Angiotensinogen gene promoter haplotype and microangiopathy-related cerebral damage: results of the Austrian Stroke Prevention Study.
OBJECTIVE
Microangiopathy-related cerebral damage (MARCD) is a common finding in the elderly. It may lead to cognitive impairment and gait disturbances. Arterial hypertension and age are the most important risk factors. We assessed the association between MARCD and sequence alterations in the promoter region of the angiotensinogen (AGT) gene.


METHODS
We studied 410 randomly selected community-dwelling individuals aged 50 to 75 years. MARCD was defined as early confluent or confluent white matter hyperintensities or lacunes on a 1.5-T MRI. The AGT promoter was analyzed by temporal temperature gradient gel electrophoresis and automated sequencing.


RESULTS
We detected 4 polymorphic sites, at positions -6, -20, -153, and -218. They created 5 haplotypes, which we coded as A (-6:g, -20:a, -153:g, -218g), B (-6:a, -20:c, -153:g, -218:g), C (-6:a, -20:c, -153:a, -218:g), D (-6:a, -20:a, -153:g, -218:g), and E (-6:a, -20:a, -153:g, -218:a). MARCD was seen in 7 subjects (63.6%) carrying 2 copies of the B haplotype (B/B), in 12 subjects (38.7%) carrying 1 copy of the B haplotype in the absence of the A haplotype (B+/A-), but in only 70 subjects (19.0%) in the remaining cohort (P:<0.001). The odds ratios for the B/B and the B+/A- genotypes were 8.0 (95% CI, 2.1 to 31.1; P:=0.003) and 1.8 (95% CI, 0.8 to 4.2; P:=0.14) after adjustment for possible confounders.


CONCLUSIONS
The B haplotype of the AGT promoter in the absence of the wild-type A haplotype might represent a genetic susceptibility factor for MARCD.
Schmidt
H
H
Institute of Medical Biochemistry and Medical Molecular Biology, Karl-Franzens University, Graz, Austria. helena.schmidt@kfunigraz.ac.at
Fazekas
F
F
Kostner
G M
GM
van Duijn
C M
CM
Schmidt
R
R
D017677:Age Distribution; D000368:Aged; D000809:Angiotensins / Q000235:genetics*; D001317:Austria / Q000453:epidemiology; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002539:Cerebral Arterial Diseases / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D002560:Cerebrovascular Circulation / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000235:genetics; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008833:Microcirculation / Q000473:pathology; D008875:Middle Aged; D016017:Odds Ratio; D017354:Point Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018570:Risk Assessment; D017678:Sex Distribution
D000809:Angiotensins