Polymorphisms of the renin–angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 78; no. 10; pp. 1083 - 1087
• Main Authors: van Rijn, M J E, Bos, M J, Isaacs, A, Yazdanpanah, M, Arias-Vásquez, A, Stricker, B H Ch, Klungel, O H, Oostra, B A, Koudstaal, P J, Witteman, J C, Hofman, A, Breteler, M M B, van Duijn, C M
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.10.2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Age; Aged; Aged, 80 and over; Angiotensinogen - genetics; Atherosclerosis; Biological and medical sciences; Blood pressure; Body mass index; Carotid arteries; Carotid Artery Diseases - genetics; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Cerebrovascular Disorders - genetics; Cholesterol; Cohort Studies; Diabetes; Disease; Female; Fundamental and applied biological sciences. Psychology; Genes; Genotype; Haplotypes; Heterozygote; Humans; Hypertension; Hypertension - genetics; Male; Medical sciences; Mens health; Mortality; Neurology; Pathology; Polymorphism, Genetic; Prospective Studies; R&D; Receptor, Angiotensin, Type 1 - genetics; Renin-Angiotensin System - genetics; Research & development; Stroke; Stroke - genetics; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs; Netherlands; Nervous system diseases; Central nervous system; Cardiovascular disease; White matter; Encephalon; Vascular disease; Anatomic pathology; Renin angiotensin system; Atherosclerosis; Arterial pressure; Blood pressure; Hemodynamics; Polymorphism
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp.2006.109819

Background:The renin–angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease.Methods:We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference.Results:We found that AGT−235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02–1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke.Conclusion:We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin–angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.