- Email: [email protected]
Genetic Risk Factors for Idiopathic Urolithiasis: A Systematic Review of the Literature and Causal Network Analysis
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Review – Stone Disease
Genetic Risk Factors for Idiopathic Urolithiasis: A Systematic Review of the Literature and Causal Network Analysis Kazumi Taguchi a,b [14_TD$IF] , Takahiro Yasui a, Dawn Schmautz Milliner c, Bernd Hoppe d, Thomas Chi b,* a
Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan;
b
Department of Urology, University of
California, San Francisco, CA, USA; c Division of Nephrology, Departments of Pediatrics and Internal Medicine, Mayo Clinic, Rochester, MN, USA; d Division of Pediatric Nephrology, Department of Pediatrics, University Hospital Bonn, Bonn, Germany
Article info
Abstract
Article history: Accepted April 29, 2017
Context: Urolithiasis has a high prevalence and recurrence rate. Prevention is key to patient management, but risk stratification is challenging. In particular, genetic predisposition for urinary stones is not fully understood. Objective: To review current evidence of potential causative genes for idiopathic urolithiasis and map their relationships to one another. This evidence is essential for future establishment of molecular targeted therapy. Evidence acquisition: A systematic literature review from 2007 to 2017 was performed in accordance with the Preferred Reporting Items for Systematic Review and Metaanalyses guidelines. The search was restricted to human studies conducted as either case–control or genome-wide association studies, and published in English. We also performed a causal network analysis of candidate genes gained from the systematic review using Ingenuity Pathway Analysis (IPA). Evidence synthesis: During the systematic screening of literature, 30 papers were selected for the review. A total of 20 genes with 42 polymorphisms/variants were found to be associated with urolithiasis risk. Their functional roles were mainly categorized as stone matrix, calcium and phosphate regulation, urinary concentration and constitution, and inflammation/oxidative stress. IPA network analysis revealed that these genes connected via signaling pathways and a proinflammatory/oxidative environment. Conclusions: This systematic review provides an updated gene list and novel causal networks for idiopathic urolithiasis risk. Although some genes such as SPP1, CASR, VDR, CLDN14, and SLC34A1 were identified by several studies and recognized by prior reviews, further investigation elucidating their roles in stone formation will be essential for future studies. Patient summary: In this review, we summarized recent literature regarding genes responsible for kidney stone risk. Based on a detailed review of 30 articles and computational network analysis, we concluded that disorder of mineral regulation with local inflammation in the kidney may cause kidney stone disease. © 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Associate Editor: James Catto Keywords: Urolithiasis Nephrolithiasis Genome-wide association study Single-nucleotide polymorphism Ingenuity Pathway Analysis Calcium Phosphate Inflammation Randall’s plaque
* Corresponding author. Department of Urology, University of California, 400 Parnassus Ave., Sixth Floor, Suite A610, San Francisco, CA 94143, USA. Tel. +1-415-353-2200; Fax: +1-415-353-2641. E-mail address: [email protected] (T. Chi).
http://dx.doi.org/10.1016/j.euf.2017.04.010 2405-4569/© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
73
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
[(Fig._1)TD$IG]
1.
Urolithiasis has a high prevalence worldwide ranging between 7% and 13% in North America, 5% and 9% in Europe, and 1% and 5% in Asia [1]. Owing to the high recurrence rate of urolithiasis, both the American Urological Association [42_TD$IF][2] and European Association of Urology [43_TD$IF][3] recommend managing and preventing future recurrences by dietary and medical assessments. Single gene mutation states such as cystinuria are known to cause nephrolithiasis in a small proportion of stone patients [4_TD$IF][4]. However, in the large majority of patients who have idiopathic stone formation, less is known about contributing genetic factors. While numerous research efforts have been performed to elucidate the pathophysiology of lithogenesis [45_TD$IF][5], the exact mechanism of stone formation is still not fully understood. Identifying genetic predisposition may lead to new prevention strategies for urolithiasis. For example, studies have demonstrated that a family history of urolithiasis increases relative risk by 2.57-fold in men [46_TD$IF][6]. In addition, the concordance rate of the disease in monozygotic twins is higher compared with that in dizygotic twins (32.4% vs 17.3%) [47_TD$IF] [7]. These lines of evidence suggest that genetic factors for urolithiasis play a pivotal role in its etiology. By extension, elucidation of responsible genes could lead to future targeted gene therapy and better prevention. Genome-wide association studies have widely been used for identifying genetic risk factors for various diseases. This approach facilitates examining entire DNA sequences to detect mutations, variants, and single-nucleotide polymorphisms (SNPs). SNPs play a crucial role in determining genes associated with urolithiasis that may serve as future diagnostic markers [48_TD$IF][8]. Understanding how these SNPs link together could potentially help unveil the genomic drivers of lithogenesis. In this review, we focus on SNPs and genome-wide association studies (GWASs) conducted for urolithiasis. We present a systematic review of genetic risk factors for stone formation and a network analysis of candidate genes. Our aim is to provide an update on genes associated with nephrolithiasis and how they may interact with one another. 2.
Exclusions
Introduction
Evidence acquisition
We performed a systematic literature review in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines [49_TD$IF][9]. In PubMed and Medline databases, the following search keywords were used: ((“genome”[MeSH]) OR (“mutation”[MeSH]) OR (“genetic”[MeSH]) OR (“single nucleotide polymorphism”[MeSH])) AND ((“urolithiasis”[MeSH]) OR (“nephrolithiasis”[MeSH]) OR (“kidney calculi”[MeSH]) OR (“urinary calculi”[MeSH]) OR (“calcium oxalate”[MeSH]) OR (“calcium phosphate”[MeSH]) OR (“uric acid”[MeSH])). The search was restricted to human studies with both an abstract and the full text available; published in English during the last 10 yr. Studies were considered only if patient cases were confirmed as
Number of papers
758 Nonhuman studies 621 Manuscripts not written in English 552 Not published within the last 10 yr 257 Abstract and full text not available 237 Case reports, meta-analyses, reviews, cohort studies 148 Patients with no evidence of urolithiasis or nephrolithiasis 30 Fig. 1 – Flow chart of the methods used to formulate this systematic literature review in accordance with PRISMA guidelines. PRISMA = Preferred Reporting Items for Systematic Review and Metaanalyses.
having either renal or ureteral stones diagnosed previously. A total of 237 papers were reviewed; 54 case reports and 33 reviews were excluded. Cohort studies; negative studies; and studies irrelevant to urolithiasis and nephrolithiasis were screened. After exclusions; 30 papers were selected for this review (Fig. 1). Existing networks among candidate genes for urolithiasis development were also analyzed. Ingenuity Pathway Analysis (IPA; QIAGEN, Hilden, Germany) uses computerized analysis with a mega knowledge base of reviewed scientific literature [50_TD$IF][10]. The use of IPA methodology allowed a causal network analysis for the candidate genes. 3.
Evidence synthesis
From the selected 30 papers, 20 genes were identified with 42 SNPs/variants reported in case–control and/or GWASs. Most investigations consisted of Asian and European patients. Table 1 summarizes the genes associated with urolithiasis risk factors. The majority of genes were
74
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
Table 1 – Genes related to urolithiasis summarized by a systematic review of manuscripts published between 2007 and 2017. Function Calcium stone Stone matrix
Calcium regulation
Phosphate (and calcium) regulation
Gene ([68_TD$IF]Coded protein)
Locus
SNP, variant
Region
Cases/controls[69_TD$IF](n)
origin
Year [ref.]
