Leukoaraiosis is associated with genes regulating blood-brain barrier homeostasis in ischaemic stroke patients.
BACKGROUND
The biologic agents causing leukoaraiosis are unknown. Our aim was to study the genetic basis of leukoaraiosis.


METHODS
We analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30,104 genotypes. Seventy-nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by ARWMC scale. We analyzed the presence of synergic associations between SNPs using the hfcc software. Finally, functional studies were performed in 56 subjects. The Ingenuity Pathways software (ipa) was used to examine the role of the identified genes.


RESULTS
Six SNPs were associated with leukoaraiosis using both measuring scales. After logistic regression adjusted for leukoaraiosis risk factors, the rs2252070 of MMP13 (OR = 4.9, 95%CI: 1.34-17.9, P = 0.016), rs662 of PON1 (OR = 0.37, 95%CI: 0.15-0.87, P = 0.024) and rs1800779 of NOS3 (OR = 3.9, 95%CI: 1.38-11.38, P = 0.01) were independently associated with leukoaraiosis under a dominant/recessive model and the rs2290608 of IL5RA (OR = 0.46, 95%CI: 0.25-0.85, P = 0.013) and rs669 of A2M (OR = 2.5, 95%CI: 1.36-4.83, P = 0.004) under an additive model. Computational analysis showed a synergic association of rs10497212-AA of ITGB6 and rs2290608-GG of IL5RA with leukoaraiosis using both scales. (i) ARWMC (P = 1.3 × 10(-4) ) and (ii) Fazekas (P = 4.5 × 10(-5) ). Functional studies showed that the rs669 SNP was associated with plasma levels of A2M (P = 0.012) and A2M levels with leukoaraiosis in Fazekas scale (P = 0.02). ipa analysis revealed that the genes associated with leukoaraiosis were involved in blood-brain barrier (BBB) homeostasis.


CONCLUSIONS
Amongst patients with ischaemic stroke, several genes associated with BBB homeostasis could be involved with a higher risk of leukoaraiosis.
Department of Neurology, Neurovascular Research Laboratory and Neurovascular Unit, Vall d'Hebron University Hospital, Barcelona, Spain.
I
I
Fernandez-Cadenas
M
M
Mendioroz
S
S
Domingues-Montanari
A
A
Del Rio-Espinola
P
P
Delgado
A
A
Ruiz
M
M
Hernandez-Guillamon
D
D
Giralt
P
P
Chacon
M
M
Navarro-Sobrino
M
M
Ribo
C A
CA
Molina
J
J
Alvarez-Sabin
A
A
Rosell
J
J
Montaner
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D053666:Interleukin-5 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D049292:Leukoaraiosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D020521:Stroke / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
C485918:IL5RA protein, human; D053666:Interleukin-5 Receptor alpha Subunit