The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population

FF Wei, L Thijs, ZY Zhang, L Jacobs, WY Yang, E Salvi, L Citterio, N Cauwenberghs, T Kuznetsova, N E A Drummen, A Hara, P Manunta, Y Li, P Verhamme, K Allegaert, D Cusi, C Vermeer, JA Staessen

Research output: Contribution to journalArticle

Abstract

Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P 
Original languageEnglish
Pages (from-to)514-522
Number of pages9
JournalNephrology Dialysis Transplantation
Volume33
Issue number3
DOIs
Publication statusPublished - 2018

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Nephrolithiasis
Vitamin K
Random Allocation
Population
Confidence Intervals
Mendelian Randomization Analysis
Incidence
Serine
Glutamic Acid
Odds Ratio
Genotype
Phosphorylation
matrix Gla protein
Calcium
Recurrence
Mortality

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The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population. / Wei, FF; Thijs, L; Zhang, ZY; Jacobs, L; Yang, WY; Salvi, E; Citterio, L; Cauwenberghs, N; Kuznetsova, T; E A Drummen, N; Hara, A; Manunta, P; Li, Y; Verhamme, P; Allegaert, K; Cusi, D; Vermeer, C; Staessen, JA.

In: Nephrology Dialysis Transplantation, Vol. 33, No. 3, 2018, p. 514-522.

Research output: Contribution to journalArticle

Wei, FF, Thijs, L, Zhang, ZY, Jacobs, L, Yang, WY, Salvi, E, Citterio, L, Cauwenberghs, N, Kuznetsova, T, E A Drummen, N, Hara, A, Manunta, P, Li, Y, Verhamme, P, Allegaert, K, Cusi, D, Vermeer, C & Staessen, JA 2018, 'The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population', Nephrology Dialysis Transplantation, vol. 33, no. 3, pp. 514-522. https://doi.org/10.1093/ndt/gfx014
Wei, FF ; Thijs, L ; Zhang, ZY ; Jacobs, L ; Yang, WY ; Salvi, E ; Citterio, L ; Cauwenberghs, N ; Kuznetsova, T ; E A Drummen, N ; Hara, A ; Manunta, P ; Li, Y ; Verhamme, P ; Allegaert, K ; Cusi, D ; Vermeer, C ; Staessen, JA. / The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population. In: Nephrology Dialysis Transplantation. 2018 ; Vol. 33, No. 3. pp. 514-522.
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title = "The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population",
abstract = "Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1{\%} women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2{\%})] associated with dp-ucMGP was 1.31 [95{\%} confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95{\%} CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2{\%}). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95{\%} CI 1.71-3.61; P ",
author = "FF Wei and L Thijs and ZY Zhang and L Jacobs and WY Yang and E Salvi and L Citterio and N Cauwenberghs and T Kuznetsova and {E A Drummen}, N and A Hara and P Manunta and Y Li and P Verhamme and K Allegaert and D Cusi and C Vermeer and JA Staessen",
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TY - JOUR

T1 - The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population

AU - Wei, FF

AU - Thijs, L

AU - Zhang, ZY

AU - Jacobs, L

AU - Yang, WY

AU - Salvi, E

AU - Citterio, L

AU - Cauwenberghs, N

AU - Kuznetsova, T

AU - E A Drummen, N

AU - Hara, A

AU - Manunta, P

AU - Li, Y

AU - Verhamme, P

AU - Allegaert, K

AU - Cusi, D

AU - Vermeer, C

AU - Staessen, JA

PY - 2018

Y1 - 2018

N2 - Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P 

AB - Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P 

U2 - 10.1093/ndt/gfx014

DO - 10.1093/ndt/gfx014

M3 - Article

VL - 33

SP - 514

EP - 522

JO - Nephrology Dialysis Transplantation

JF - Nephrology Dialysis Transplantation

SN - 0931-0509

IS - 3

ER -