on January 15, 2009
Published online before print January 15, 2009, doi: 10.1161/ATVBAHA.108.178103
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Submitted on September 29, 2008
Accepted on December 29, 2008
Identification of Quantitative Trait Loci for Fibrin Clot Phenotypes. The EuroCLOT Study
Frances M.K. Williams *;
From the Twin Research & Genetic Epidemiology Unit (F.M.K.W., B.K., M.F., G.S., T.D.S.), King's College London, St Thomas' Hospital, UK; the Division of Cardiovascular and Diabetes Research (A.M.C., P.J.G.), Leeds University, UK; the Institute of Regional Health Services Research (K.O.K.), University of Southern Denmark, Odense; The Danish Twin Registry, Epidemiology (L.B., K.O.K.), Institute of Public Health, University of Southern Denmark, Odense; the Finnish Genome Centre (A.P.), University of Helsinki, Finland; and Genomic Medicine, Faculty of Medicine (M.F.), Imperial College London, UK.
* To whom correspondence should be addressed. E-mail: frances.williams{at}kcl.ac.uk.
Objectives—Fibrin makes up the structural basis of an occlusive arterial thrombus, and variability in fibrin phenotype relates to cardiovascular risk. The aims of the current study from the EU consortium EuroCLOT were to (1) determine the heritability of fibrin phenotypes and (2) identify QTLs associated with fibrin phenotypes.
Methods and Results—447 dizygotic (DZ) and 460 monozygotic (MZ) pairs of healthy UK white female twins and 199 DZ twin pairs from Denmark were studied. D-dimer, an indicator of fibrin turnover, was measured by ELISA and measures of clot formation, morphology, and lysis were determined by turbidimetric assays. Heritability estimates and genome-wide linkage analysis were performed. Estimates of heritability for d-dimer and turbidometric variables were in the range 17% to 46%, with highest levels for maximal absorbance which provides an estimate of clot density. Genome-wide linkage analysis revealed 6 significant regions with LOD >3 on 5 chromosomes (5, 6, 9, 16, and 17).
Conclusions—The results indicate a significant genetic contribution to variability in fibrin phenotypes and highlight regions in the human genome which warrant further investigation in relation to ischemic cardiovascular disorders and their therapy.
Key words: linkage • quantitative trait loci • twin • cardiovascular disease • thrombosis