title: Renin-angiotensin system genetic polymorphisms and brain white matter lesions in older Australians.
abstract: BACKGROUND
  White matter lesions (WMLs), seen as hyperintensities on T2-weighted magnetic resonance imaging brain scans, are common in the brains of healthy older individuals. They are thought to be related to cerebral small vessel disease and to have a genetic component to their aetiology, and hypertension is thought to be an important risk factor. Genetic polymorphisms in hypertension-related genes may therefore be associated with the formation of WMLs.
  
  
  METHODS
  In this study, a sample of 445 Australians aged 60-65 years was drawn from a larger longitudinal epidemiological study, the Personality and Total Health Through Life Project. The associations of single nucleotide polymorphisms (SNPs) in the genes encoding angiotensinogen (AGT, rs699), angiotensin-converting enzyme (ACE, rs4362), and angiotensin II receptor type 1 (AGTR1, rs5182) with WMLs were examined.
  
  
  RESULTS
  No individual SNPs showed a significant association with WMLs for the whole sample. When the cohort was stratified by sex, ACE rs4362 and AGT rs699 showed significant associations with WMLs in men only (P = 0.01 and P = 0.03, respectively), and remained significant after controlling for hypertension. Although the AGTR1 SNP did not show any association with WMLs, the interaction of the AGT rs699 and AGTR1 rs5182 SNPs with WMLs was significant before (P = 0.03) and after adjustment for hypertension (P = 0.045).
  
  
  CONCLUSIONS
  The results provide evidence for association of polymorphisms in the renin-angiotensin system genes with WMLs, independent of hypertension. Male-only associations with WMLs were found for the AGT rs699 and ACE rs362 polymorphisms. Moreover, for the entire sample an interaction between AGT and AGTR1 rs5182 genotypes on WMLs was observed.
authors.affiliation: Neuroscience Research Australia, Sydney, Australia; Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; Collaborative Research Network for Mental Health and Well-being, University of New England, Armidale, Australia; a.assareh@unsw.edu.au.
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Assareh
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia;
authors.forename: Karen A
authors.initials: KA
authors.lastname: Mather
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia;
authors.forename: John D
authors.initials: JD
authors.lastname: Crawford
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia;
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.affiliation: Ageing Research Unit, Centre for Mental Health Research, Australian National University, Canberra, Australia;
authors.forename: Kaarin J
authors.initials: KJ
authors.lastname: Anstey
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, Australia;
authors.forename: Simon
authors.initials: S
authors.lastname: Easteal
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, Australia;
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Tan
authors.affiliation: Neuroscience Research Australia, Sydney, Australia;
authors.forename: Holly A
authors.initials: HA
authors.lastname: Mack
authors.affiliation: Neuroscience Research Australia, Sydney, Australia; School of Medical Science, University of New South Wales, Sydney, Australia.
authors.forename: John B J
authors.initials: JB
authors.lastname: Kwok
authors.affiliation: Neuroscience Research Australia, Sydney, Australia; School of Medical Science, University of New South Wales, Sydney, Australia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia;
authors.forename: Perminder S
authors.initials: PS
authors.lastname: Sachdev
mesh_terms: D000367:Age Factors; D000368:Aged; D000808:Angiotensinogen / Q000235:genetics; D001315:Australia / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D012307:Risk Factors; D012737:Sex Factors
chemical_list: C534931:AGT protein, human; C544065:AGTR1 protein, human; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A
keywords: angiotensin II receptor type 1; angiotensin-converting enzyme; angiotensinogen; blood pressure; hypertension; sex differences; single nucleotide polymorphism; white matter lesion.