A polymorphism of matrix Gla protein gene is associated with kidney stone in the Chinese Han population
Highlights
► Polymorphisms of MGP gene were first investigated in the Chinese Han population. ► An SNP was found to be associated with kidney stone in the Chinese Han population. ► The association was confirmed in the Chinese and Japanese populations.
Introduction
Kidney stone is a complex disease resulting from an interaction between environmental and genetic factors. About 2–5% of the population in Asia and 8–15% in Europe and North America develop renal stones in their lifetime (Pak, 1998). Wide geographical variations and racial differences exist in stone incidence and composition. Racial genetic polymorphisms may affect intricate interactions between promoting and inhibiting stone formation factors in renal tubules and are associated with the risk of kidney stone disease. We previously identified a variant of the human MGP (matrix Gla protein) gene associated with the individual sensitivity to kidney stone disease within the Japanese population (Gao et al., 2007). This association needs to be confirmed by further replication studies, particularly in other ethnic populations. The differences in risk allele frequencies and linkage disequilibrium (LD) structure across ethnicities can provide further insights to exact the association information and identify the true risk variant.
MGP is a molecular determinant regulating calcification of the extracellular matrix, and is expressed at high levels in the kidney, bone, lung and heart. A previous study showed that MGP expression was higher in calcified human atherosclerotic plaques and inhibited calcification (Canfield et al., 2002, Proudfoot et al., 1998). Luo et al. showed that homozygous MGP-deficient mice were observed to die within 8 weeks as a result of arterial calcification that led to blood vessel rupture (Luo et al., 1997). Kidney stone is a common ectopic calcification similar to vascular calcification, such as forming calcific plaques, increasing expression of calcification inhibitors and regulating actively calcification process. MGP gene expression was detected to maintain a high level in the renal tubular epithelial cells (Fraser and Price, 1988, Wang et al., 2000, Yasui et al., 1999), and was upregulated following an exposure to calcium oxalate monohydrate (COM) and oxalate (Gao et al., 2010). Lian et al. reported that a fragment of MGP, gamma-carboxyglutamic acid was found in the calcium-containing kidney stone matrix (Lian et al., 1977). These observations show that MGP is not only an important biomarker of atherosclerotic calcification, but may also be associated with stone formation in the kidney.
Understanding the genetic basis of complex human diseases has been increasingly emphasized. The human MGP gene is located at 12p13.1–p12.3 and consists of 4 exons (Cancela et al., 1990). Domains of MGP corresponding to each exon were found in all known vitamin K-dependent vertebrate proteins: a transmembrane signal peptide, followed by a putative gamma-carboxylation recognition site and a Gla-containing domain that have a high affinity for calcium, phosphate ions and hydroxyapatite crystals (Price, 1989). To confirm whether the MGP genetic polymorphism was universally associated with the risk of kidney stone, we further investigated the genetic polymorphisms of MGP in the Chinese Han population in the present study.
Section snippets
Study subjects
Our study group consisted of a total of 354 unrelated Chinese patients (mean age ± SD 54.3 ± 12.8 years) with kidney stones, who underwent treatment at Shenyang Medical College Hospital from 2008 to 2011. The clinical characteristics of all of the patients are listed in Table 1. Stone number was confirmed by X-ray before treatment, and was considered “multiple” when the stone number was more than two. The stone composition was analyzed by infrared spectroscopy. The primary age and stone frequency
Polymorphisms and linkage disequilibrium analysis in the human MGP gene
The human MGP gene was re-sequenced in 26 cases and 28 controls. A total of 18 polymorphism loci were genotyped (Fig. 1, Table 2). All polymorphisms were in Hardy–Weinberg equilibrium (p > 0.05). Fourteen SNPs with minor allele frequencies of < 1% were removed from further statistical analysis. The remaining 4 polymorphisms with minor allele frequencies of ≥ 1% were used to test the allele frequency differences and calculate the degree of linkage disequilibrium between these pairs of SNPs loci.
Discussion
MGP is an important inhibition protein of arterial calcification. However, its role in kidney stone formation is still unclear. The increasing expression in the kidneys of the stone-forming rats suggested that MGP protein may be involved in renal calcification. In the present study, we investigated the MGP genetic polymorphism, and found that SNPrs4236 was significantly associated with calcium oxalate kidney stones in the Han population in northeast China.
Calcium oxalate stones are the most
Acknowledgments
This study was supported by grants from National Natural Science Foundation of China (no. 31171111), the Scientific Research Foundation for Liaoning Provincial Education Board (no. LTQ2011110) and the Shenyang Human Resources and Social Security Bureau.
References (19)
- et al.
Reduced crystallization inhibition by urine from women with nephrolithiasis
Kidney Int.
(2002) - et al.
Molecular structure, chromosome assignment, and promoter organization of the human matrix Gla protein gene
J. Biol. Chem.
(1990) - et al.
Lung, heart, and kidney express high levels of mRNA for the vitamin K-dependent matrix Gla protein. Implications for the possible functions of matrix Gla protein and for the tissue distribution of the gamma-carboxylase
J. Biol. Chem.
(1988) - et al.
A polymorphism of matrix Gla protein gene is associated with kidney stones
J. Urol.
(2007) - et al.
Tamm–Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation
Kidney Int.
(2004) Kidney stones
Lancet
(1998)Altered gene expression in kidneys of mice with 2,8-dihydroxyadenine nephrolithiasis
Kidney Int.
(2000)- et al.
Modulatory effect of the 23-kD calcium oxalate monohydrate binding protein on calcium oxalate stone formation during oxalate stress
Nephron Physiol.
(2004) The involvement of matrix glycoproteins in vascular calcification and fibrosis: an immunohistochemical study
J. Pathol.
(2002)
Cited by (27)
High Concentration of Calcium Promotes Mineralization in NRK-52E Cells Via Inhibiting the Expression of Matrix Gla Protein
2018, UrologyCitation Excerpt :More and more studies reveal that MGP is not only involved in the inhibition of vascular calcification but also in the formation of kidney stones. The A allele carrier in SNPrs4236 is reported more likely to suffer kidney stone risk compared with G allele carriers.12-14 A number of experimental studies have been conducted to detect the expression change of MGP in kidney of hyperoxaluric rats and an up-regulated expression is observed in almost every study.
Matrix-Gla Protein rs4236 [A/G] gene polymorphism and serum and GCF levels of MGP in patients with subgingival dental calculus
2016, Archives of Oral BiologyCitation Excerpt :When we looked the literature, could not find any study which investigated MGP gene polymorphism together with dental calculus. But it was demonstrated that single nucleotide polymorphism (SNP) of MGP gene was associated with calcium oxalate kidney stone disease (Gao et al., 2007; Lu et al., 2012). Also MGP gene polymorphism may be associated with vascular calcification (Herrmann et al., 2000; Farzaneh-Far et al., 2001) and in Keutel syndrome, mutations in MGP gene were detected (Meier, Weng, Alexandrakis, Ruschoff, & Goeckenjan, 2001).
Roles of vitamin K‑dependent protein in biomineralization (Review)
2024, International Journal of Molecular MedicineVitamins as regulators of calcium-containing kidney stones — new perspectives on the role of the gut microbiome
2023, Nature Reviews UrologyEvolutionary genetics and acclimatization in nephrology
2021, Nature Reviews NephrologyRandall’s plaque and calcium oxalate stone formation: role for immunity and inflammation
2021, Nature Reviews Nephrology