SPP1 (osteopontin)
4p22.1
CASR (calcium-sensing receptor)
3q13.33-q21.1
144 and 145 T-593A rs1126616 rs17524488 c.240T>C c.708C>T rs11439060 rs1042636
[70_TD$IF]promoter promoter exon 7 promoter exon 6 exon 7 prompter [7_TD$IF]exon 7
126/214 121/100 121/100 249/247 65/50 65/50 230/250 99/107, 115/141, 200/200
Japan Turkey Turkey Taiwan Turkey Turkey China Iran, [78_TD$IF]Italy, India
rs1801725
exon 7
99/107, 200/200
Iran, India
exon 7 promoter 1 promoter 1 [84_TD$IF]intron 1 intron 1 [84_TD$IF]intron 1
99/107 165/208 155/141 200/200 200/200 136/500
Iran Italy Italy India India China
2007 [71_TD$IF][13] 2010 [72_TD$IF][16] 2010 [73_TD$IF][16] 2010 [74_TD$IF][14] 2012 [75_TD$IF][17] 2012 [76_TD$IF][17] 2016 [15_TD$IF][15] 2010 [79_TD$IF][21], 2014 [22], 2015 [18] 2010 [80_TD$IF][22], 2015 [18] 2010 [81_TD$IF][21] 2013 [82_TD$IF][19] 2014 [83_TD$IF][22] 2015 [85_TD$IF][18] 2015 [86_TD$IF][18] 2011 [2_TD$IF][25]
CLDN14 (claudin 14)
21q22.13
ORAI1 (calcium releaseactivated calcium modulator) VDR [87_TD$IF](vitamin D receptor)
12q24.31
E1011Q rs6776158 rs1501899 rs219780 rs219778 rs12313273
12q12-14
rs2228570
[8_TD$IF]start codon
106/109
Iran
2012 [89_TD$IF][27]
intron 8 [ romoter 70_TD$IF]p exon 3 [93_TD$IF]exon 1
98/70 108/51 426/282 92/63
Turkey Turkey China France
2016 [90_TD$IF][28] 2011 [91_TD$IF][29] 2013 [92_TD$IF][30] 2008 [94_TD$IF][31]
KL (klotho)
13q13.1
NHERF1 (sodium-hydrogen antiporter 3 regulator 1)
17q25.1
rs1544410 G395A rs3752472 L110V
12p13.32
R153Q E225K rs7955866
exon 2 exon 3 [93_TD$IF]exon 3
92/63 92/63 106/87
France France Italy
2008 [95_TD$IF][31] 2008 [96_TD$IF][31] 2012 [97_TD$IF][32]
17q11.2
[98_TD$IF]3’UTR+18C>T rs72570683 rs3214144 1550V
3’UTR intron 1 intron 1 exon 12
105/101 105/101 105/101 105/107
Iran Iran Iran Japan
2013 [9_TD$IF][33] 2013 [10_TD$IF][33] 2013 [29_TD$IF][33] 2007 [10_TD$IF][34]
11p11.2 2q14.1
rs5896 2/2 genotype
[93_TD$IF]exon 6 [84_TD$IF]intron 2
216/216 65/85
Thailand Turkey
2012 31_TD$IF][[ 35] 2013 [103_TD$IF][36]
7q21.3
rs854560
158/138
Turkey
2016 [3_TD$IF][37]
CARD8 (caspase recruitment domain family member 8)
19q13.33
rs2043211
[93_TD$IF]exon 5
396/403
China
2015 [104_TD$IF][39]
UGT1A1 (UDP glucuronosyltransferase family 1 member A1)
2q37.1
rs10929303
[93_TD$IF]exon 5
31/47
Japan
2014 [35_TD$IF][41]
rs1042640 rs8330
[93_TD$IF]exon 5 exon 5
31/47 31/47
Japan Japan
2014 105_TD$IF][[ 41] 2014 106_TD$IF][[ 41]
FGF23 (fibroblast growth factor 23) CALCR (calcitonin receptor)
Urinary inhibitor of stone formation Anti-inflammatory and [102_TD$IF]-oxidative stress
SLC13A2 (Na+/dicarboxylate cotransporter-1) F2 (prothrombin) IL-RN VNTR (interleukin 1 receptor antagonist) PON 1 (paraoxonase-1)
7q21.3
Uric acid stone
Atazanavir containing stone
associated with calcium-containing stones, whereas only two papers examined rare stone patients: uric acid– and atazanavir-containing stones. For calcium-containing stones, the following genes were reported to have a possible causative role in urolithiasis: osteopontin (OPN) coding gene (SPP1) related to the stone matrix, calcium-sensing receptor (CASR)/claudin 14 (CLDN14)/calcium release-activated calcium modulator 1 (ORAI1) related to calcium regulation, vitamin D receptor (VDR)/klotho (KL)/sodium hydrogen antiporter 3 regulator 1 (NHERF1)/fibroblast growth factor 23 (FGF23)/calcitonin receptor (CALCR) related to phosphate as well as calcium regulation, solute carrier family 13 member 2 (SLC13A2)/prothrombin (F2)
related to urinary inhibition of stone formation, and interleukin 1 receptor antagonist (IL-RN VNTR)/paranoxonase-1 (PON1) related to anti-inflammatory and antioxidative stress. Additionally, four GWASs including a validation case– control study were conducted during the study review period (Table 2). The SNPs of phosphate carrier NPT2a (SLC34A1) and CLDN14 were identified from two different GWASs. SLC34A1, CLDN14, AQP1, diacyl glycerol kinase (DGKH), CASR, and transient receptor potential cation channel subfamily V member 5 (TRPV5) were also associated with other SNPs related to urolithiasis prevalence in case– control studies.
75
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
Table 2 – Genes related to urolithiasis identified by a systematic review of GWAS [107_TD$IF]studies published between 2007 and 2017. Gene ([68_TD$IF]Coded protein)
Locus
SNP
Cases ([108_TD$IF]n)/controls (n)
Markers (n)
Origin
Year [ref.]
SLC34A1 (phosphate carrier NPT2a)
5q35.3
rs11746443a[93_TD$IF] rs12654812a
CLDN14 (claudin 14)
21q22.13
rs219780b[10_TD$IF]
[109_TD$IF]5,892/17,809 5,892/17,809 5,419/279,870 [1_TD$IF]3,773/42,510
712,726 712,726 28,300,000 303,120
2012 [43] 2012 [43] 2015 [37_TD$IF][23] 2009 [12_TD$IF][24]
AQP1 (aquaporin 1)
7q14.3
DGKH (diacyl glycerol kinase) ALPL (alkaline phosphatase) CASR (calcium-sensing receptor) TRPV5 (transient receptor potential cation channel subfamily V member 5)
13q14.1 1p36.12 3q21.1 7q34
rs199565725 rs1000597 rs12669187 rs4142110c rs1256328 rs7627468 p.L530A
5,419/279,870 [13_TD$IF]5,892/17,809 5,892/17,809 5,892/17,809 [15_TD$IF]5,419/279,870 [15_TD$IF]5,419/279,870 [15_TD$IF]5,419/279,870
28,300,000 712,726 712,726 712,726 28,300,000 28,300,000 28,300,000
Japan Japan Iceland Iceland, The Netherlands Iceland Japan Japan Japan Iceland Iceland Iceland
a b c
2015 2012 2012 2012 2015 2015 2015
[37_TD$IF][23] [43] [43] [43] [37_TD$IF][23] [37_TD$IF][23] [18_TD$IF][23]
Validated by a case–control study (601 cases vs 201 controls, Japan) [39_TD$IF][42]. Validated by a case–control study (200 cases vs 200 controls, India) [21_TD$IF][18]. Validated by a case–control study (507 cases vs 505 controls, China) [40_TD$IF][44].
