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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4277-4283
Variation at the von Willebrand Factor (vWF) Gene Locus Is
Associated With Plasma vWF:Ag Levels: Identification of Three Novel
Single Nucleotide Polymorphisms in the vWF Gene Promoter
Angela M. Keightley,
Y. Miu Lam,
Jolene N. Brady,
Cherie L. Cameron, and
David Lillicrap
From the Departments of Pathology and Community Health and
Epidemiology, Queen's University, Kingston, Ontario, Canada.
Both genetic and environmental factors contribute to the normal
population variability of plasma von Willebrand Factor (vWF) levels,
however, regulatory mechanisms at the vWF gene locus itself have not
yet been identified. We have investigated the association between
polymorphic variation in the 5'-regulatory region of the vWF gene
and levels of plasma vWF:Ag in a study of 261 group O blood donors.
Three novel single nucleotide polymorphisms (SNPs) were identified in
the vWF promoter: C/T at -1234, A/G at -1185, and G/A at -1051. These
SNPs had identical allele frequencies of 0.36 for the -1234C, -1185A,
and -1051G alleles and 0.64 for the -1234T, -1185G, and -1051A alleles
and were in strong linkage disequilibrium. In fact, these polymorphisms
segregated as two distinct haplotypes: -1234C/-1185A/-1051G (haplotype
1) and -1234T/-1185G/-1051A (haplotype 2) with 12.6% of subjects
homozygous for haplotype 1, 40.6% homozygous for haplotype 2, and
42.5% of subjects heterozygous for both haplotypes. Only 4.3% of
individuals had other genotypes. A significant association between
promoter genotype and level of plasma vWF:Ag was established (analysis
of covariance [ANCOVA], P = .008; Kruskal-Wallis test,
P = .006); individuals with the CC/AA/GG genotype had the
highest mean vWF:Ag levels (0.962 U/mL), intermediate values of vWF:Ag
(0.867 U/mL) were observed for heterozygotes (CT/AG/GA), and those with
the TT/GG/AA genotype had the lowest mean plasma vWF:Ag levels (0.776 U/mL). Interestingly, when the sample was subgrouped according to age,
the significant association between promoter genotype and plasma vWF:Ag
level was accentuated in subjects > 40 years of age (analysis of
variance [ANOVA], P = .003; Kruskal-Wallis test, P
= .001), but was not maintained for subjects  40 years of age
(ANOVA, P > .4; Kruskal-Wallis test, P > .4). In
the former subgroup, mean levels of plasma vWF:Ag for subjects with the
CC/AA/GG, CT/AG/GA, and TT/GG/AA genotypes were 1.075, 0.954, and 0.794 U/mL, respectively. By searching a transcription factor binding site
profile database, these polymorphic sequences were predicted to
interact with several transcription factors expressed in endothelial
cells, including Sp1, GATA-2, c-Ets, and NF B. Furthermore, the
binding sites at the -1234 and -1051 SNPs appeared to indicate allelic
preferences for some of these proteins. Electrophoretic mobility shift
assays (EMSAs) performed with recombinant human NFB p50 showed
preferential binding of the -1234T allele (confirmed by supershift
EMSAs), and EMSAs using bovine aortic endothelial cell (BAEC) nuclear extracts produced specific binding of a nuclear protein to the -1051A
allele, but not the -1051G allele. These findings suggest that
circulating levels of vWF:Ag may be determined, at least in part, by
polymorphic variation in the promoter region of the vWF gene, and that
this association may be mediated by differential binding of nuclear
proteins involved in the regulation of vWF gene expression.
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