A single nucleotide polymorphism at nucleotide −1793 in the von Willebrand factor (VWF) regulatory region is associated with plasma VWF:Ag levels

Abstract 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 NFκB. 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 NFκB 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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Polymorphism C/T-13910 of the LCT gene regulatory region and lactase deficiency in Eurasian populations

Ecological genetics ◽

10.17816/ecogen5325-34 ◽

2007 ◽

Vol 5 (3) ◽

pp. 25-34

Author(s):

Maria V Sokolova ◽

Eugene V Vasilyev ◽

Andrey I Kozlov ◽

Denis V Rebrikov ◽

Svetlana S Senkeeva ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Regulatory Region ◽

Recessive Trait ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Genetic Determination ◽

Asian Populations ◽

Genotype Frequencies ◽

European Part Of Russia ◽

Genetically Determined

Genetically determined deficiency of the lactase enzyme in adults (primary hypolactasia) is a recessive trait. As shown earlier, in some European populations primary hypolactasia is determined by carrying the CC genotype at the single-nucleotide polymorphism (SNP) LCT*С/T-13910. In this work allele and genotype frequencies were estimated for the single-nucleotide polymorphism (SNP) LCT*C/ T-13910 in 7 samples (346 individuals in total), representing Eurasian populations (Saami, Mari, Russians from the Volga-Ural Area, Kazakhs, Uyghurs, Buriats, Arabs). For part of these groups and for some of the earlier studied groups the frequencies of the CC genotype are similar to the epidemiological-clinical data on hypolactasia frequency reported for respective or closely located populations (in Russians, Ukrainians, Byelorussians, Kola Saami, Mari, Komi-Permyaks, Udmurts, Pamir Mountain dwellers, and in Chukchi, Iranians and Arabs). For the Asian populations, the data are contradictory, and evaluation of genetic determination of hypolactasia in these populations requires further studies of larger samples. Considering association of primary hypolactasia with CC genotype in the Russian sample found by us earlier, the obtained results point that the CC genotype at SNP LCT*C/ T-13910 is the main genetic determinant of primary hypolactasia for populations of the European part of Russia.

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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

Blood ◽

10.1182/blood.v93.12.4277.412k03_4277_4283 ◽

1999 ◽

Vol 93 (12) ◽

pp. 4277-4283 ◽

Cited By ~ 4

Author(s):

Angela M. Keightley ◽

Y. Miu Lam ◽

Jolene N. Brady ◽

Cherie L. Cameron ◽

David Lillicrap

Keyword(s):

Single Nucleotide Polymorphisms ◽

Von Willebrand Factor ◽

Gene Locus ◽

Strong Linkage Disequilibrium ◽

Nucleotide Polymorphisms ◽

Polymorphic Variation ◽

Single Nucleotide ◽

Haplotype 1 ◽

Von Willebrand ◽

Willebrand Factor

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 NFκB. 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 NFκB 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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Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Blood ◽

10.1182/blood-2010-08-300152 ◽

2011 ◽

Vol 117 (19) ◽

pp. 5224-5230 ◽

Cited By ~ 32

Author(s):

Marco Campos ◽

Wei Sun ◽

Fuli Yu ◽

Maja Barbalic ◽

Weihong Tang ◽

...

Keyword(s):

Von Willebrand Factor ◽

Von Willebrand Disease ◽

Blood Type ◽

Nucleotide Polymorphisms ◽

Genetic Determinants ◽

Single Nucleotide ◽

Distinct Haplotype ◽

Von Willebrand ◽

And Storage ◽

Willebrand Factor

Abstractvon Willebrand factor (VWF) is an essential component of hemostasis and has been implicated in thrombosis. Multimer size and the amount of circulating VWF are known to impact hemostatic function. We associated 78 VWF single nucleotide polymorphisms (SNPs) and haplotypes constructed from those SNPs with VWF antigen level in 7856 subjects of European descent. Among the nongenomic factors, age and body mass index contributed 4.8% and 1.6% of VWF variation, respectively. The SNP rs514659 (tags O blood type) contributed 15.4% of the variance. Among the VWF SNPs, we identified 18 SNPs that are associated with levels of VWF. The correlative SNPs are either intronic (89%) or silent exonic (11%). Although SNPs examined are distributed throughout the entire VWF gene without apparent cluster, all the positive SNPs are located in a 50-kb region. Exons in this region encode for VWF D2, D′, and D3 domains that are known to regulate VWF multimerization and storage. Mutations in the D3 domain are also associated with von Willebrand disease. Fifteen of these 18 correlative SNPs are in 2 distinct haplotype blocks. In summary, we identified a cluster of intronic VWF SNPs that associate with plasma levels of VWF, individually or additively, in a large cohort of healthy subjects.

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Single Nucleotide Polymorphism (SNP) Analysis of orexin Gene 5′ Regulatory Region in Chinese Indigenous Cattle Populations

Agricultural Sciences in China ◽

10.1016/s1671-2927(11)60119-3 ◽

2011 ◽

Vol 10 (8) ◽

pp. 1273-1279 ◽

Cited By ~ 1

Author(s):

Ai-ling ZHANG ◽

Li ZHANG ◽

Liang-zhi ZHANG ◽

Xian-yong LAN ◽

Cun-lei ZHANG ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Regulatory Region ◽

Snp Analysis ◽

Nucleotide Polymorphism ◽

Indigenous Cattle ◽

Single Nucleotide

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Faculty Opinions recommendation of Association of a TNFSF13B (BAFF) regulatory region single nucleotide polymorphism with response to rituximab in antineutrophil cytoplasmic antibody-associated vasculitis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726889146.793548117 ◽

2018 ◽

Author(s):

Charles Pusey

Keyword(s):

Single Nucleotide Polymorphism ◽

Regulatory Region ◽

Antineutrophil Cytoplasmic Antibody ◽

Nucleotide Polymorphism ◽

Single Nucleotide

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Cosegregation of von Willebrand factor gene polymorphisms and possible germinal mosaicism in type IIB von Willebrand disease

Blood ◽

10.1182/blood.v77.7.1476.1476 ◽

1991 ◽

Vol 77 (7) ◽

pp. 1476-1483 ◽

Cited By ~ 8

Author(s):

EW Murray ◽

AR Giles ◽

PJ Bridge ◽

IR Peake ◽

DP Lillicrap

Keyword(s):

Von Willebrand Factor ◽

Von Willebrand Disease ◽

Nucleotide Substitutions ◽

Gene Encoding ◽

Single Nucleotide ◽

Unaffected Parent ◽

Von Willebrand ◽

Willebrand Factor ◽

Germinal Mosaicism ◽

Significant Linkage

Abstract Recent reports of the mutations resulting in von Willebrand disease (vWD) have indicated that some cases of type IIA vWD are caused by single nucleotide substitutions in the gene encoding von Willebrand factor (vWF). However, the molecular pathogenesis of type IIB vWD remains unresolved and, with the complex posttranslational processing required for fully functional vWF, the mutations responsible for this phenotype may occur at loci other than the vWF gene. This study has used six intragenic vWF polymorphisms to assess the linkage of type IIB vWD to this gene in three families (48 individuals). The results of these studies indicate that there is significant linkage between the vWF gene and the type IIB phenotype (logarithm of the odds ratio of 7.2 at theta = 0), suggesting that the mutations responsible for this disorder frequently occur at this locus. Results from one of these families indicates that the disorder has been transmitted from an unaffected parent to two children who have inherited the same vWF gene as seven unaffected siblings. This finding is suggestive of the presence of germinal mosaicism for the mutation in the father.

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