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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2356-2362.
Prepublished online as a Blood First Edition Paper on June 14, 2005; DOI 10.1182/blood-2005-02-0723.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The TUBB1 Q43P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure
Kathleen Freson,
Rita De Vos,
Christine Wittevrongel,
Chantal Thys,
Johan Defoor,
Luc Vanhees,
Jos Vermylen,
Kathelijne Peerlinck, and
Chris Van Geet
From the Center for Molecular and Vascular Biology, Department of Pathology, Cardiovascular Rehabilitation Unit, Department of Rehabilitation Sciences, Faculty of Physical Education and Physical Therapy, and Department of Pediatrics, University of Leuven, Belgium.
The discoid form of platelets is maintained by a marginal band of tightly coiled microtubules.  1-tubulin is the major isoform within platelet and megakaryocyte microtubules. In 24.2% of 33 unrelated inherited macrothrombocytopenia patients and in 10.6% of 272 subjects of a healthy population a P for Q substitution in 1-tubulin was found in the highly conserved residue 43. Heterozygous carriers of the Q43P variant showed a reduced platelet protein 1-tubulin expression. Transfection of green fluorescent protein (GFP)-tagged Q43P 1-tubulin in megakaryocytic MEG01 cells resulted in a disturbed tubulin organization. Electron microscopy revealed enlarged spherocytic platelets with a disturbed marginal band and organelle-free zones. In addition, platelets with the Q43P 1-tubulin variant had reduced adenosine triphosphate (ATP) secretion, thrombin receptor activating peptide (TRAP)-induced aggregation and collagen adhesion. The prevalence of the Q43P 1-tubulin variant was also 2 times higher (odds ratio, [OR] = 2.1;95% confidence interval [CI], 1.22-3.59) among control subjects than among patients with cardiovascular disease (10.4% versus 5.2%, P < .001). By analyzing this protective factor in men and women separately, this association was only found in men. This study thus presents the functional consequences of the platelet Q43P 1-tubulin substitution that is frequent in the healthy population and may protect men against arterial thrombosis.
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