(Hypertension. 2001;38:110.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Angiotensinogen Polymorphism M235T, Carotid Atherosclerosis, and Small-Vessel Disease-Related Cerebral Abnormalities
From the Department of Neurology (R.S., F.F., K.N., P.K., A.L.), Institute of Medical Biochemistry and Medical Molecular Biology (H.S., G.M.K.), and MRI Center (R.S., F.F., P.K.), Karl-Franzens University, Graz, Austria; and the National Institute on Aging, National Institutes of Health (L.J.L.), Bethesda, Md.
Correspondence to Dr Reinhold Schmidt, Department of Neurology, Karl-Franzens University Graz, Auenbruggerplatz 22, A-8036 Graz, Austria. E-mail reinhold.schmidt{at}kfunigraz.ac.at
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Abstract |
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Abstract—— The angiotensinogen M235T polymorphism has been linked to hypertension and cardiovascular disease. We studied the role of this polymorphism as a risk factor for carotid atherosclerosis and small-vessel disease-related brain abnormalities. A total of 431 randomly selected community-dwelling subjects without clinical evidence for strokes underwent angiotensinogen genotyping and carotid Duplex scanning; 1.5-T brain magnetic resonance imaging (MRI) was done in 396 individuals. At 3-year follow-up, we reexamined 343 and 267 study participants by ultrasound and brain MRI, respectively. Carotid atherosclerosis was graded on a 5-point scale. Small-vessel disease-related brain abnormalities were deep or subcortical white matter lesions or lacunes. Progression of carotid atherosclerosis and MRI findings was rated by direct imaging comparison by 3 independent raters. The M/M, M/T, and T/T genotypes were seen in 20.9%, 52.9%, and 18.1% of subjects, respectively. The M235T polymorphism was neither associated with baseline carotid findings nor with progression of carotid atherosclerosis. There was a trend toward more frequent small-vessel disease-related MRI abnormalities in the T/T than in the other genotypes at the baseline examination. Progression of brain lesions occurred significantly more commonly in T/T than in M/M and M/T carriers (P<0.001). Logistic regression analysis identified the T/T genotype (odds ratio, 3.19; P=0.002) and arterial hypertension (odds ratio, 3.06; P=0.03) as significant independent predictors of lesion progression. These data suggest that the angiotensinogen T/T genotype at position 235 is a genetic marker for brain lesions from and progression of small vessel disease but not for extracranial carotid atherosclerosis.
Key Words: angiotensinogen • genetics • carotid arteries • atherosclerosis • vessels
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Introduction |
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Angiotensinogen is a liver protein that interacts with renin to produce angiotensin I, the prohormone of angiotensin II, which increases vascular tone and promotes sodium retention. The plasma concentrations of angiotensinogen have been directly related to arterial blood pressure and were found to be modified by variations in the angiotensinogen gene.1 A missense mutation in exon 2 of the angiotensinogen gene (T704-C) encoding threonine instead of methionine at position 235 (M235T) of the amino acid sequence commonly occurs among various ethnic groups. The frequency of the T235 allele ranges from 0.35 in whites to approximately 0.80 in blacks.2 A recent meta-analysis with an overall sample size of 27 906 subjects attributed an increased risk for arterial hypertension to the presence of the T-allele. In comparison with the MM reference group, the excess risk was 31% in TT homozygotes and 11% in MT heterozygotes.3 Moreover, several studies found this genetic variant to be associated with coronary artery disease and myocardial infarction.4–7
There is little information on a possible link between this genetic variant and cerebrovascular disease. Two studies showed no relation with carotid intima-media-thickness,8,9 but there have been no investigations assessing the relation of the M
T interchange with atheromatous carotid disease and intracranial small vessel disease, for which arterial hypertension is the most important risk factor.10 It is also undetermined as to whether the M235T polymorphism relates to progression of extracranial or intracranial atherosclerosis. We therefore extended previous work by investigating the association between the M235T polymorphism with carotid atherosclerosis and with small-vessel disease-related cerebral damage in the setting of a longitudinal study in community-dwelling middle-aged and elderly persons. We used Doppler sonography and brain magnetic resonance imaging (MRI) to monitor the study participants over a time period of 3 years.
