Abstract
Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus, and then tested variants for contributions to sympathetic function and blood pressure. We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single nucleotide polymorphisms (SNPs) and one tetranucleotide repeat were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned four common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine ex...Continue Reading
References
Apr 1, 1990·Circulation·R J ParmerD T O'Connor
Jan 1, 1990·Life Sciences·B Kennedy, M G Ziegler
Apr 13, 1995·Nature·Q Y ZhouR D Palmiter
Jul 15, 1997·Nucleic Acids Research·D A NickersonS L Taylor
Jan 1, 1997·Genetic Epidemiology·L AlmasyJ Blangero
May 23, 1998·American Journal of Human Genetics·L Almasy, J Blangero
Oct 17, 1998·Hypertension·P SharmaM J Brown
May 8, 2000·Statistics in Medicine·K A DoN G Martin
Sep 12, 2000·Current Hypertension Reports·D T O'ConnorR J Parmer
Mar 20, 2001·American Journal of Human Genetics·M StephensP Donnelly
Feb 19, 2002·Chemical Reviews·Torgeir Flatmark, Raymond C. Stevens
Mar 5, 2004·American Journal of Human Genetics·Dale R Nyholt
Sep 16, 2004·Physiological Genomics·Lian ZhangDaniel T O'Connor
Aug 18, 2005·Biochemical and Biophysical Research Communications·Kazuto Kobayashi, Toshiharu Nagatsu
Citations
Jul 13, 2012·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Fokko J BoskerHarold Snieder
Jan 20, 2012·Pharmacogenetics and Genomics·Laxmi V GhimireDaniel Kurnik
Dec 2, 2014·Journal of Psychosomatic Research·Lianbin XiangGailen D Marshall
Dec 8, 2009·Neuroscience and Biobehavioral Reviews·Ting WuEco de Geus
May 5, 2009·Pharmacology, Biochemistry, and Behavior·Toni-Kim Clarke, Gunter Schumann
Sep 14, 2010·Physiological Measurement·Enrique Spinelli, Marcelo Haberman
Apr 12, 2013·Psychosomatic Medicine·Ting WuHarold Snieder
Apr 4, 2009·Physiological Reviews·Richard KvetnanskyMiklos Palkovits
Jan 5, 2018·Journal of Cardiovascular Pharmacology·Martin I SigurdssonWilliam Maixner
Jul 17, 2014·Circulation. Cardiovascular Genetics·Xueli YangTanika N Kelly