Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels

Anne Yaël Nossent, J H Robben, P M T Deen, H L Vos, F R Rosendaal, C J M Doggen, J L Hansen, S P Sheikh, R M Bertina, J C J Eikenboom

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

SUMMARY OBJECTIVES: Stimulation of arginine vasopressin 2 receptor (V2R) with arginine vasopressin (AVP) results in a rise in von Willebrand factor (VWF) and factor VIII plasma levels. We hypothesized that gain-of-function variations in the V2R gene (AVPR2) would lead to higher plasma levels of VWF and FVIII. METHODS AND RESULTS: We genotyped the control populations of two population-based studies for four AVPR2 variations: a-245c, G12E, L309L, and S331S. Rare alleles of a-245c, G12E, and S331S, which were in linkage disequilibrium, were associated with higher VWF propeptide, VWF and FVIII levels. The functionality of the G12E variant was studied in stably transfected MDCKII cells, expressing constructs of either 12G-V2R or 12E-V2R. Both V2R variants were fully glycosylated and expressed on the basolateral membrane. The binding affinity of V2R for AVP was increased three-fold in 12E-V2R-green fluorescent protein (GFP) cells, which is in accordance with increased levels of VWF propeptide associated with the 12E variant. The dissociation constant (K(D)) was 4.5 nm [95% confidence interval (CI) 3.6-5.4] for 12E-V2R-GFP and 16.5 nm (95% CI 10.1-22.9) for 12G-V2R-GFP. AVP-induced cAMP generation was enhanced in 12E-V2R-GFP cells. CONCLUSIONS: The 12E-V2R variant has increased binding affinity for AVP, resulting in increased signal transduction, and is associated with increased levels of VWF propeptide, VWF, and FVIII.
OriginalsprogEngelsk
TidsskriftJournal of Thrombosis and Haemostasis
Vol/bind8
Udgave nummer7
Sider (fra-til)1547-54
Antal sider8
ISSN1538-7933
DOI
StatusUdgivet - 1. jul. 2010

Fingeraftryk

Vasopressin Receptors
von Willebrand Factor
Green Fluorescent Proteins
Confidence Intervals
Linkage Disequilibrium
Population

Citer dette

Nossent, A. Y., Robben, J. H., Deen, P. M. T., Vos, H. L., Rosendaal, F. R., Doggen, C. J. M., ... Eikenboom, J. C. J. (2010). Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels. Journal of Thrombosis and Haemostasis, 8(7), 1547-54. https://doi.org/10.1111/j.1538-7836.2010.03884.x
Nossent, Anne Yaël ; Robben, J H ; Deen, P M T ; Vos, H L ; Rosendaal, F R ; Doggen, C J M ; Hansen, J L ; Sheikh, S P ; Bertina, R M ; Eikenboom, J C J. / Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels. I: Journal of Thrombosis and Haemostasis. 2010 ; Bind 8, Nr. 7. s. 1547-54.
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title = "Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels",
abstract = "SUMMARY OBJECTIVES: Stimulation of arginine vasopressin 2 receptor (V2R) with arginine vasopressin (AVP) results in a rise in von Willebrand factor (VWF) and factor VIII plasma levels. We hypothesized that gain-of-function variations in the V2R gene (AVPR2) would lead to higher plasma levels of VWF and FVIII. METHODS AND RESULTS: We genotyped the control populations of two population-based studies for four AVPR2 variations: a-245c, G12E, L309L, and S331S. Rare alleles of a-245c, G12E, and S331S, which were in linkage disequilibrium, were associated with higher VWF propeptide, VWF and FVIII levels. The functionality of the G12E variant was studied in stably transfected MDCKII cells, expressing constructs of either 12G-V2R or 12E-V2R. Both V2R variants were fully glycosylated and expressed on the basolateral membrane. The binding affinity of V2R for AVP was increased three-fold in 12E-V2R-green fluorescent protein (GFP) cells, which is in accordance with increased levels of VWF propeptide associated with the 12E variant. The dissociation constant (K(D)) was 4.5 nm [95{\%} confidence interval (CI) 3.6-5.4] for 12E-V2R-GFP and 16.5 nm (95{\%} CI 10.1-22.9) for 12G-V2R-GFP. AVP-induced cAMP generation was enhanced in 12E-V2R-GFP cells. CONCLUSIONS: The 12E-V2R variant has increased binding affinity for AVP, resulting in increased signal transduction, and is associated with increased levels of VWF propeptide, VWF, and FVIII.",
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Nossent, AY, Robben, JH, Deen, PMT, Vos, HL, Rosendaal, FR, Doggen, CJM, Hansen, JL, Sheikh, SP, Bertina, RM & Eikenboom, JCJ 2010, 'Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels', Journal of Thrombosis and Haemostasis, bind 8, nr. 7, s. 1547-54. https://doi.org/10.1111/j.1538-7836.2010.03884.x

Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels. / Nossent, Anne Yaël; Robben, J H; Deen, P M T; Vos, H L; Rosendaal, F R; Doggen, C J M; Hansen, J L; Sheikh, S P; Bertina, R M; Eikenboom, J C J.

