Renin-angiotensin system genetic polymorphisms and brain white matter lesions in older Australians

Amelia A Assareh; Karen A Mather; John D Crawford; Wei Wen; Kaarin J Anstey; Simon Easteal; Xiaoyun Tan; Holly A Mack; John B J Kwok; Peter R Schofield; Perminder S Sachdev

doi:10.1093/ajh/hpu035

Renin-angiotensin system genetic polymorphisms and brain white matter lesions in older Australians

Am J Hypertens. 2014 Sep;27(9):1191-8. doi: 10.1093/ajh/hpu035. Epub 2014 Mar 12.

Authors

Affiliations

¹ 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; [email protected].
² Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia;
³ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia;
⁴ Ageing Research Unit, Centre for Mental Health Research, Australian National University, Canberra, Australia;
⁵ John Curtin School of Medical Research, Australian National University, Canberra, Australia;
⁶ Neuroscience Research Australia, Sydney, Australia;
⁷ Neuroscience Research Australia, Sydney, Australia; School of Medical Science, University of New South Wales, Sydney, Australia.

PMID: 24622918
DOI: 10.1093/ajh/hpu035

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.

Keywords: angiotensin II receptor type 1; angiotensin-converting enzyme; angiotensinogen; blood pressure; hypertension; sex differences; single nucleotide polymorphism; white matter lesion..

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
Aged
Angiotensinogen / genetics
Australia / epidemiology
Female
Gene Frequency
Genetic Predisposition to Disease
Humans
Leukoencephalopathies / diagnosis
Leukoencephalopathies / epidemiology
Leukoencephalopathies / genetics*
Longitudinal Studies
Magnetic Resonance Imaging
Male
Middle Aged
Peptidyl-Dipeptidase A / genetics
Phenotype
Polymorphism, Single Nucleotide*
Receptor, Angiotensin, Type 1 / genetics
Renin-Angiotensin System / genetics*
Risk Factors
Sex Factors

Substances

AGT protein, human
AGTR1 protein, human
Receptor, Angiotensin, Type 1
Angiotensinogen
ACE protein, human
Peptidyl-Dipeptidase A