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

Ioana Cotlarciuc; Rainer Malik; Elizabeth G. Holliday; Kourosh R. Ahmadi; Guillaume Paré; Bruce M. Psaty; Myriam Fornage; Nazeeha Hasan; Paul E. Rinne; M. Arfan Ikram; Hugh S. Markus; Jonathan Rosand; Braxton D. Mitchell; Steven J. Kittner; James F. Meschia; Joyce B.J. Van Meurs; Andre G. Uitterlinden; Bradford B. Worrall; Martin Dichgans; Pankaj Sharma

doi:10.1161/STROKEAHA.114.005208

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

Ioana Cotlarciuc, Rainer Malik, Elizabeth G. Holliday, Kourosh R. Ahmadi, Guillaume Paré, Bruce M. Psaty, Myriam Fornage, Nazeeha Hasan, Paul E. Rinne, M. Arfan Ikram, Hugh S. Markus, Jonathan Rosand, Braxton D. Mitchell, Steven J. Kittner, James F. Meschia, Joyce B.J. Van Meurs, Andre G. Uitterlinden, Bradford B. Worrall, Martin Dichgans, Pankaj Sharma

Neurology

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1920-1924
Number of pages	5
Journal	Stroke
Volume	45
Issue number	7
DOIs	https://doi.org/10.1161/STROKEAHA.114.005208
State	Published - Jul 2014

Keywords

genetic association studies
genetic risk score
homocysteine
stroke

ASJC Scopus subject areas

Clinical Neurology
Cardiology and Cardiovascular Medicine
Advanced and Specialized Nursing

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10.1161/STROKEAHA.114.005208

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Cotlarciuc, I., Malik, R., Holliday, E. G., Ahmadi, K. R., Paré, G., Psaty, B. M., Fornage, M., Hasan, N., Rinne, P. E., Ikram, M. A., Markus, H. S., Rosand, J., Mitchell, B. D., Kittner, S. J., Meschia, J. F., Van Meurs, J. B. J., Uitterlinden, A. G., Worrall, B. B., Dichgans, M., & Sharma, P. (2014). Effect of genetic variants associated with plasma homocysteine levels on stroke risk. Stroke, 45(7), 1920-1924. https://doi.org/10.1161/STROKEAHA.114.005208

Cotlarciuc, I, Malik, R, Holliday, EG, Ahmadi, KR, Paré, G, Psaty, BM, Fornage, M, Hasan, N, Rinne, PE, Ikram, MA, Markus, HS, Rosand, J, Mitchell, BD, Kittner, SJ, Meschia, JF, Van Meurs, JBJ, Uitterlinden, AG, Worrall, BB, Dichgans, M & Sharma, P 2014, 'Effect of genetic variants associated with plasma homocysteine levels on stroke risk', Stroke, vol. 45, no. 7, pp. 1920-1924. https://doi.org/10.1161/STROKEAHA.114.005208

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title = "Effect of genetic variants associated with plasma homocysteine levels on stroke risk",

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.",

keywords = "genetic association studies, genetic risk score, homocysteine, stroke",

author = "Ioana Cotlarciuc and Rainer Malik and Holliday, {Elizabeth G.} and Ahmadi, {Kourosh R.} and Guillaume Par{\'e} and Psaty, {Bruce M.} and Myriam Fornage and Nazeeha Hasan and Rinne, {Paul E.} and Ikram, {M. Arfan} and Markus, {Hugh S.} and Jonathan Rosand and Mitchell, {Braxton D.} and Kittner, {Steven J.} and Meschia, {James F.} and {Van Meurs}, {Joyce B.J.} and Uitterlinden, {Andre G.} and Worrall, {Bradford B.} and Martin Dichgans and Pankaj Sharma",

year = "2014",

month = jul,

doi = "10.1161/STROKEAHA.114.005208",

language = "English (US)",

volume = "45",

pages = "1920--1924",

journal = "Stroke",

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T1 - Effect of genetic variants associated with plasma homocysteine levels on stroke risk

AU - Cotlarciuc, Ioana

AU - Malik, Rainer

AU - Holliday, Elizabeth G.

AU - Ahmadi, Kourosh R.

AU - Paré, Guillaume

AU - Psaty, Bruce M.

AU - Fornage, Myriam

AU - Hasan, Nazeeha

AU - Rinne, Paul E.

AU - Ikram, M. Arfan

AU - Markus, Hugh S.

AU - Rosand, Jonathan

AU - Mitchell, Braxton D.

AU - Kittner, Steven J.

AU - Meschia, James F.

AU - Van Meurs, Joyce B.J.

AU - Uitterlinden, Andre G.

AU - Worrall, Bradford B.

AU - Dichgans, Martin

AU - Sharma, Pankaj

PY - 2014/7

Y1 - 2014/7

N2 - 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.

AB - 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.

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KW - genetic risk score

KW - homocysteine

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JO - Stroke

JF - Stroke

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

Abstract

Keywords

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