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Methods |
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Subjects and Design
The study population consisted of participants of the Austrian Stroke Prevention Study, a single-center, prospective follow-up study on the cerebral effects of vascular risk factors in the normal elderly population of the city of Graz, Austria. The study was approved by the institutional review committee of the Department of Neurology and by the ethics committee of the Karl-Franzens University Graz, Austria. The procedure of recruitment and diagnostic workup of study participants has been described previously.11 The baseline cohort consisted of 2000 persons without a history or signs of neuropsychiatric disease. Every fourth study participant or, in case of refusal, the next, was invited to enter phase II of the study, which included carotid Doppler sonography and brain MRI. From a total of 496 phase II participants, all underwent Duplex scanning of the carotid arteries, and 461 volunteered to undergo an MRI study. Since 1993, blood sampling for DNA analysis was done in a total of 431 individuals. There were 207 men and 224 women. The mean age was 60.2±6.1years. The sample consisted exclusively of whites of central European origin. Doppler sonography was available in all of them and MRI in 396 individuals. At the second study panel 3 years after baseline, we were able to reexamine 341 individuals of the 431 participants who underwent neuroimaging and DNA sampling, following the same protocol. From the 90 individuals who could not be reexamined, 7 had died and another 7 had had a stroke, which is an end point in our study. Sixty-five subjects were contacted by telephone but refused to undergo the extensive diagnostic workup a second time. Eleven individuals could not be reinvited because we were unable to reach them after 3 phone calls and a letter. All attendees who were reexamined after 3 years underwent a second duplex scanning, but 74 refused to undergo a second MRI study because of claustrophobic sensations at the initial evaluation. The individuals who participated in the duplex scan and MRI follow-up studies did not differ from those who dropped out in age, gender, and risk factors for stroke. They were also comparable in terms of genotype frequency and baseline sonographic and MRI findings.
Historic information and laboratory findings at baseline were considered for risk factor diagnosis. The definitions for risk factor diagnosis have been previously described.11
DNA Isolation and Genotyping
Genomic DNA was isolated from whole blood by Qiagen genomic tips. The M235T polymorphism was identified by a nonisotropic method involving restriction typing after polymerase chain reaction, as described elsewhere.12 The DNA was visualized directly by ethidium bromide staining. After digestion, the M235 allele that lacked the restriction site was a 163-bp fragment and the T235 allele that had the restriction site was a 140-bp fragment.
Carotid Duplex Scanning
Color-coded equipment (Diasonics, VingMed CFM 750) was used to determine atherosclerotic vessel wall abnormalities of the carotid arteries at baseline and 3-year follow-up examination. All B-mode and Doppler data were transferred to a Macintosh personal computer for processing and storage on optical disk. The imaging protocol involved scanning of both common carotid arteries (CCA) and internal carotid arteries (ICA) in multiple longitudinal and transverse planes and has been previously described.13 The examinations were performed by 3 readers without knowledge of the clinical data of the individuals. Image quality was assessed and graded as good (CCA and ICA clearly visible and ICA detectable over a distance of >2 cm), fair (CCA and ICA sufficiently visible and ICA detectable over a distance of at least 2 cm), and poor (CCA or ICA insufficiently visible or ICA detectable over a distance of <2 cm). There was no poor quality study at the baseline and follow-up examination. At baseline and follow-up, the extent of atherosclerosis was graded according to the most severe visible changes in the CCA and ICA as 0, normal; 1,vessel wall thickening >1 mm; 2, minimal plaque (<2 mm); 3, moderate plaque (2 to 3 mm); 4, severe plaque (>3 mm), and 5, lumen completely obstructed. The interrater variability for grading the extent of sonographic changes was independently assessed in 200 vessels in 50 subjects. The 
values for interrater agreement for the sonographic score between the 3 sonographers ranged from 0.89 to 0.95. The most severe change in any vessel and the sum of scores of the 4 vessels has been recorded. The difference of the sum of scores of both CCA and ICA between baseline and follow-up was used to define regression or progression of carotid atherosclerosis.
