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Effect of genetic variants associated with plasma homocysteine levels on stroke risk.

TitleEffect of genetic variants associated with plasma homocysteine levels on stroke risk.
Publication TypeJournal Article
Year of Publication2014
AuthorsCotlarciuc, I, Malik, R, Holliday, EG, Ahmadi, KR, Paré, G, Psaty, BM, Fornage, M, Hasan, N, Rinne, PE, Ikram, AM, Markus, HS, Rosand, J, Mitchell, BD, Kittner, SJ, Meschia, JF, van Meurs, JBJ, Uitterlinden, AG, Worrall, BB, Dichgans, M, Sharma, P
Corporate/Institutional AuthorsMETASTROKE and the International Stroke Genetics Consortium
Date Published2014 Jul
KeywordsBrain Ischemia, Cohort Studies, Europe, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome, Homocysteine, Humans, Polymorphism, Single Nucleotide, Risk, Stroke
Abstract<p><b>BACKGROUND AND PURPOSE: </b>Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.</p><p><b>METHODS: </b>Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.</p><p><b>RESULTS: </b>One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.</p><p><b>CONCLUSIONS: </b>This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.</p>
Alternate JournalStroke
PubMed ID24846872
PubMed Central IDPMC4083192
Grant List / / Medical Research Council / United Kingdom
/ / Department of Health / United Kingdom
P30 DK072488 / DK / NIDDK NIH HHS / United States
Z99 OD999999 / / Intramural NIH HHS / United States
/ / Wellcome Trust / United Kingdom