Variants at APOE influence risk of deep and lobar intracerebral hemorrhage.
OBJECTIVE
Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied.


METHODS
We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification.


RESULTS
Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 × 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 × 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 × 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes.


CONCLUSIONS
APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Alessandro
A
Biffi
Akshata
A
Sonni
Christopher D
CD
Anderson
Brett
B
Kissela
Jeremiasz M
JM
Jagiella
Helena
H
Schmidt
Jordi
J
Jimenez-Conde
Björn M
BM
Hansen
Israel
I
Fernandez-Cadenas
Lynelle
L
Cortellini
Alison
A
Ayres
Kristin
K
Schwab
Karol
K
Juchniewicz
Andrzej
A
Urbanik
Natalia S
NS
Rost
Anand
A
Viswanathan
Thomas
T
Seifert-Held
Eva-Maria
EM
Stoegerer
Marta
M
Tomás
Raquel
R
Rabionet
Xavier
X
Estivill
Devin L
DL
Brown
Scott L
SL
Silliman
Magdy
M
Selim
Bradford B
BB
Worrall
James F
JF
Meschia
Joan
J
Montaner
Arne
A
Lindgren
Jaume
J
Roquer
Reinhold
R
Schmidt
Steven M
SM
Greenberg
Agnieszka
A
Slowik
Joseph P
JP
Broderick
Daniel
D
Woo
Jonathan
J
Rosand
D001741:Black or African American; D000368:Aged; D000369:Aged, 80 and over; D053329:Apolipoprotein E2 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D016657:Cerebral Amyloid Angiopathy; D002543:Cerebral Hemorrhage / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D003431:Cross-Cultural Comparison; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D008957:Models, Genetic; D025341:Principal Component Analysis; D011859:Radiography; D012307:Risk Factors; D044465:White People
D053329:Apolipoprotein E2; D053327:Apolipoprotein E4