Magnetic Resonance Imaging
MRI was performed on 1.5-T superconducting magnets (Gyroscan S 15 and ACS, Philips) with proton-density and T2-weighted (TR/TE 2000 to 2500/30 to 90 ms) sequences in the transverse orientation. T1-weighted images (TR/TE 600/30 ms) were generated in the sagittal plane. Slice thickness was 5 mm, and the matrix size used was 128x256 pixels. MRI protocols at baseline and 3-year follow-up were identical. The scanning plane was always determined by a sagittal and coronal pilot to ensure consistency in image angulation throughout the study. The baseline and follow-up scans of each study participant were read independently by 3 investigators blinded to the clinical data of study participants. Blinding of the readers for the date of the examinations was impossible because the format of hard copies changed from baseline to follow-up. The scans were evaluated for small-vessel disease-related abnormalities. According to numerous histopathological correlations, these changes consisted of white matter hyperintensities (WMH) and lacunar lesions.14,15 WMH were graded according to our scheme as absent (grade 0), punctate (grade 1), early confluent (grade 2), and confluent (grade 3).16 The values for interrater agreement regarding WMH grade ranged from 0.63 to 0.70. The number of WMH was also recorded. Caps and periventricular lining were disregarded because these changes probably represent normal anatomical variants.15 Lacunes were focal cerebrospinal fluid-containing lesions that involved the basal ganglia, the internal capsule, the thalamus, or brain stem not exceeding a maximum diameter of 10 mm. Progression of small-vessel disease-related brain lesion was defined to be present if WMH increased in grade or number or if new lacunar lesions occurred at the follow-up examination. Rating of lesion progression was determined by direct scan comparison and relied on majority judgment of the 3 assessors. In the case of complete disagreement, consensus was found in a joint reading session. The values for interrater agreement for progression of small-vessel disease-related brain abnormalities ranged from 0.61 to 0.69. We also looked at different grades of progression. We considered a change from baseline by 1 to 4 punctate WMH to represent minor progression. Progression was rated to be marked if there was a difference of more than 4 WMH or a transition to early confluent or confluent WMH or if new lacunar lesions were seen. The Figure displays examples for punctate and confluent WMH representing the range of WMH extent seen in our study as well as examples for lacunes and for WMH progression.
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Statistical Analysis
We used the Statistical Package for Social Sciences (SPSS 8.0) for data analysis. The degree of agreement for sonographic and MRI rating was expressed by the means of statistics. According to Fleiss,17 a value <0.40 reflects poor agreement; between 0.40 and 0.75, fair to good agreement; and >0.75, excellent agreement. Categoric variables among the M235T genotypes were compared by means of the 
2 test. Assumption of normal distribution for continuous variables was assessed by Lilliefors statistics. Normally distributed continuous variables were compared by 1-way ANOVA; the Kruskal-Wallis test was used for comparison of nonnormally distributed variables. Allele frequencies were calculated by the gene-counting method, and Hardy-Weinberg equilibrium was assessed by means of the 2 test. Logistic regression analysis assessed the relative contribution of the M235T genotypes on carotid ultrasound and brain MRI findings. Analyses with ultrasound findings as the dependent variable were adjusted for age and gender. In the selection of covariates for analyses on small-vessel disease-related brain damage, we followed a recent review on risk factors for these MRI lesions.18 Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from the ß coefficients and their standard errors.
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Results |
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The frequencies of the M and T alleles were 0.55 and 0.45. The MM, MT, and TT genotypes were noted in 125 (29.0%), 228 (52.9%), and 78 (18.1%) study participants. The genotypes were in Hardy-Weinberg equilibrium. Table 1 compares demographic variables and vascular risk factors among the genotype subsets. As can be seen from this table, TT carriers were older and had a higher frequency of heart disease and arterial hypertension. There was also a nonsignificant trend toward higher diastolic blood pressure values at examination in participants with the TT genotype. The association with hypertension was more pronounced in women than in men. A total of 16 (26.2%) and 29 (24.4%) women with the MM and MT genotype were hypertensive as opposed to 21 (47.7%) female TT carriers (P=0.03). The figures in men were 22 (34.4%), 37 (33.9%), and 14 (41.2%), respectively (P=0.57). The systolic and diastolic blood pressure values were also highest in the TT genotype subset in both genders. Yet, when ANCOVA was used to correct for the between-group differences in age and antihypertensive medication, the association remained only significant for diastolic blood pressure in women (P=0.04).
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A total of 231 (53.6%) study participants showed atherosclerotic changes of the carotid arteries. They occurred in 74 (59.2%) subjects with the MM genotype, 117(51.3%) with the MT genotype, and 40 (51.3%) with the TT genotype (P=0.33). A breakdown of the severity of carotid atherosclerosis by genotype is given in Table 2. There were no significant differences among the 3 investigational subsets. At the 3-year follow-up examination, regression of carotid lesions occurred in 2 (0.6%) individuals, 259 (75.5%) subjects had stable findings, and 82 (23.9%) participants showed plaque progression. Plaque progression occurred at similar frequencies among the 3 genotypes. It was seen in 27 (28.1%) MM carriers, 40 (21.9%) MT carriers, and 15 (23.4%) TT carriers (P=0.57). There existed no gender difference for the associations between the M235T variant and baseline frequency or progression of carotid atherosclerosis. The age- and gender-adjusted odds ratios of the MT and TT genotypes relative to the MM genotype for the presence of carotid atherosclerosis were 0.73 (95% CI, 0.45 to 1.16; P=0.18) and 0.61 (95% CI, 0.33 to 1.11; P=0.11). Those for progression of sonographic findings were 0.69 (95% CI, 0.28 to 1.23; P=0.21) and 0.72 (95% CI, 0.39 to 1.54; P=0.40).