3.1.
Stone macromolecule, matrix
OPN is a highly phosphorylated glycoprotein originally identified in bone that functions as an adhesion motif of protein to integrins and CD44. It was also identified as one of the organic (matrix) components of calcium-based urinary stones. Some reported that OPN knockout mice produce calcium oxalate crystals [51_TD$IF][11], whereas others indicate that OPN facilitates crystal development by mineralization and inflammation processes mediated by other cytokines and immune cells including macrophages [52_TD$IF][12]. Three studies from eastern Asia demonstrated SNPs of SPP1 related to urolithiasis patients. Gao et al [1_TD$IF][13] reported that the SPP1 haplotype SNP carrier with G-T-T-G in the 145 and 144 positions had a higher risk of developing nephrolithiasis compared with other haplotypes (odds ratio [OR] = 1.676), whereas the haplotype T-G-T-G carrier in the same position has a lower risk (OR = 0.351). Liu et al [13_TD$IF][14] showed that the delG/delG genotype of SNP rs17524488 was also associated with a significantly higher risk of developing calcium urolithiasis (OR = 1.95) and a higher urinary calcium to OPN ratio than those with G/G genotype. Xiao et al [15_TD$IF] [15] demonstrated that carriers with the SPP1 rs11439060 insertion types were over-represented in urolithiasis patients compared with controls (OR = 1.55). In addition, two Turkish studies reported that the SPP1 haplotypes between SNPs T-593A and rs1126616 demonstrated a significant lower or higher OR for developing kidney stones; CA haplotype had a lower (OR = 0.283), whereas TT haplotype had a higher (OR = 1.963) risk for kidney stones [12_TD$IF] [16]. Among the pediatric population, C allele frequency of c.240T>C polymorphism (OR = 2.13) and T allele frequency of c.708C>T polymorphism (OR = 2.183) were higher in nephrolithiasis patients than in controls [14_TD$IF][17]. 3.2.
Genes related to calcium regulation
3.2.1.
Calcium-sensing receptor
CASR is located on chromosome 3q13.33-q21.1 and consists of 11 exons. It is a G protein–coupled receptor that
modulates cell activity according to the extracellular calcium concentration. This protein is expressed in the parathyroid gland and the thick ascending limb of the Henle loop. Its activation induces increased calcium excretion in the kidney via regulation of parathyroid hormone (PTH) production and renal tubular calcium reabsorption [53_TD$IF] [18,19]. Earlier studies summarized that activating the Arg990Gly polymorphism (rs1042636) may predispose to nephrolithiasis by increasing calcium excretion [54_TD$IF][20]. Four case–control studies and one GWAS have investigated CASR SNPs. The G allele of rs1042636 was associated with a significant risk of stone disease (OR = 8.06) [18_TD$IF][21], and the variant genotype GG was associated with 20-fold increased risk for kidney stone disease (OR = 20.76) [21_TD$IF] [18]. Stone risk of patients with primary hyperparathyroidism was also higher in patients carrying a G allele at rs1042636 [20_TD$IF][22]. An S allele of rs1801725 was reported to confer an OR = 2.55 [18_TD$IF][21] and a T allele was reported with OR = 2.54 [21_TD$IF][18] for risk of stone disease. Moreover, one study reported that a GG genotype for rs6776158 demonstrated an increased risk of nephrolithiasis (OR = 5.8) by multinomial logistic regression analysis [19_TD$IF][19]. In addition to the risk for kidney stone development, a QQ genotype with respect to the 1011 locus was related to significantly lower serum total calcium in patients [18_TD$IF][21]. Furthermore, Oddsson et al [37_TD$IF][23] found SNP rs7627468 of CASR associated with kidney stones (OR = 1.21) from a GWAS comparing 5419 kidney stone cases with 279 870 controls during examination of 28.3 million sequence variants. 3.2.2.
Claudin 14
CLDN14 is a member of the claudin family of membrane proteins that regulate paracellular passage of ions and small solutes at epithelial tight junctions. CLDN14 is expressed in the kidney, both in the loop of Henle and in proximal tubules, as well as in the epithelia of several other organs, and has been observed to selectively decrease permeability of Ca2+[41_TD$IF] through tight junctions [38_TD$IF][24]. Earlier studies indicated that CLDN14 expression is strongly upregulated by activation of CASR, and dysregulation of the renal CASR-
76
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
CLDN14 pathway could contribute to the development of kidney stones [21_TD$IF][18]. Thorleifsson et al [38_TD$IF][24] found the SNP rs219780 in exon 7 associated with kidney stone incidence (OR = 1.25) by conducting a GWAS in 3773 cases and 42 150 controls from Iceland and the Netherlands. The homozygous carriers of rs219780 were estimated to have 1.64 times greater risk of developing kidney stone compared with noncarriers. This SNP was validated by a GWAS from a different population: patients with two base pair deletion correlating with rs219780 had a strong association with kidney stones (r2 = 0.82, OR = 0.81) [23]. Additionally, a case–control study demonstrated that SNPs rs219778 and rs219780 were significantly associated with kidney stone disease (OR = 3.46 and OR = 2.63, respectively) [21_TD$IF][18]. 3.2.3.
Calcium release-activated calcium modulator 1
ORAI1 is located on chromosome 12q24.31 and consists of two exons. ORAI1 is a membrane calcium channel subunit that is activated when calcium stores are depleted. Mutation of this gene resulted in a deficiency of store-operated calcium-dependent signaling pathways, leading to immune system dysfunction [5_TD$IF][25]. Chou et al [25] reported that two SNPs, rs12313273 and rs6486795, of the ORAI1 gene were associated with nephrolithiasis risk (p = 0.006 and 0.035, respectively). The CC and CT genotypes of rs12313273 carried an increased risk of nephrolithiasis compared with the TT genotype (OR = 2.10 and 1.82, respectively). Moreover, the CC and CT genotypes conferred an increased risk for stone recurrence compared with the TT genotype (OR = 3.73 and 2.31, respectively). 3.3.
Genes related to calcium/phosphate regulation
3.3.1.
Vitamin D receptor
VDR is a 50- to 60-kDa cellular polypeptide whose gene is located on 12q13.11 consisting of 11 exons. This gene encodes the nuclear hormone receptor for vitamin D3. It plays a central role in mineral metabolism, including intestinal calcium absorption and renal calcium absorption. A prior meta-analysis of VDR polymorphisms indicated that the f allele and ff + Ff genotype in Fokl as well as the t allele and tt + Tt genotype in Taql were related to an increased risk of urolithiasis [56_TD$IF][26]. Two case–control studies of VDR SNPs were reported from Iran and Turkey. Basiri et al [23_TD$IF][27] indicated that the C allele of rs2228570 was more prevalent in male active stone formers (OR = 11.1 for TC genotype, OR = 10.7 for CC genotype). On the contrary, the B allele of rs1544410 was found to increase the risk of nephrolithiasis by approximately 1.5fold (OR = 1.55) [24_TD$IF][28]. 3.3.2.
