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Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.

Authors :
Rannikmäe K
Davies G
Thomson PA
Bevan S
Devan WJ
Falcone GJ
Traylor M
Anderson CD
Battey TW
Radmanesh F
Deka R
Woo JG
Martin LJ
Jimenez-Conde J
Selim M
Brown DL
Silliman SL
Kidwell CS
Montaner J
Langefeld CD
Slowik A
Hansen BM
Lindgren AG
Meschia JF
Fornage M
Bis JC
Debette S
Ikram MA
Longstreth WT
Schmidt R
Zhang CR
Yang Q
Sharma P
Kittner SJ
Mitchell BD
Holliday EG
Levi CR
Attia J
Rothwell PM
Poole DL
Boncoraglio GB
Psaty BM
Malik R
Rost N
Worrall BB
Dichgans M
Van Agtmael T
Woo D
Markus HS
Seshadri S
Rosand J
Sudlow CL
Source :
Neurology [Neurology] 2015 Mar 03; Vol. 84 (9), pp. 918-26. Date of Electronic Publication: 2015 Feb 04.
Publication Year :
2015

Abstract

Objectives: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.<br />Methods: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).<br />Results: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.<br />Conclusions: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.<br /> (© 2015 American Academy of Neurology.)

Details

Language :
English
ISSN :
1526-632X
Volume :
84
Issue :
9
Database :
MEDLINE
Journal :
Neurology
Publication Type :
Academic Journal
Accession number :
25653287
Full Text :
https://doi.org/10.1212/WNL.0000000000001309