Published Online
on August 18, 2005

A more recent version of this article appeared on September 1, 2005

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Submitted on February 5, 2005
Revised on May 29, 2005
Accepted on June 14, 2005

Associations of the Angiotensin II Type 1 Receptor A¹¹⁶⁶C and the Endothelial NO Synthase G⁸⁹⁴T Gene Polymorphisms With Silent Subcortical White Matter Lesions in Essential Hypertension

Léon H.G. Henskens MD; Abraham A. Kroon MD, PhD^*; Martin P.J. van Boxtel MD, PhD; Paul A.M. Hofman MD, PhD; and Peter W. de Leeuw MD, PhD, FAHA

From the Department of Internal Medicine (L.H.G.H., A.A.K., P.W.d.), University Hospital Maastricht, The Netherlands; and Departments of Psychiatry and Neuropsychology (M.P.J.v.) and Radiology (P.A.M.H.), Maastricht University, The Netherlands.

^* To whom correspondence should be addressed. E-mail: akr{at}sint.azm.nl.

Background and Purpose--Silent white matter lesions (WMLs) may represent early target organ damage of the brain in patients with hypertension. Because these lesions may have a genetic background, we assessed the associations between polymorphisms of the renin-angiotensin system and the endothelial NO synthase (NOS3) genes and silent WMLs.

Methods--Ninety-three hypertensive individuals were studied. MRI of the brain was performed to obtain estimates of the total volume of subcortical and the extent of periventricular WMLs. Patients were genotyped for the angiotensinogen (M²³⁵T), the angiotensin-converting enzyme (insertion/deletion [I/D]), the angiotensin II type 1 receptor (AGTR1 A¹¹⁶⁶C), and the NOS3 (G⁸⁹⁴T) genes. A linear regression model was used to assess the relationship of these gene polymorphisms with both subtypes of WMLs.

Results--When adjusted for age, diabetes mellitus, and blood pressure, subcortical WML volume was lowest in the presence of 1 or 2 AGTR1 C alleles (unstandardized , -38.8 [95% CI, -66.1 to -11.4] and -112.6 [CI, -188.9 to -36.4], respectively), whereas it was highest in the presence of an NOS3 T allele (3.1 [CI, 3.6 to 58.4]). No interaction between these polymorphisms on WMLs could be demonstrated. No associations were present with the other polymorphisms, either with subcortical or periventricular lesions.

Conclusions--We found the AGTR1 A¹¹⁶⁶C as well as the NOS3 G⁸⁹⁴T polymorphisms to be associated with silent WMLs in the subcortical area.

Key words: hypertension • nitric oxide synthase • polymorphism • renin-angiotensin • white matter

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