Klotho
Klotho is a type-I transmembrane protein related to betaglucosidase, a novel regulator of renal calcium and phosphate homeostasis. Its coding gene, KL, is located on chromosome 13q13.1, consisting of six exons. Klotho is expressed in tissues responsible for calcium homeostasis including the kidney, parathyroid gland, and epithelium of the choroid plexus in the
brain. Klotho also plays an important role in increased calcium uptake in the kidneys via TRPV5 and regulation of phosphate homeostasis via FGF23 [57_TD$IF][29,30]. A Turkish study indicated that patients with a GG genotype of the G395A KL polymorphism had a two-fold increased kidney stone risk compared with AA and GA genotypes (OR = 1.849). They also found that a GG genotype had a significantly higher risk of stone-related metabolic abnormalities such as hypercalcemia (OR = 33.05) and hypophosphatemia (OR = 0.07) [25_TD$IF][29]. The CT + TT genotype of rs3752472 was found to be associated with nephrolithiasis risk when compared with a CC genotype (OR = 1.512) in the Chinese population [26_TD$IF][30]. 3.3.3.
Sodium hydrogen antiporter 3 regulator 1
NHERF1, also known as SLC9A3R1, is located on chromosome 17q25.1 and consists of six exons. NHERF1 binds renal tubular transporters including the Na+[37_TD$IF] phosphate cotransporter 2a (NPT2a) and the PTH type 1 receptor. NHERF1 knockout mice demonstrate increased urinary calcium, phosphate, and uric acid excretion, with resultant renal calcium phosphate crystal deposits [58_TD$IF][11]. Karim et al [31] identified three mutations of NHERF1— L110 V, R153Q, and E225K—from 158 patients, 95 cases of which were located in France. In addition, NHERF1 appeared to cause renal phosphate loss by increasing cyclic AMP generation via PTH in an in vitro model. 3.3.4.
Fibroblast growth factor 23
FGF23 is located on 12q13.32 and consists of three exons. This recently identified growth factor regulates renal phosphate homeostasis by decreasing renal reabsorption and intestinal absorption of phosphate. FGF23 reduces phosphate by downregulating NPT2 cotransporters, resulting in urinary phosphate wasting. It also acts to decrease serum phosphorus levels by reducing the bioavailability of vitamin D3 [59_TD$IF][29,32]. The SNP rs7955856 in FGF23 was reported in stone formers with a renal phosphate leak. The T allele and CT genotype rates within rs7955856 in those patients were significantly higher compared with those in controls (p < 0.03). Moreover, the T allele of rs7955856 carriers showed significantly lower levels of serum phosphate and TmPi/GFR compared with noncarriers (p < 0.03) [28_TD$IF][32]. 3.3.5.
Calcitonin receptor
Calcitonin, a 32-amino-acid protein, binds its receptor, CALCR, on bone osteoclasts as well as within renal tubular cells. Calcitonin acts as a renal calcium-conserving hormone by increasing Ca2+ and Mg2+ reabsorption and decreasing phosphate reabsorption in kidneys. While CALCR polymorphisms were reported to be associated with bone mineral density changes in different populations, few studies have established the association of its SNPs with urolithiasis [29_TD$IF][33]. Shakhssalim et al [29_TD$IF][33] detected nine polymorphisms from a cohort of 105 male recurrent calcium stone patients and 101 controls. Among these SNPs, the T allele of the 30 UTR + 18C > T polymorphism, as well as the C and A7
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
alleles of rs72570683 and rs3214144 conferred a significant risk for stone disease (OR = 36.72 and 1.95, respectively). 3.4.
Genes related to urinary inhibitors of stone formation
3.4.1.
Solute carrier family 13 member 2
SLC13A2 is located on chromosome 17q11.2, consists of 14 exons, and encodes Na+/dicarboxylate cotransporter-1 (NaDC-1). NaDC-1 plays an important role in citrate reabsorption in the apical membrane of the proximal tubule; thus, this protein is a major determinant of urinary citrate excretion. Genetic predisposition rather than metabolic abnormality may thus be a major cause for idiopathic hypocitraturia generating interest in NaDC-1 [30_TD$IF][34]. From a Japanese cohort of 105 recurrent renal calcium stone formers and 107 controls, 1550 polymorphisms were detected. Although no significant differences in allele frequencies were observed (p = 0.47), individuals with the BB genotype of 1550 V showed significantly lower urinary citrate excretion than those with bb genotype (p = 0.005) [30_TD$IF][34]. 3.4.2.
Prothrombin
F2 controls synthesis of prothrombin, also known as coagulation factor II, a serine-protease coagulation protein in the blood stream that converts soluble fibrinogen into insoluble strands of fibrin and catalyzes many other coagulationrelated reactions. F2 is located on chromosome 11p11.2, consists of 14 exons, and encodes urinary prothrombin fragment 1 (UPTF1). UPTF1 was initially detected as a crystal matrix protein within calcium oxalate crystals, and it is considered to be a potent inhibitor of calcium oxalate growth and aggregation in urine [31_TD$IF][35]. The SNP rs5896 was found in exon 6 using whole exon sequencing of F2. Furthermore, the frequency of the C allele of rs5896 in kidney stone patients was significantly lower than that of the controls (OR = 0.68). Particularly in female patients, genotype (OR = 0.49) and allele frequencies (OR = 0.59) were significantly different between stone patients and controls [31_TD$IF][35], suggesting a potential protective role of F2 against stone formation. 3.5.
Genes related to anti-inflammatory and antioxidative
stress 3.5.1.
Interleukin 1 receptor antagonist
Interleukin (IL)-1 is one of the major proinflammatory cytokines facilitating tissue inflammation. Its receptor, IL1 receptor antagonist, is coded by IL-RN and exhibits an anti-inflammatory function by binding to the same receptor with IL-1a and IL-1b. IL-RN is located on chromosome 2q14.1 and consists of 11 exons. A penta-allelic polymorphic site in intron 2 of this gene consisting of variable number tandem repeats has been investigated extensively in relation to a variety of pathological conditions [32_TD$IF][36]. A Turkish study examined its polymorphisms associated with urolithiasis. A significant genotype distribution of ILRN polymorphisms between urolithiasis and control groups was seen (p = 0.047), and urolithiasis patients had a higher frequency of allele 2 in IL-RN (p = 0.007) [32_TD$IF][36].
3.5.2.
77
Paraoxonase-1
PON1 is a serum high-density lipoprotein–bound enzyme with an antioxidant function. Its activity is reduced in environments of high oxidative stress and associated with increased lipid peroxidation, which might be a factor for determining predisposition to stone formation. PON1 clusters with three related paraoxonase genes at chromosome 7q21.3 [60_TD$IF][37]. Atar et al [37] reported that the PON1 L55M polymorphism was significantly more prevalent in urolithiasis patients (p = 0.002). Those with an MM genotype showed a greater risk for urolithiasis compared with those with an LM genotype (OR = 9.88). 3.6.
Genes for uric acid stones
While a number of researches have sought SNPs associated with hyperuricemia and/or gout by GWASs [61_TD$IF][38], few studies have reported the association between SNPs and uric acid stone formers for the past 10 yr. One study reported the possible association of an SNP in caspase activation and recruitment domain 8 (CARD8) gene in stone formers with gout [34_TD$IF][39]. CARD8 is a component of innate immunity involved in the suppression of nuclear factor kB activation. CARD8 suppresses the immune response and inflammatory activities. It is located on chromosome 19q13.33 and consists of 22 exons. Gout patients carrying a TT genotype of the CARD8 rs2043211 polymorphism had an increased risk of kidney stone compared with those carrying the AA genotype (p = 0.03). 3.7.
