title: Urotensin-II system in genetic control of blood pressure and renal function.
abstract: Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Debiec
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Christofidou
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Denniff
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Bloomer
authors.affiliation: Department of Internal Medicine, Metabolic Disorders and Hypertension, Medical University of Poznan, Poznan, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Bogdanski
authors.affiliation: Department of Urology and Oncological Urology, Medical University of Poznan, Poznan, Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wojnar
authors.affiliation: Department of Internal Medicine, Metabolic Disorders and Hypertension, Medical University of Poznan, Poznan, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Musialik
authors.affiliation: School of Science and Engineering, University of Ballarat, Ballarat, Australia.
authors.forename: Fadi J
authors.initials: FJ
authors.lastname: Charchar
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.affiliation: GlaxoSmithKline, Philadelphia, Pennsylvania, United States of America.
authors.forename: Dawn
authors.initials: D
authors.lastname: Waterworth
authors.affiliation: GlaxoSmithKline, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kijoung
authors.initials: K
authors.lastname: Song
authors.affiliation: Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.affiliation: Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Gerard
authors.initials: G
authors.lastname: Waeber
authors.affiliation: Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Zukowska-Szczechowska
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Lambert
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology*; D015331:Cohort Studies; D019143:Evolution, Molecular; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005919:Glomerular Filtration Rate / Q000235:genetics / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D036361:Peptide Hormones / Q000235:genetics* / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011323:Primates / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000502:physiology*; D014579:Urotensins / Q000235:genetics* / Q000502:physiology*; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; C479080:UTS2B protein, human; C121697:UTS2R protein, human; D014579:Urotensins; C029677:urotensin II