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.
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).



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.



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 < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results.



Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established.
Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Fang-Fei
FF
Wei
Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Lutgarde
L
Thijs
Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Zhen-Yu
ZY
Zhang
Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Lotte
L
Jacobs
Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Wen-Yi
WY
Yang
Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy.
Erika
E
Salvi
Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute and School of Nephrology, University Vita-Salute San Raffaele, Milan, Italy.
Lorena
L
Citterio
Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Nicholas
N
Cauwenberghs
Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Tatiana
T
Kuznetsova
R&D Group VitaK, Maastricht University, Maastricht, The Netherlands.
Nadja
N
E A Drummen
Department of Social Pharmacy and Public Health, Showa Pharmaceutical University, Tokyo, Japan.
Azusa
A
Hara
Division of Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute and School of Nephrology, University Vita-Salute San Raffaele, Milan, Italy.
Paolo
P
Manunta
Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Yan
Y
Li
Research Unit of Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Peter
P
Verhamme
Research Unit of Organ Systems, KU Leuven Department of Development and Regeneration, University of Leuven, Leuven, Belgium.
Karel
K
Allegaert
Genomics and Bioinformatics Platform at Filarete Foundation, Department of Health Sciences and Graduate School of Nephrology, Division of Nephrology, San Paolo Hospital, University of Milan, Italy.
Daniele
D
Cusi
R&D Group VitaK, Maastricht University, Maastricht, The Netherlands.
Cees
C
Vermeer
Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.|R&D Group VitaK, Maastricht University, Maastricht, The Netherlands.
Jan A
JA
Staessen
D000328:Adult; D001530:Belgium / Q000453:epidemiology; D015415:Biomarkers / Q000097:blood*; D002135:Calcium-Binding Proteins / Q000097:blood* / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000097:blood* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D053040:Nephrolithiasis / Q000097:blood* / Q000453:epidemiology / Q000209:etiology*; D010766:Phosphorylation; D011379:Prognosis; D014812:Vitamin K / Q000378:metabolism*; D014813:Vitamin K Deficiency / Q000150:complications*; D055815:Young Adult; D000097568:Matrix Gla Protein
D015415:Biomarkers; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D014812:Vitamin K; D000097568:Matrix Gla Protein