Genes for atazanavir-containing stones
Atazanavir-induced nephrolithiasis is a rare condition among all uroliths, and the exact mechanism for their formation is not fully understood. Based on a large cohort study [62_TD$IF][40], atazanavir use was significantly associated with renal stones (hazard ratio = 10.44), and the median time from commencement of atazanavir to stone diagnosis was 24.5 mo. Atazanavir is reported to be excreted whole in the urine, leading to the hypothesis that metabolism of atazanavir in the human body may be related to developing stones. UDP glucuronosyltransferase family 1 member A1 (UGT1A1) is expressed primarily in the liver and gastrointestinal tract, and plays a role in bilirubin elimination. Given that UGT1A1 is known for its association with atazanavirinduced unconjugated hyperbilirubinemia, it is also thought to be involved in atazanavir metabolism. Nishijima et al [35_TD$IF][41] reported that the TC genotype of rs10929303, GC genotype of rs1042640, and G allele of rs8330 of UGT1A-30 UTR were independent risk factors for atazanavir-induced nephrolithiasis among HIV-positive patients (OR = 3.7, 5.8, and 5.8, respectively). 3.8.
Other genes identified by GWASs
3.8.1.
Phosphate carrier NPT2a
SLC34A1 located on chromosome 5q35.3 encodes NPT2a, a member of the type IIa sodium phosphate cotransporter
78
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
family. NPT2a is responsible for phosphate absorption at the apical membrane of renal proximal tubular cells [39_TD$IF][42]. Npt2a knockout mice demonstrate hypercalciuria and renal calcium phosphate crystal deposits [51_TD$IF][11]. Mutations of SLC34A1 appear to be associated with hypophosphatemic nephrolithiasis and osteoporosis in humans [39_TD$IF][42]. Two GWASs detected SLC34A1 polymorphisms associated with kidney stone, and one case–control study validated these results. Rs1176443 was identified as a novel locus for nephrolithiasis (OR = 1.19) from 5892 Japanese nephrolithiasis patients. Subsequent analyses in 21 842 Japanese individuals revealed that the risk allele of rs11746443 was associated with a reduction in the estimated glomerular filtration rate [36_TD$IF][43]. SNP rs12654812 was found to be associated with kidney stones from 5892 Japanese and 5419 Icelander kidney stone patients (OR = 1.16 and 1.18, respectively) [36_TD$IF][43]. This SNP was also associated with decreased serum PTH and phosphate levels [37_TD$IF][23]. A separate population study validated its association with nephrolithiasis (OR = 1.43) and decreased serum phosphorus level (p = 0.0353) [39_TD$IF][42]. 3.8.2.
Aquaporin-1
Aquaporin-1 is abundantly expressed in the kidney, mainly in the proximal tubule, functioning as a water channel. Aqp1 knockout mice show reduced osmotic permeability and developed hydration after water deprivation. AQP1 is located on chromosome 7p14.3 and consists of seven exons. Rs100597 and rs12669187 were detected as the SNPs significantly associated with nephrolithiasis (each OR = 1.22). These SNPs are thought to affect the urine concentration process and thereby increase the risk of nephrolithiasis [36_TD$IF][43]. 3.8.3.
Diacyl glycerol kinase
DGKH is expressed in the brain and is known to be related to psychiatric disorders such as bipolar and major depressive disease. DGKH belongs to the DGK family, which is involved in transplasmalemmal calcium ion influx [40_TD$IF][44]. Its coding gene, DGKH, is located on chromosome 13q.14.11 and consists of 38 exons. A Japanese GWAS detected the SNP rs4142110 associated with nephrolithiasis (OR = 1.14) [36_TD$IF][43]. A case–control study further indicated that rs4142110 was associated with a risk of calcium oxalate stones and hypercalciuria (p < 0.05). The CT, TT, and CT + TT genotypes of rs4142110 were significantly correlated with decreased calcium oxalate stone risk (OR = 0.666, 0.562, and 0.466, respectively). In addition, the CT, TT, and CT + TT genotypes showed a significant decrease in hypercalciuria (OR = 0.666, 0.562, and 0.466, respectively) [40_TD$IF][44]. 3.8.4.
Alkaline phosphatase
Alkaline phosphatase (ALPL) is a member of the alkaline phosphatase family as a tissue nonspecific form and a membrane-bound glycosylated enzyme. ALPL is expressed in the proximal tubules of the kidney and hydrolyzes pyrophosphate to free phosphate, suggesting its facilitative role in kidney stone formation. ALPL is located on chromosome 1p36.12 and consists of 14 exons. The SNP rs1256328 of ALPL was found to be associated with both incident (OR = 1.21)
and recurrent (OR = 1.23) kidney stones. Rs1256328 also had a significant association with increased serum alkaline phosphatase levels (p < 0.001) [37_TD$IF][23]. 3.8.5.
Transient receptor potential cation channel subfamily V
member 5
TRPV5 is a highly selective epithelial calcium channel expressed at the apical membrane of the distal renal tubule epithelial cells, which mediates calcium transport in the kidney and constitutes the rate-limiting step of active calcium reabsorption. TRPV5 is located on chromosome 7q34 and consists of 15 exons, and Trpv5 knockout mice exhibited severe hypercalciuria. The TRPV5 p.Leu530Arg variant was detected to be significantly associated with recurrent kidney stones (OR = 3.62) [37_TD$IF][23]. 3.9.
Causal gene networks for lithogenesis
Fig. 2 illustrates the result of gene network analysis among the candidate genes listed in Tables 1 and 2. Each gene has been categorized by its location in the kidney and function. Genes related to stone matrix, calcium and phosphate regulation, and inflammation are connected via c-Jun Nterminal kinase signaling pathways, beta-estradiol, leptin, caspase, and proinflammatory cytokines. In particular, FGF23, VDR, SPP1, and IL1RN play primarily roles, interfacing with other genes for lithogenesis. Interestingly, these networks are relatively similar to the gene networks surrounding Randall’s plaques (RPs), which are considered potential origin nidi for calcium stone. A recent microarray study reported that cellular transporters and ion channels also formed networks with proinflammatory cytokines and signaling pathways, indicating that RPs develop by urothelial/ interstitial/tubular cellular apoptosis followed by OPN aggregation, mediated by tissue inflammation and oxidative stress [63_TD$IF][45]. In addition, several genes shown in this systematic review and gene network analysis in RP [63_TD$IF][45] are known to be responsible for hereditary developed kidney stone disease, which are typically expressed in pediatric patients. CASR is associated with autosomal dominant hypocalcemic hypercalciuria and Bartter syndrome. CASR and VDR are related to hypercalcemia in the context of hypercalciuriafamilial isolated hyperparathyroidism and idiopathic hypercalciuria. SLC34A1 is associated with persistent hypophosphatemia in urolithiasis and osteoporosis. Moreover, genes significantly expressed around RPs, including SLC12A1 and potassium voltage-gated channel subfamily J (KCNJ) [63_TD$IF][45], are associated with Bartter syndrome, a genetic disorder with an extremely high incidence of urinary stones [64_TD$IF][46]. While multiple studies have demonstrated these genes to be closely associated with a risk for urolithiasis, the complexities of their interactions have yet to be completely determined. As a result, the exact pathogenesis of idiopathic kidney stones is still unknown with regard to genetic factors. Further investigation, combining GWASs and omics analyses, will be essential for improving the understanding of the genetic causes of idiopathic urolithiasis.