I: Journal of Thrombosis and Haemostasis, Bind 8, Nr. 7, 01.07.2010, s. 1547-54.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels

AU - Nossent, Anne Yaël

AU - Robben, J H

AU - Deen, P M T

AU - Vos, H L

AU - Rosendaal, F R

AU - Doggen, C J M

AU - Hansen, J L

AU - Sheikh, S P

AU - Bertina, R M

AU - Eikenboom, J C J

PY - 2010/7/1

Y1 - 2010/7/1

N2 - SUMMARY OBJECTIVES: Stimulation of arginine vasopressin 2 receptor (V2R) with arginine vasopressin (AVP) results in a rise in von Willebrand factor (VWF) and factor VIII plasma levels. We hypothesized that gain-of-function variations in the V2R gene (AVPR2) would lead to higher plasma levels of VWF and FVIII. METHODS AND RESULTS: We genotyped the control populations of two population-based studies for four AVPR2 variations: a-245c, G12E, L309L, and S331S. Rare alleles of a-245c, G12E, and S331S, which were in linkage disequilibrium, were associated with higher VWF propeptide, VWF and FVIII levels. The functionality of the G12E variant was studied in stably transfected MDCKII cells, expressing constructs of either 12G-V2R or 12E-V2R. Both V2R variants were fully glycosylated and expressed on the basolateral membrane. The binding affinity of V2R for AVP was increased three-fold in 12E-V2R-green fluorescent protein (GFP) cells, which is in accordance with increased levels of VWF propeptide associated with the 12E variant. The dissociation constant (K(D)) was 4.5 nm [95% confidence interval (CI) 3.6-5.4] for 12E-V2R-GFP and 16.5 nm (95% CI 10.1-22.9) for 12G-V2R-GFP. AVP-induced cAMP generation was enhanced in 12E-V2R-GFP cells. CONCLUSIONS: The 12E-V2R variant has increased binding affinity for AVP, resulting in increased signal transduction, and is associated with increased levels of VWF propeptide, VWF, and FVIII.

AB - SUMMARY OBJECTIVES: Stimulation of arginine vasopressin 2 receptor (V2R) with arginine vasopressin (AVP) results in a rise in von Willebrand factor (VWF) and factor VIII plasma levels. We hypothesized that gain-of-function variations in the V2R gene (AVPR2) would lead to higher plasma levels of VWF and FVIII. METHODS AND RESULTS: We genotyped the control populations of two population-based studies for four AVPR2 variations: a-245c, G12E, L309L, and S331S. Rare alleles of a-245c, G12E, and S331S, which were in linkage disequilibrium, were associated with higher VWF propeptide, VWF and FVIII levels. The functionality of the G12E variant was studied in stably transfected MDCKII cells, expressing constructs of either 12G-V2R or 12E-V2R. Both V2R variants were fully glycosylated and expressed on the basolateral membrane. The binding affinity of V2R for AVP was increased three-fold in 12E-V2R-green fluorescent protein (GFP) cells, which is in accordance with increased levels of VWF propeptide associated with the 12E variant. The dissociation constant (K(D)) was 4.5 nm [95% confidence interval (CI) 3.6-5.4] for 12E-V2R-GFP and 16.5 nm (95% CI 10.1-22.9) for 12G-V2R-GFP. AVP-induced cAMP generation was enhanced in 12E-V2R-GFP cells. CONCLUSIONS: The 12E-V2R variant has increased binding affinity for AVP, resulting in increased signal transduction, and is associated with increased levels of VWF propeptide, VWF, and FVIII.

KW - Alleles

KW - Animals

KW - Arginine Vasopressin

KW - Dogs

KW - Factor VIII

KW - Genetic Variation

KW - Genotype

KW - Humans

KW - Linkage Disequilibrium

KW - Protein Binding

KW - Receptors, Vasopressin

KW - Signal Transduction

KW - von Willebrand Factor

U2 - 10.1111/j.1538-7836.2010.03884.x

DO - 10.1111/j.1538-7836.2010.03884.x

M3 - Journal article

VL - 8

SP - 1547

EP - 1554

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

IS - 7

ER -