title: Genome-wide studies of von Willebrand factor propeptide identify loci contributing to variation in propeptide levels and von Willebrand factor clearance.
abstract: Essentials Variants at ABO, von Willebrand Factor (VWF) and 2q12 contribute to the variation in plasma in VWF. We performed a genome-wide association study of plasma VWF propeptide in 3,238 individuals. ABO, VWF and 2q12 loci had weak or no association or linkage with plasma VWFpp levels. VWF associated variants at ABO, VWF and 2q12 loci primarily affect VWF clearance rates.
  
  
  
  Background Previous studies identified common variants at the ABO and VWF loci and unknown variants in a chromosome 2q12 linkage interval that contributed to the variation in plasma von Willebrand factor (VWF) levels. Whereas the association with ABO haplotypes can be explained by differential VWF clearance, little is known about the mechanisms underlying the association with VWF single-nucleotide polymorphisms (SNPs) or with variants in the chromosome 2 linkage interval. VWF propeptide (VWFpp) and mature VWF are encoded by the VWF gene and secreted at the same rate, but have different plasma half-lives. Therefore, comparison of VWFpp and VWF association signals can be used to assess whether the variants are primarily affecting synthesis/secretion or clearance. Methods We measured plasma VWFpp levels and performed genome-wide linkage and association studies in 3238 young and healthy individuals for whom VWF levels had been analyzed previously. Results and conclusions Common variants in an intergenic region on chromosome 7q11 were associated with VWFpp levels. We found that ABO serotype-specific SNPs were associated with VWFpp levels in the same direction as for VWF, but with a much lower effect size. Neither the association at VWF nor the linkage on chromosome 2 previously reported for VWF was observed for VWFpp. Taken together, these results suggest that the major genetic factors affecting plasma VWF levels, i.e. variants at ABO, VWF and a locus on chromosome 2, operate primarily through their effects on VWF clearance.
authors.affiliation: Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Ozel
authors.affiliation: Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: B
authors.initials: B
authors.lastname: McGee
authors.affiliation: Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Siemieniak
authors.affiliation: The Blood Center of Wisconsin, Milwaukee, WI, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Jacobi
authors.affiliation: The Blood Center of Wisconsin, Milwaukee, WI, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Haberichter
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Brody
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Mills
authors.affiliation: School of Medicine, Trinity College Dublin, Dublin, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Molloy
authors.affiliation: Human Genetics, University of Michigan, Ann Arbor, MI, USA.|Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.|Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.|Department of Pediatrics and Communicable Disease, University of Michigan, Ann Arbor, MI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ginsburg
authors.affiliation: Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J Z
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Pediatrics and Communicable Disease, University of Michigan, Ann Arbor, MI, USA. kdesch@umich.edu.
authors.forename: K C
authors.initials: KC
authors.lastname: Desch
mesh_terms: D000017:ABO Blood-Group System; D000293:Adolescent; D000328:Adult; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D010641:Phenotype; D011498:Protein Precursors / Q000097:blood*; D055815:Young Adult; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000017:ABO Blood-Group System; D011498:Protein Precursors; D014841:von Willebrand Factor
keywords: genetic linkage analysis; genome-wide association study; venous thromboembolism; von Willebrand disease; von Willebrand factor