Genetic risk factors for cerebral small-vessel disease in hypertensive patients from a genetically isolated population.
BACKGROUND
Asymptomatic cerebral lesions on MRI such as white matter lesions (WML), lacunes and microbleeds are commonly seen in older people. We examined the role of a series of candidate genes involved in blood pressure regulation and amyloid metabolism.


METHODS
The study was embedded in a family-based cohort sampled from a Dutch genetically isolated population. We selected individuals between 55 and 75 years of age with hypertension (N=129). Volumes of WML and presence of lacunes and microbleeds were assessed with MRI. We studied three genes involved in blood pressure regulation (angiotensin, angiotensin II type 1 receptor, α-adducin) and two genes involved in the amyloid pathway (apolipoprotein E (APOE) and sortilin-related receptor gene (SORL1)).


RESULTS
All participants had WML (median volume, 3.1 ml; interquartile range, 1.5-6.5 ml); lacunar infarcts were present in 15.5% and microbleeds in 23.3%. Homozygosity for the APOE ε4 allele was associated with lacunes (OR, 4.8; 95% CI, 1.2 to 19.3). Individuals carrying two copies of the variant allele of four single nucleotide polymorphism (SNPs) located at the 3'-end of SORL1 (rs1699102, rs3824968, rs2282649, rs1010159) had significantly more often microbleeds (highest OR, 6.87; 95% CI, 1.78 to 26.44).


CONCLUSIONS
The association of SORL1 with microbleeds suggests that the amyloid cascade is involved in the aetiology of microbleeds in populations with hypertension.
Schuur
M
M
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
van Swieten
J C
JC
Schol-Gelok
S
S
Ikram
M A
MA
Vernooij
M W
MW
Liu
F
F
Isaacs
A
A
de Boer
R
R
de Koning
I
I
Niessen
W J
WJ
Vrooman
H
H
Oostra
B A
BA
van der Lugt
A
A
Breteler
M M B
MM
van Duijn
C M
CM
D000368:Aged; D000682:Amyloid / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D001794:Blood Pressure / Q000502:physiology; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000473:pathology; D002561:Cerebrovascular Disorders / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics*; D003072:Cognition Disorders / Q000209:etiology / Q000523:psychology; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D026502:LDL-Receptor Related Proteins / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D000099291:Adducins
D000682:Amyloid; D001057:Apolipoproteins E; D002148:Calmodulin-Binding Proteins; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D044140:Receptor, Angiotensin, Type 1; D000099291:Adducins; C102582:SORL1 protein, human