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At baseline, MRI detected WMH in 183 (46.2%) study participants. Lacunar lesions were seen in 32 (8.1%) subjects. Homozygotes for the T allele had higher grades of WMH and tended to show lacunes more frequently than their counterparts with either the MM or MT genotypes (Table 3). The number of WMH was also highest in the TT subset, but the differences to the other genotypes were not significant. The difference for WMH grade between the 3 genotypes seen in the univariate analysis was no longer significant when multinominal logistic regression analysis was used to correct for possible confounding by age, gender, hypertension, heart disease, and systolic and diastolic blood pressure. After 3 years, we noted progression of small-vessel disease-related cerebral abnormalities, including both WMH or lacunes in 52 (19.5%) participants. As shown in Table 3, lesion progression was more than twice as common in subjects with the TT genotype than in the comparative groups (P<0.001). The most pronounced difference between the genotype subsets was seen for marked progression. The association between the TT genotype and progression of brain abnormalities was significant in women (P=0.03) and in men (P=0.01). Logistic regression analysis yielded an unadjusted OR of 3.78 (95% CI, 1.89 to 7.56; P<0.0001) for lesion progression in the TT genotype relative to the two other genotypes. Adjustment for age and gender altered the OR only marginally to 3.42 (95% CI, 1.70 to 6.66; P=0.001) and 3.75 (95% CI, 1.87 to 7.52; P<0.0001). We used multivariable logistic regression to assess the relative contribution of the TT relative to the other two genotypes combined on the progression of small-vessel disease-related brain abnormalities with adjustment for the putative confounders age, gender, arterial hypertension, hypertensive treatment, diabetes mellitus, heart disease, and plasma fibrinogen. Table 4 displays this risk factor model. As can be seen from this table, the TT genotype and arterial hypertension were the only variables found to be significantly associated with the progression of small-vessel disease-related brain abnormalities. The interaction term arterial hypertensionxTT genotype was not associated with lesion progression (OR, 0.67; P=0.58).
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Discussion |
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WMHs and lacunes represent small-vessel disease-related brain damage, which, in early stages, is often clinically silent.18 Our study in an elderly population has shown that the T235 variant of the angiotensinogen gene is associated with the presence and progression of these brain abnormalities. The relation between the M235T polymorphism and lesion progression occurred independent of arterial hypertension, which per se was moderately linked to both the genomic variant and lesion progression. Clinically, progression of small-vessel disease-related cerebral abnormalities is thought to be associated with cognitive dysfunction and gait disturbances, symptoms known to be a major source of disability in our aging societies.18 Identification of factors relating to the progression of this type of brain damage is thus of relevance regarding the prediction of possible clinical consequences and the development and initiation of preventive measures.
In line with the population-based ARIC study and the NHLBI family heart study,9 which measured intima-media thickness of the common carotid arteries, and a single case-control study8 assessing also the degree of stenosis, we failed to show a relation between the M235T polymorphism and carotid atherosclerosis. The lack of association with carotid atherosclerosis in the presence of an association with brain lesions linked to arteriolosclerosis appears contradictory at first glance. Yet, large- and small-vessel disease represent distinct vascular pathologies, which may also be reflected by differences in the profiles of genetic susceptibility factors.
