title: High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11.
abstract: High factor VIII (FVIII) levels are known to be a risk factor for deep venous thrombosis, but the mechanisms responsible for high FVIII levels remain unclear. Here, a new phenotype "FVIII level residuum" (FVIII-R) was defined in order to eliminate the impact of common determinants on FVIII levels. We studied 13 families of patients with thrombosis and reproducibly high FVIII levels of unknown origin. Since familial clustering was evident, we looked for a possible genetic basis. A genome scan was performed with 402 evenly spaced microsatellite markers. A quantitative linkage analysis using variance component methods showed suggestive evidence for linkage of FVIII-R with a locus on chromosome 8 (logarithm of odds [LOD] = 2.1). In addition, we performed parametric exploratory linkage analysis of dichotomized FVIII-R, taking a parent-of-origin effect into account. Single-trait-locus MOD-score analysis showed suggestive evidence for linkage under an imprinting model at chromosomes 5 and 11. Furthermore, a 2-trait-locus analysis under a multiplicative model for the loci of chromosomes 5 and 11 yielded a remarkable LOD of 4.44. It confirmed the finding of paternal imprinting, obtained by single-trait-locus analysis, at both loci. Our results suggest that high FVIII levels in venous thromboembolism represent a complex trait caused by several genetic factors.
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Berger
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.forename: Bettina
authors.initials: B
authors.lastname: Kulle
authors.forename: Henriette
authors.initials: H
authors.lastname: Schmidt
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Tom H
authors.initials: TH
authors.lastname: Lindner
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.forename: Christian M
authors.initials: CM
authors.lastname: Schambeck
mesh_terms: D002880:Chromosomes, Human, Pair 11; D002895:Chromosomes, Human, Pair 5; D005167:Factor VII / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D020246:Venous Thrombosis / Q000097:blood / Q000235:genetics*
chemical_list: D005167:Factor VII