title: Associations of Renin-Angiotensin-Aldosterone System Genes With Blood Pressure Changes and Hypertension Incidence.
abstract: BACKGROUND
  The renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure (BP) regulation. The current study uses single-marker and gene-based analyses to examine the association between RAAS genes and longitudinal BP phenotypes in a Han Chinese population.
  
  
  METHODS
  A total of 1,768 participants from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study were included in the current study. Twenty-seven BP measurements were taken using random-zero sphygmomanometers at baseline and 2 follow-up visits. Mixed-effect models were used to assess the additive associations of 106 single-nucleotide polymorphisms (SNPs) in 10 RAAS genes with longitudinal BP changes and hypertension incidence. Gene-based analyses were conducted using the truncated product method. Attempts were made to replicate significant findings among Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). False discovery rate procedures were used to adjust for multiple testing.
  
  
  RESULTS
  During an average of 7.2 years of follow-up, average systolic and diastolic BP increased, and 32.1% (512) of participants free from hypertension at baseline developed hypertension. NR3C2 SNPs rs7694064 and rs6856803 were significantly associated with longitudinal changes in systolic BP (P interaction = 6.9×10(-5) and 8.2×10(-4), respectively). Through gene-based analysis, NR3C2 was found to be significantly associated with longitudinal systolic BP change (P value of 1.00×10(-7)), even after removal of significant markers rs7694064 and rs6856803 from the analysis. The association between NR3C2 and longitudinal systolic BP change was replicated in Asian MESA participants (P value of 1.00×10(-4)).
  
  
  CONCLUSIONS
  These findings indicate that NR3C2 may play an important role in BP progression and development of hypertension.
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, USA; Isidore Newman School, New Orleans, Louisiana, USA;
authors.forename: William J
authors.initials: WJ
authors.lastname: He
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, USA;
authors.forename: Changwei
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Biostatistics, Washing University School of Medicine, St. Louis, Missouri, USA;
authors.forename: Dabeeru C
authors.initials: DC
authors.lastname: Rao
authors.affiliation: Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, USA;
authors.forename: James E
authors.initials: JE
authors.lastname: Hixson
authors.affiliation: Department of Evidence Based Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Evidence Based Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.affiliation: Division of Biostatistics, Washing University School of Medicine, St. Louis, Missouri, USA;
authors.forename: Treva K
authors.initials: TK
authors.lastname: Rice
authors.affiliation: Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, USA;
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Shimmin
authors.affiliation: Department of Evidence Based Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Gu
authors.affiliation: Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, USA; tkelly@tulane.edu.
authors.forename: Tanika N
authors.initials: TN
authors.lastname: Kelly
mesh_terms: D044466:Asian People / Q000235:genetics; D001795:Blood Pressure Determination; D002681:China / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018161:Receptors, Mineralocorticoid / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics*
chemical_list: C561839:NR3C2 protein, human; D018161:Receptors, Mineralocorticoid
keywords: blood pressure; blood pressure changes; genetics; hypertension; rennin–angiotensin–aldosterone system (RAAS).
references.citation: Hypertension. 2005 Dec;46(6):1227-35
references.pmid: 16286565
references.citation: Curr Hypertens Rep. 2013 Jun;15(3):134-6
references.pmid: 23536128
references.citation: Hum Genet. 2007 Aug;122(1):33-40
references.pmid: 17492314
references.citation: Lancet. 2005 Jan 15-21;365(9455):217-23
references.pmid: 15652604
references.citation: BMJ. 2009;338:b1665
references.pmid: 19454737
references.citation: Blood Press. 2011 Aug;20(4):204-10
references.pmid: 21342026
references.citation: Hypertension. 2003 May;41(5):1027-34
references.pmid: 12695419
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D975-9
references.pmid: 24297256
references.citation: Nat Genet. 2005 Nov;37(11):1217-23
references.pmid: 16244653
references.citation: Circ Cardiovasc Genet. 2013 Dec;6(6):598-607
references.pmid: 24165912
references.citation: Nat Genet. 2007 Oct;39(10):1181-6
references.pmid: 17898773
references.citation: Science. 2000 Jul 7;289(5476):119-23
references.pmid: 10884226
references.citation: Curr Hypertens Rep. 2010 Feb;12(1):17-25
references.pmid: 20425154
references.citation: Hypertension. 2010 Nov;56(5):995-1002
references.pmid: 20855654
references.citation: Hypertension. 1999 Sep;34(3):423-9
references.pmid: 10489388
references.citation: Am J Hypertens. 2009 Jun;22(6):649-55
references.pmid: 19325532
references.citation: J Hypertens. 2012 May;30(5):861-73
references.pmid: 22495127
references.citation: J Hypertens. 2010 Jun;28(6):1210-20
references.pmid: 20486282
references.citation: Am J Hypertens. 1999 Dec;12(12 Pt 3):205S-213S
references.pmid: 10619573
references.citation: Science. 1996 May 3;272(5262):676-80
references.pmid: 8614826
references.citation: Lancet. 2008 May 3;371(9623):1513-8
references.pmid: 18456100
references.citation: Genet Epidemiol. 2002 Feb;22(2):170-85
references.pmid: 11788962
references.citation: Hypertension. 2001 Nov;38(5):1204-9
references.pmid: 11711524
references.citation: Am J Hypertens. 2002 Jul;15(7 Pt 1):653-4
references.pmid: 12118915
references.citation: BMC Proc. 2009 Dec 15;3 Suppl 7:S89
references.pmid: 20018085
references.citation: BMC Genomics. 2008;9:431
references.pmid: 18803882
references.citation: Nat Genet. 1998 Jul;19(3):279-81
references.pmid: 9662404
references.citation: Am J Hypertens. 2013 Apr;26(4):465-72
references.pmid: 23467202
references.citation: PLoS Genet. 2010 Sep;6(9):e1001094
references.pmid: 20838585
references.citation: J Hum Hypertens. 2007 Aug;21(8):639-46
references.pmid: 17443206
references.citation: PLoS Genet. 2013;9(2):e1003321
references.pmid: 23468652
references.citation: Hypertension. 2004 Mar;43(3):598-602
references.pmid: 14967847