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
[(Fig._2)TD$IG]
79
Fig. 2 – Causal networks of genes associated with urolithiasis revealed from the current systematic review. Different shapes and their relationship are as follows: red molecules = stone matrix genes; yellow molecules = calcium regulation genes; green molecules = phosphate (and calcium) regulation genes; cyan molecule = urinary inhibitor of stone formation genes; purple molecules = inflammation genes; gray molecules = other genes. ALPL = alkaline phosphatase; AQP1 = aquaporin-1; CALCR = calcitonin receptor; CASR = calcium-sensing receptor; CLDN14 = claudin 14; DGKH = diacyl glycerol kinase; FGF23 = fibroblast growth factor 23; IL = interleukin; Jnk = c-Jun N-terminal kinase; KL = klotho; LEP = leptin; SLC = solute carrier; TRPV5 = potential cation channel subfamily V member 5; UGT1A1 = UDP glucuronosyltransferase family 1 member A1; VDR = vitamin D receptor.
Limitations should be recognized for this study. Since we limited our inclusion to literature for last 10 yr, earlier similar studies in other populations may implicate somewhat different genes, and may convey a different impression of geographic distribution of the risk factors and incidence of idiopathic urolithiasis. Additionally, excluding studies related to monogenic causes of urolithiasis without appropriate control cases may result in a selection bias of articles, reflecting limited analysis result for current specific literature.
Author contributions: Thomas Chi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Taguchi, Yasui, Chi. Acquisition of data: Taguchi. Analysis and interpretation of data: Taguchi, Chi. Drafting of the manuscript: Taguchi, Hoppe, Milliner, Chi. Critical revision of the manuscript for important intellectual content: Yasui, Hoppe, Milliner, Chi. Statistical analysis: None. Obtaining funding: Taguchi, Yasui. Administrative, technical, or material support: None.
4.
Conclusions
Supervision: Chi. Other: None.
This systematic review demonstrates that genes related to stone matrix, calcium and phosphate regulation, inflammation, and oxidative stress are associated with modulating risk for idiopathic urolithiasis. These results are consistent with previous gene expression profiling of RPs and appear to be linked to some hereditary renal diseases. Translational research studies have tried to elucidate the mechanisms by which these genes are involved in a variety of approaches [51_TD$IF] [11]. With continued study, multimodal efforts by researchers may result in the development of feasible gene targeting therapy for urolithiasis in the future.
Financial disclosures: Thomas Chi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Kazumi Taguchi has received JSPS KAKENHI Grant #16K11054, the Naito Foundation Research Grant, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research Grant. Thomas Chi has received NIH grant funding (P20-DK100863 and R21-DK-109433). Funding/Support and role of the sponsor: None.
80
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
References
[24] Thorleifsson G, Holm H, Edvardsson V, et al. Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral
[1] Sorokin I, Mamoulakis C, Miyazawa K, Rodgers A, Talati J, Lotan Y.
density. Nat Genet 2009;41:926–30.
Epidemiology of stone disease across the world. World J Urol 2017.
[25] Chou Y-H, Juo S-HH, Chiu Y-C, et al. A Polymorphism of the ORAI1
http://dx.doi.org/10.1007/s00345-017-2008-6, PMID:28213860 [Epub
gene is associated with the risk and recurrence of calcium nephro-
ahead of print].
lithiasis. J Urol 2011;185:1742–6.
[2] Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of
[26] Lin Y, Mao Q, Zheng X, Chen H, Yang K, Xie L. Vitamin D receptor
kidney stones: AUA guideline. J Urol 2014;192:316–24. [3] Türk C, Petrík A, Sarica K, et al. EAU guidelines on diagnosis and
genetic polymorphisms and the risk of urolithiasis: a meta-analysis.
conservative management of urolithiasis. Eur Urol 2016;69:468–74.
[27] Basiri A, Shakhssalim N, Houshmand M, et al. Coding region analysis
[4] Monico CG, Milliner DS. Genetic determinants of urolithiasis. Nat
of vitamin D receptor gene and its association with active calcium
Rev Nephrol 2011;8:151–62. [5] Khan SR, Pearle MS, Robertson WG, et al. Kidney stones. Nat Rev Dis Prim 2016;2:16008. [6] Curhan GC, Willett WC, Rimm EB, Stampfer MJ. Family history and risk of kidney stones. J Am Soc Nephrol 1997;8:1568–73.
Urol Int 2011;86:249–55.
stone disease. Urol Res 2012;40:35–40. [28] Cakir OO, Yilmaz A, Demir E, Incekara K, Kose MO, Ersoy N. Association of the BsmI, ApaI, TaqI, Tru9I and FokI polymorphisms of the vitamin D receptor gene with nephrolithiasis in the Turkish population. Urol J 2016;13:2509–18.
[7] Goldfarb DS, Fischer ME, Keich Y, Goldberg J. A twin study of genetic
[29] Telci D, Dogan AU, Ozbek E, et al. KLOTHO gene polymorphism of
and dietary influences on nephrolithiasis: a report from the Viet-
G395A is associated with kidney stones. Am J Nephrol 2011;
nam Era Twin (VET) Registry. Kidney Int 2005;67:1053–61. [8] Yasui T, Okada A, Hamamoto S, et al. Pathophysiology-based treatment of urolithiasis. Int J Urol 2017;24:32–8. [9] Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1. [10] Krä Mer A, Green J, Pollard J, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 2014; 30:523–30. [11] Tzou DT, Taguchi K, Chi T, Stoller ML. Animal models of urinary stone disease. Int J Surg 2016;36:596–606.
33:337–43. [30] Xu C, Song R, Yang J, et al. Klotho gene polymorphism of rs3752472 is associated with the risk of urinary calculi in the population of Han nationality in eastern China. Gene 2013;526:494–7. [31] Karim Z, Gérard B, Bakouh N, et al. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 2008;359: 1128–35. [32] Rendina D, Esposito T, Mossetti G, et al. A functional allelic variant of the FGF23 gene is associated with renal phosphate leak in calcium nephrolithiasis. J Clin Endocrinol Metab 2012;97: E840–4.
[12] Kohri K, Yasui T, Okada A, et al. Biomolecular mechanism of urinary
[33] Shakhssalim N, Basiri A, Houshmand M, et al. Genetic polymor-
stone formation involving osteopontin. Urol Res 2012;40:623–37.
phisms in calcitonin receptor gene and risk for recurrent kidney
[13] Gao B, Yasui T, Itoh Y, et al. Association of osteopontin gene haplotypes with nephrolithiasis. Kidney Int 2007;72:592–8.
calcium stone disease. Urol Int 2014;92:356–62. [34] Okamoto N, Aruga S, Matsuzaki S, Takahashi S, Matsushita K,
[14] Liu C-C, Huang S-P, Tsai L-Y, et al. The impact of osteopontin
Kitamura T. Associations between renal sodium-citrate cotranspor-
promoter polymorphisms on the risk of calcium urolithiasis. Clin
ter (hNaDC-1) gene polymorphism and urinary citrate excretion in
Chim Acta 2010;411:739–43.
recurrent renal calcium stone formers and normal controls. Int J
[15] Xiao X, Dong Z, Ye X, et al. Association between OPN genetic variations and nephrolithiasis risk. Biomed Rep 2016;5:321–6. [16] Gögebakan B, Igci YZ, Arslan A, et al. Association between the T593A and C6982T polymorphisms of the osteopontin gene and risk of developing nephrolithiasis. Arch Med Res 2010;41:442–8. [17] Tekin G, Ertan P, Horasan G, Berdeli A. SPP1 gene polymorphisms associated with nephrolithiasis in Turkish pediatric patients. Urol J 2012;9:640–7.
