03225nas a2200541 4500008004100000022001400041245009000055210006900145260001300214300001100227490000700238520164600245653001901891653001901910653001101929653003201940653001701972653003801989653002202027653001102049653001702060653001102077653003602088653000902124653001102133100002202144700001802166700002702184700002302211700002102234700002002255700002002275700001902295700001902314700002002333700002002353700002102373700002502394700002302419700002202442700002602464700002802490700002502518700002102543700001902564710006402583856003602647 2014 eng d a1524-462800aEffect of genetic variants associated with plasma homocysteine levels on stroke risk.0 aEffect of genetic variants associated with plasma homocysteine l c2014 Jul a1920-40 v453 a
BACKGROUND AND PURPOSE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
10aBrain Ischemia10aCohort Studies10aEurope10aGenetic Association Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGenome10aHomocysteine10aHumans10aPolymorphism, Single Nucleotide10aRisk10aStroke1 aCotlarciuc, Ioana1 aMalik, Rainer1 aHolliday, Elizabeth, G1 aAhmadi, Kourosh, R1 aParé, Guillaume1 aPsaty, Bruce, M1 aFornage, Myriam1 aHasan, Nazeeha1 aRinne, Paul, E1 aIkram, Arfan, M1 aMarkus, Hugh, S1 aRosand, Jonathan1 aMitchell, Braxton, D1 aKittner, Steven, J1 aMeschia, James, F1 avan Meurs, Joyce, B J1 aUitterlinden, André, G1 aWorrall, Bradford, B1 aDichgans, Martin1 aSharma, Pankaj1 aMETASTROKE and the International Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/6556