The frequency of M and T homozygotes in our sample paralleled that of population samples from France and North America,1 New Zealand,4 and Germany,7 indicating that there was no sample bias in this community-dwelling cohort. The modest overall association between the T235 polymorphism with arterial hypertension is in keeping with a previous meta-analysis of 69 case-control studies.3 Blood pressure directly relates to plasma concentration of angiotensinogen, with the angiotensinogen level being elevated in subjects carrying the T235 variant.1 We observed a much closer relation between the T235 variant and blood pressure among women. Angiotensinogen gene expression is known to be estrogen-dependent,19 but all female participants in our study were postmenopausal. This implies other estrogen-independent yet undetermined differential gene-gene or gene-environment interactions across genders to contribute to the gender-specific difference in the blood pressure of homozygotes for the T allele, at least in higher age groups. Notably, the NHLBI Family Heart Study, which had an age distribution similar to the current cohort, also reported a greater association between the T235 polymorphism and hypertension in women than in men.20
Several histopathologic correlations substantiate that lacunes and WMH are linked to small-vessel disease of the brain. Lacunes represent small cavities caused by infarctions, which are often located in areas irrigated by the deep and superficial cerebral arterioles,14 whereas the histological correlates of WMH show much greater diversity.15 Punctate lesions frequently correspond to a perivascular reduction in myelin content with atrophy of the neuropil and thus constitute only minor tissue damage, probably from low permeability through thickened arteriolar walls. Early confluent and confluent WMH indicate more extensive tissue damage including myelin pallor, loss of fibers, reactive gliosis, and sometimes even small lacunar cavities consistent with more advanced microangiopathy. Arterial hypertension is the most important risk factor for small-vessel disease-related brain changes besides age.11,18
The mechanism(s) responsible for the effect(s) of the angiotensinogen T235 variant on progression of small-vessel disease-related cerebral abnormalities remains speculative at this time. It is clear from our data that elevated blood pressure can only partly explain this association because homozygosity for the T allele predicted lesion progression independent of arterial hypertension. One explanation for the relation is that the T235 variant represents merely a marker in linkage disequilibrium, with a close-by etiologically important polymorphism. Conceivably, this could be a recently identified mutation in the promoter region of the angiotensinogen gene (A-6), which was seen to be in tight linkage disequilibrium with T235 and caused elevated angiotensinogen expression.21 Angiotensinogen is the precursor peptide of the vasoactive hormone angiotensin II, which has multiple proatherogenic effects, including induction of smooth muscle cell hypertrophy, stimulation of vascular fibrosis, plasminogen activator inhibitor-1 stimulation, free radical formation, and increased endothelin secretion.22 Most importantly in the context of our results, there exists an independent renin-angiotensin system in the brain that might contribute to or amplify cerebral small-vessel disease, an effect that might not be reflected in the systemic circulation.23 The fact that the M235T angiotensinogen polymorphism is at some distance from the angiotensin cleavage site supports that this genomic variant is rather a marker for another functionally important mutation in the vicinity. However, one cannot exclude with certainty that angiotensinogen has other yet unknown functions unrelated to its role as a prohormone. These functions could then be altered by mutations distant from the site of cleavage, such as T235. The large ratio of the size of the precursor (452 to 453 amino acids) to product (10 amino acids) encourages a teleological argument regarding alternate functions of angiotensinogen.24 By contrast, a relatively high degree of sequence divergence (>35%) between rodents and human angiotensinogens argues against such functions because it shows that there is little pressure to conserve much of the amino acid sequence of this protein.24 Whatever mechanism is responsible for the association between the angiotensinogen M235T polymorphism and progression of brain abnormalities caused by small-vessel disease, our data suggest components of the renin-angiotensin system to play a role in the pathogenesis of arteriolosclerosis independent of their effects on blood pressure. Consequently, intervention in the renin-angiotensin system could exert beneficial effects on the evolution of small-vessel disease-related brain damage and its clinical consequences beyond what can be expected from the lowering of blood pressure alone.
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Acknowledgments |
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The study was funded by the Austrian Science Fund, project P13180-MED. The authors are grateful to Birgit Reinhart for administrative work and to Johann Semmler and Irmgard Pölzl for excellent technical assistance.
Received October 13, 2000; first decision November 16, 2000; accepted January 10, 2001.
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C. Sierra, A. Coca, E. Gomez-Angelats, E. Poch, J. Sobrino, and A. de la Sierra Renin-Angiotensin System Genetic Polymorphisms and Cerebral White Matter Lesions in Essential Hypertension Hypertension, February 1, 2002; 39(2): 343 - 347. [Abstract] [Full Text] [PDF]
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P. N. Hopkins, S. C. Hunt, X. Jeunemaitre, B. Smith, D. Solorio, N. D.L. Fisher, N. K. Hollenberg, and G. H. Williams Angiotensinogen Genotype Affects Renal and Adrenal Responses to Angiotensin II in Essential Hypertension Circulation, April 23, 2002; 105(16): 1921 - 1927. [Abstract] [Full Text] [PDF]
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