Effect of Genetic Variants Associated With Plasma Homocysteine Levels on Stroke Risk
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Overview
abstract
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.
