title: Left ventricular diastolic function associated with common genetic variation in ATP12A in a general population.
abstract: BACKGROUND
  Left ventricular (LV) function depends on the activity of transmembrane electrolyte transporters. Failing human myocardium has lower Na(+)/K(+) ATPase expression and higher intracellular sodium concentrations. The ATP12A gene encodes a catalytic subunit of an ATPase that can function as a Na(+)/K(+) pump. We, therefore, investigated the association between LV function and common genetic variants in ATP12A.
  
  
  METHODS
  A random sample of 1166 participants (53.7% women; mean age 49.5 years, 44.8% hypertensive) was recruited in Belgium, Poland, Italy and Russia. We measured transmitral early and late diastolic velocities (E and A) by pulsed wave Doppler, and mitral annular velocities (e' and a') by tissue Doppler. Using principal component analysis, we summarized 7 Doppler indexes - namely, E, A, e' and a' velocities, and their ratios (E/A, e'/a', and E/e') - into a single diastolic score. We genotyped 5 tag SNPs (rs963984, rs9553395, rs10507337, rs12872010, rs2071490) in ATP12A. In our analysis we focused on rs10507337 because it is located within a transcription factor binding site.
  
  
  RESULTS
  In the population-based analyses while adjusting for covariables and accounting for family clusters and country, rs10507337 C allele carriers had significantly higher E/A (P = 0.003), e' (P = 5.8×10(-5)), e'/a' (P = 0.003) and diastolic score (P = 0.0001) compared to TT homozygotes. Our findings were confirmed in the haplotype analysis and in the family-based analyses in 74 informative offspring.
  
  
  CONCLUSIONS
  LV diastolic function as assessed by conventional and tissue Doppler indexes including a composite diastolic score was associated with genetic variation in ATP12A. Further experimental studies are necessary to clarify the role of ATP12A in myocardial relaxation.
authors.affiliation: KU Leuven Department of Cardiovascular Sciences, Research Unit Hypertension and Cardiovascular Epidemiology, University of Leuven, Leuven, Belgium. Judita.Knez@med.kuleuven.be.|Hypertension Division, Department of Internal Medicine, University Clinical Centre Ljubljana, Ljubljana, Slovenia. Judita.Knez@med.kuleuven.be.
authors.forename: Judita
authors.initials: J
authors.lastname: Knez
authors.affiliation: Department of Health, University of Milano and Genomics and Bioinformatics Platform, Fondazione Filarete, Milano, Italy. erika.salvi@unimi.it.
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy. v.tikhonoff@ucl.ac.uk.|MRC Unit for Lifelong Health and Ageing at University College London, London, UK. v.tikhonoff@ucl.ac.uk.
authors.forename: Valérie
authors.initials: V
authors.lastname: Tikhonoff
authors.affiliation: First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College, Krakow, Poland. katarzyna_stolarz@poczta.onet.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stolarz-Skrzypek
authors.affiliation: Institute of Internal and Preventive Medicine, Novosibirsk, Russian Federation. a_ryabikov@hotmail.com.|Novosibirsk State Medical University, Novosibirsk, Russian Federation. a_ryabikov@hotmail.com.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ryabikov
authors.affiliation: KU Leuven Department of Cardiovascular Sciences, Research Unit Hypertension and Cardiovascular Epidemiology, University of Leuven, Leuven, Belgium. Lutgarde.Thijs@med.kuleuven.be.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Thijs
authors.affiliation: Department of Health, University of Milano and Genomics and Bioinformatics Platform, Fondazione Filarete, Milano, Italy. daniele.braga@hotmail.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Braga
authors.affiliation: First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College, Krakow, Poland. malgorzata.kloch-badelek@uj.edu.pl.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kloch-Badelek
authors.affiliation: Institute of Internal and Preventive Medicine, Novosibirsk, Russian Federation. smalyutina@hotmail.com.|Novosibirsk State Medical University, Novosibirsk, Russian Federation. smalyutina@hotmail.com.
authors.forename: Sofia
authors.initials: S
authors.lastname: Malyutina
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy. edoardo.casiglia@unipd.it.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Casiglia
authors.affiliation: First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College, Krakow, Poland. danuta.czarnecka@uj.edu.pl.
authors.forename: Danuta
authors.initials: D
authors.lastname: Czarnecka
authors.affiliation: First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College, Krakow, Poland. mckaweck@cyf-kr.edu.pl.
authors.forename: Kalina
authors.initials: K
authors.lastname: Kawecka-Jaszcz
authors.affiliation: Department of Health, University of Milano and Genomics and Bioinformatics Platform, Fondazione Filarete, Milano, Italy. daniele.cusi@unimi.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: Department of Public Health, Occupational and Environmental Medicine, KU Leuven, Leuven, Belgium. tim.nawrot@uhasselt.be.|Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium. tim.nawrot@uhasselt.be.
authors.forename: Tim
authors.initials: T
authors.lastname: Nawrot
authors.affiliation: KU Leuven Department of Cardiovascular Sciences, Research Unit Hypertension and Cardiovascular Epidemiology, University of Leuven, Leuven, Belgium. Jan.Staessen@med.kuleuven.be.|Department of Epidemiology, Maastricht University, Maastricht, Netherlands. Jan.Staessen@med.kuleuven.be.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
authors.affiliation: KU Leuven Department of Cardiovascular Sciences, Research Unit Hypertension and Cardiovascular Epidemiology, University of Leuven, Leuven, Belgium. tatiana.kouznetsova@med.kuleuven.be.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kuznetsova
mesh_terms: D000328:Adult; D000368:Aged; D003971:Diastole; D015150:Echocardiography, Doppler; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D016277:Ventricular Function, Left
chemical_list: C088641:ATP12A protein, human; D017506:H(+)-K(+)-Exchanging ATPase