Early-onset ischaemic stroke: Analysis of 58 polymorphisms in 17 genes involved in methionine metabolism

Betti Giusti; Claudia Saracini; Paola Bolli; Alberto Magi; Ida Martinelli; Flora Peyvandi; Maurizia Rasura; Massimo Volpe; Luca A. Lotta; Speranza Rubattu; Pier Mannuccio Mannucci; Rosanna Abbate

doi:10.1160/TH09-11-0748

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(02): 231-242
DOI: 10.1160/TH09-11-0748

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Early-onset ischaemic stroke: Analysis of 58 polymorphisms in 17 genes involved in methionine metabolism

Betti Giusti

¹Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy

,

Claudia Saracini

¹Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy

,

Paola Bolli

¹Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy

,

Alberto Magi

¹Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy

,

Ida Martinelli

²Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan and Department of Medicine and Medical Specialities, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Luigi Villa Foundation, Milan, Italy

,

Flora Peyvandi

²Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan and Department of Medicine and Medical Specialities, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Luigi Villa Foundation, Milan, Italy

,

Maurizia Rasura

³Department of Neurology-Stroke Unit, IInd School of Medicine, Sapienza University, Ospedale S. Andrea, Rome, Italy

,

Massimo Volpe

⁴Department of Cardiology, IInd School of Medicine, Sapienza University, Ospedale S. Andrea, Rome, Italy

⁵IRCCS Neuromed, Pozzilli (Is), Italy

,

Luca A. Lotta

²Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan and Department of Medicine and Medical Specialities, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Luigi Villa Foundation, Milan, Italy

,

Speranza Rubattu

⁴Department of Cardiology, IInd School of Medicine, Sapienza University, Ospedale S. Andrea, Rome, Italy

⁵IRCCS Neuromed, Pozzilli (Is), Italy

,

Pier Mannuccio Mannucci

²Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan and Department of Medicine and Medical Specialities, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Luigi Villa Foundation, Milan, Italy

,

Rosanna Abbate

¹Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy

› Author Affiliations

Abstract

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Summary

The hypothesis underlying this study is that variations in genes involved in methionine metabolism may contribute to genetic susceptibility for early-onset ischaemic stroke. We investigated 58 polymorphisms in AHCY, BHMT, BHMT2, CBS, ENOSF1, FOLH1, MTHFD1, MTHFR, MTR, MTRR, NNMT, PON1, PON2, SLC19A1, SHMT1, TCN2, TYMS genes on genomic DNA from 501 young patients who survived ischaemic stroke and 1,211 sex and age comparable controls. Genotype distribution was significantly different between patients and controls for the following SNPs: rs10037045 BHMT, rs682985 BHMT2, rs1051319 CBS, rs202680 FOLH1, rs2274976 MTHFR, rs1979277 SHMT1, rs20721958 TCN2. On multiple logistic regression analysis adjusted for traditional risk factors, rs10037045 BHMT, rs682985 BHMT2, rs1051319 CBS, and rs202680 FOLH1 remained independent risk factors for stroke. After haplotype reconstruction, generalised linear model analyses adjusted for traditional risk factors and using the FDR multiple testing correction showed significant associations between ischaemic stroke and BHMT, CBS, FOLH1, MTR, PON2, TCN2 and TYMS haplotypes. This study identifies significant genetic associations between premature ischaemic stroke and haplotypes in BHMT, CBS, FOLH1, MTR, PON2, TCN2 and TYMS genes involved in methionine metabolism.

Keywords

Ischaemic stroke - methionine metabolism - homocysteine - polymor-phism - haplotype

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References

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