, Michael G et al. (2014) Plasma volume and flight duration effects on post-spaceflight soluble adhesion molecules. Aviat Space Environ Med 85:912-8
Zhang, Kuixing; Deacon, Dekker C; Rao, Fangwen et al. (2014) Human heart rate: heritability of resting and stress values in twin pairs, and influence of genetic variation in the adrenergic pathway at a microribonucleic acid (microrna) motif in the 3'-UTR of cytochrome b561 [corrected]. J Am Coll Cardiol 63:358-68
Hook, Vivian; Brennand, Kristen J; Kim, Yongsung et al. (2014) Human iPSC neurons display activity-dependent neurotransmitter secretion: aberrant catecholamine levels in schizophrenia neurons. Stem Cell Reports 3:531-8
Pasha, Dalal N; Davis, Jason T; Rao, Fangwen et al. (2013) Heritable influence of DBH on adrenergic and renal function: twin and disease studies. PLoS One 8:e82956

Showing the most recent 10 out of 160 publications