Urol 2007;14:344–9. [35] Rungroj N, Sudtachat N, Nettuwakul C, et al. Association between human prothrombin variant (T165M) and kidney stone disease. PLoS One 2012;7:e45533. [36] Çoker Gurkan A, Arisan S, Arisan ED, Sönmez NC, Palavan Ünsal N. Association between IL-1RN VNTR, IL-1b -511 and IL-6 (-174, -572, -597) gene polymorphisms and urolithiasis. Urol Int 2013;91: 220–6.
[18] Guha M, Bankura B, Ghosh S, et al. Polymorphisms in CaSR and CLDN14
[37] Atar A, Gedikbasi A, Sonmezay E, et al. Serum paraoxonase-1 gene
genes associated with increased risk of kidney stone disease in
polymorphism and enzyme activity in patients with urolithiasis.
patients from the eastern part of India. PLoS One 2015;10:e0130790. [19] Vezzoli G, Terranegra A, Aloia A, et al. Decreased transcriptional activity of calcium-sensing receptor gene promoter 1 is associated with calcium nephrolithiasis. J Clin Endocrinol Metab 2013;98: 3839–47. [20] Vezzoli G, Terranegra A, Soldati L. Calcium-sensing receptor gene polymorphisms in patients with calcium nephrolithiasis. Curr Opin Nephrol Hypertens 2012;21:355–61. [21] Shakhssalim N, Kazemi B, Basiri A, et al. Association between calcium-sensing receptor gene polymorphisms and recurrent calcium kidney stone disease: a comprehensive gene analysis. Scand J Urol Nephrol 2010;44:406–12.
Ren Fail 2016;38:378–82. [38] Merriman TR. An update on the genetic architecture of hyperuricemia and gout. Arthritis Res Ther 2015;17:98. [39] Chen Y, Ren X, Li C, et al. CARD8 rs2043211 polymorphism is associated with gout in a Chinese male population. Cell Physiol Biochem 2015;35:1394–400. [40] Hamada Y, Nishijima T, Watanabe K, et al. High incidence of renal stones among HIV-infected patients on ritonavir-boosted atazanavir than in those receiving other protease inhibitor-containing antiretroviral therapy. Clin Infect Dis 2012;55:1262–9. [41] Nishijima T, Tsuchiya K, Tanaka N, et al. Single-nucleotide polymorphisms in the UDP-glucuronosyltransferase 1A-30 untranslated
[22] Vezzoli G, Scillitani A, Corbetta S, et al. Risk of nephrolithiasis in
region are associated with atazanavir-induced nephrolithiasis in
primary hyperparathyroidism is associated with two polymorphisms
patients with HIV-1 infection: a pharmacogenetic study. J Antimi-
of the calcium-sensing receptor gene. J Nephrol 2015;28:67–72.
crob Chemother 2014;69:3320–8.
[23] Oddsson A, Sulem P, Helgason H, et al. Common and rare variants
[42] Yasui T, Okada A, Urabe Y, et al. A replication study for three
associated with kidney stones and biochemical traits. Nat Commun
nephrolithiasis loci at 5q35.3, 7p14.3 and 13q14.1 in the Japanese
2015;6:7975.
population. J Hum Genet 2013;58:588–93.
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
[43] Urabe Y, Tanikawa C, Takahashi A, et al. A genome-wide association
81
[45] Taguchi K, Hamamoto S, Okada A, et al. Genome-wide gene expres-
study of nephrolithiasis in the Japanese population identifies novel
sion profiling of Randall’s plaques in calcium oxalate stone formers.
susceptible loci at 5q35.3, 7p14.3, and 13q14.1. PLoS Genet 2012;8:
J Am Soc Nephrol 2017;28:333–47.
e1002541. [44] Xu Y, Zeng G, Mai Z, Ou L. Association study of DGKH gene polymorphisms with calcium oxalate stone in Chinese population. Urolithiasis 2014;42:379–85.
[46] Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and urolithiasis in children. Kidney Int 2011;80:1278–91.
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Review – Stone Disease
Genetic Risk Factors for Idiopathic Urolithiasis: A Systematic Review of the Literature and Causal Network Analysis Kazumi Taguchi a,b [14_TD$IF] , Takahiro Yasui a, Dawn Schmautz Milliner c, Bernd Hoppe d, Thomas Chi b,* a
Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan;
b
Department of Urology, University of
California, San Francisco, CA, USA; c Division of Nephrology, Departments of Pediatrics and Internal Medicine, Mayo Clinic, Rochester, MN, USA; d Division of Pediatric Nephrology, Department of Pediatrics, University Hospital Bonn, Bonn, Germany
Article info
Abstract
Article history: Accepted April 29, 2017
Context: Urolithiasis has a high prevalence and recurrence rate. Prevention is key to patient management, but risk stratification is challenging. In particular, genetic predisposition for urinary stones is not fully understood. Objective: To review current evidence of potential causative genes for idiopathic urolithiasis and map their relationships to one another. This evidence is essential for future establishment of molecular targeted therapy. Evidence acquisition: A systematic literature review from 2007 to 2017 was performed in accordance with the Preferred Reporting Items for Systematic Review and Metaanalyses guidelines. The search was restricted to human studies conducted as either case–control or genome-wide association studies, and published in English. We also performed a causal network analysis of candidate genes gained from the systematic review using Ingenuity Pathway Analysis (IPA). Evidence synthesis: During the systematic screening of literature, 30 papers were selected for the review. A total of 20 genes with 42 polymorphisms/variants were found to be associated with urolithiasis risk. Their functional roles were mainly categorized as stone matrix, calcium and phosphate regulation, urinary concentration and constitution, and inflammation/oxidative stress. IPA network analysis revealed that these genes connected via signaling pathways and a proinflammatory/oxidative environment. Conclusions: This systematic review provides an updated gene list and novel causal networks for idiopathic urolithiasis risk. Although some genes such as SPP1, CASR, VDR, CLDN14, and SLC34A1 were identified by several studies and recognized by prior reviews, further investigation elucidating their roles in stone formation will be essential for future studies. Patient summary: In this review, we summarized recent literature regarding genes responsible for kidney stone risk. Based on a detailed review of 30 articles and computational network analysis, we concluded that disorder of mineral regulation with local inflammation in the kidney may cause kidney stone disease. © 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Associate Editor: James Catto Keywords: Urolithiasis Nephrolithiasis Genome-wide association study Single-nucleotide polymorphism Ingenuity Pathway Analysis Calcium Phosphate Inflammation Randall’s plaque
* Corresponding author. Department of Urology, University of California, 400 Parnassus Ave., Sixth Floor, Suite A610, San Francisco, CA 94143, USA. Tel. +1-415-353-2200; Fax: +1-415-353-2641. E-mail address: [email protected] (T. Chi).
http://dx.doi.org/10.1016/j.euf.2017.04.010 2405-4569/© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
73
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
[(Fig._1)TD$IG]
1.
