title: The TUBB1 Q43P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure.
abstract: The discoid form of platelets is maintained by a marginal band of tightly coiled microtubules. beta1-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 beta1-tubulin was found in the highly conserved residue 43. Heterozygous carriers of the Q43P variant showed a reduced platelet protein beta1-tubulin expression. Transfection of green fluorescent protein (GFP)-tagged Q43P beta1-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 beta1-tubulin variant had reduced adenosine triphosphate (ATP) secretion, thrombin receptor activating peptide (TRAP)-induced aggregation and collagen adhesion. The prevalence of the Q43P beta1-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 beta1-tubulin substitution that is frequent in the healthy population and may protect men against arterial thrombosis.
authors.affiliation: Center for Molecular and Vascular Biology, Department of Pathology, Cardiovascular Rehabilitation Unit, University of Leuven, Belgium. kathleen.freson@med.kuleuven.be
authors.forename: Kathleen
authors.initials: K
authors.lastname: Freson
authors.forename: Rita
authors.initials: R
authors.lastname: De Vos
authors.forename: Christine
authors.initials: C
authors.lastname: Wittevrongel
authors.forename: Chantal
authors.initials: C
authors.lastname: Thys
authors.forename: Johan
authors.initials: J
authors.lastname: Defoor
authors.forename: Luc
authors.initials: L
authors.lastname: Vanhees
authors.forename: Jos
authors.initials: J
authors.lastname: Vermylen
authors.forename: Kathelijne
authors.initials: K
authors.lastname: Peerlinck
authors.forename: Chris
authors.initials: C
authors.lastname: Van Geet
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D001792:Blood Platelets / Q000166:cytology* / Q000502:physiology / Q000648:ultrastructure; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics*; D002448:Cell Adhesion; D003094:Collagen / Q000378:metabolism; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D008854:Microscopy, Electron; D008858:Microscopy, Phase-Contrast; D008875:Middle Aged; D008969:Molecular Sequence Data; D016017:Odds Ratio; D010477:Perfusion; D010973:Platelet Adhesiveness; D011110:Polymorphism, Genetic; D020033:Protein Isoforms; D012737:Sex Factors; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics*; D013927:Thrombosis / Q000235:genetics / Q000517:prevention & control; D014162:Transfection; D014404:Tubulin / Q000235:genetics* / Q000502:physiology
chemical_list: D018076:DNA, Complementary; D020033:Protein Isoforms; C578986:TUBB1 protein, human; D014404:Tubulin; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D003094:Collagen