Urolithiasis has a high prevalence worldwide ranging between 7% and 13% in North America, 5% and 9% in Europe, and 1% and 5% in Asia [1]. Owing to the high recurrence rate of urolithiasis, both the American Urological Association [42_TD$IF][2] and European Association of Urology [43_TD$IF][3] recommend managing and preventing future recurrences by dietary and medical assessments. Single gene mutation states such as cystinuria are known to cause nephrolithiasis in a small proportion of stone patients [4_TD$IF][4]. However, in the large majority of patients who have idiopathic stone formation, less is known about contributing genetic factors. While numerous research efforts have been performed to elucidate the pathophysiology of lithogenesis [45_TD$IF][5], the exact mechanism of stone formation is still not fully understood. Identifying genetic predisposition may lead to new prevention strategies for urolithiasis. For example, studies have demonstrated that a family history of urolithiasis increases relative risk by 2.57-fold in men [46_TD$IF][6]. In addition, the concordance rate of the disease in monozygotic twins is higher compared with that in dizygotic twins (32.4% vs 17.3%) [47_TD$IF] [7]. These lines of evidence suggest that genetic factors for urolithiasis play a pivotal role in its etiology. By extension, elucidation of responsible genes could lead to future targeted gene therapy and better prevention. Genome-wide association studies have widely been used for identifying genetic risk factors for various diseases. This approach facilitates examining entire DNA sequences to detect mutations, variants, and single-nucleotide polymorphisms (SNPs). SNPs play a crucial role in determining genes associated with urolithiasis that may serve as future diagnostic markers [48_TD$IF][8]. Understanding how these SNPs link together could potentially help unveil the genomic drivers of lithogenesis. In this review, we focus on SNPs and genome-wide association studies (GWASs) conducted for urolithiasis. We present a systematic review of genetic risk factors for stone formation and a network analysis of candidate genes. Our aim is to provide an update on genes associated with nephrolithiasis and how they may interact with one another. 2.
Exclusions
Introduction
Evidence acquisition
We performed a systematic literature review in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines [49_TD$IF][9]. In PubMed and Medline databases, the following search keywords were used: ((“genome”[MeSH]) OR (“mutation”[MeSH]) OR (“genetic”[MeSH]) OR (“single nucleotide polymorphism”[MeSH])) AND ((“urolithiasis”[MeSH]) OR (“nephrolithiasis”[MeSH]) OR (“kidney calculi”[MeSH]) OR (“urinary calculi”[MeSH]) OR (“calcium oxalate”[MeSH]) OR (“calcium phosphate”[MeSH]) OR (“uric acid”[MeSH])). The search was restricted to human studies with both an abstract and the full text available; published in English during the last 10 yr. Studies were considered only if patient cases were confirmed as
Number of papers
758 Nonhuman studies 621 Manuscripts not written in English 552 Not published within the last 10 yr 257 Abstract and full text not available 237 Case reports, meta-analyses, reviews, cohort studies 148 Patients with no evidence of urolithiasis or nephrolithiasis 30 Fig. 1 – Flow chart of the methods used to formulate this systematic literature review in accordance with PRISMA guidelines. PRISMA = Preferred Reporting Items for Systematic Review and Metaanalyses.
having either renal or ureteral stones diagnosed previously. A total of 237 papers were reviewed; 54 case reports and 33 reviews were excluded. Cohort studies; negative studies; and studies irrelevant to urolithiasis and nephrolithiasis were screened. After exclusions; 30 papers were selected for this review (Fig. 1). Existing networks among candidate genes for urolithiasis development were also analyzed. Ingenuity Pathway Analysis (IPA; QIAGEN, Hilden, Germany) uses computerized analysis with a mega knowledge base of reviewed scientific literature [50_TD$IF][10]. The use of IPA methodology allowed a causal network analysis for the candidate genes. 3.
Evidence synthesis
From the selected 30 papers, 20 genes were identified with 42 SNPs/variants reported in case–control and/or GWASs. Most investigations consisted of Asian and European patients. Table 1 summarizes the genes associated with urolithiasis risk factors. The majority of genes were
74
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
Table 1 – Genes related to urolithiasis summarized by a systematic review of manuscripts published between 2007 and 2017. Function Calcium stone Stone matrix
Calcium regulation
Phosphate (and calcium) regulation
Gene ([68_TD$IF]Coded protein)
Locus
SNP, variant
Region
Cases/controls[69_TD$IF](n)
origin
Year [ref.]
SPP1 (osteopontin)
4p22.1
CASR (calcium-sensing receptor)
3q13.33-q21.1
144 and 145 T-593A rs1126616 rs17524488 c.240T>C c.708C>T rs11439060 rs1042636
[70_TD$IF]promoter promoter exon 7 promoter exon 6 exon 7 prompter [7_TD$IF]exon 7
126/214 121/100 121/100 249/247 65/50 65/50 230/250 99/107, 115/141, 200/200
Japan Turkey Turkey Taiwan Turkey Turkey China Iran, [78_TD$IF]Italy, India
rs1801725
exon 7
99/107, 200/200
Iran, India
exon 7 promoter 1 promoter 1 [84_TD$IF]intron 1 intron 1 [84_TD$IF]intron 1
99/107 165/208 155/141 200/200 200/200 136/500
Iran Italy Italy India India China
2007 [71_TD$IF][13] 2010 [72_TD$IF][16] 2010 [73_TD$IF][16] 2010 [74_TD$IF][14] 2012 [75_TD$IF][17] 2012 [76_TD$IF][17] 2016 [15_TD$IF][15] 2010 [79_TD$IF][21], 2014 [22], 2015 [18] 2010 [80_TD$IF][22], 2015 [18] 2010 [81_TD$IF][21] 2013 [82_TD$IF][19] 2014 [83_TD$IF][22] 2015 [85_TD$IF][18] 2015 [86_TD$IF][18] 2011 [2_TD$IF][25]
CLDN14 (claudin 14)
21q22.13
ORAI1 (calcium releaseactivated calcium modulator) VDR [87_TD$IF](vitamin D receptor)
12q24.31
E1011Q rs6776158 rs1501899 rs219780 rs219778 rs12313273
12q12-14
rs2228570
[8_TD$IF]start codon
106/109
Iran
2012 [89_TD$IF][27]
intron 8 [ romoter 70_TD$IF]p exon 3 [93_TD$IF]exon 1
98/70 108/51 426/282 92/63
Turkey Turkey China France
2016 [90_TD$IF][28] 2011 [91_TD$IF][29] 2013 [92_TD$IF][30] 2008 [94_TD$IF][31]
KL (klotho)
13q13.1
NHERF1 (sodium-hydrogen antiporter 3 regulator 1)
17q25.1
rs1544410 G395A rs3752472 L110V
12p13.32
R153Q E225K rs7955866
exon 2 exon 3 [93_TD$IF]exon 3
92/63 92/63 106/87
France France Italy
2008 [95_TD$IF][31] 2008 [96_TD$IF][31] 2012 [97_TD$IF][32]
17q11.2
[98_TD$IF]3’UTR+18C>T rs72570683 rs3214144 1550V
3’UTR intron 1 intron 1 exon 12
105/101 105/101 105/101 105/107
Iran Iran Iran Japan
2013 [9_TD$IF][33] 2013 [10_TD$IF][33] 2013 [29_TD$IF][33] 2007 [10_TD$IF][34]
11p11.2 2q14.1
rs5896 2/2 genotype
[93_TD$IF]exon 6 [84_TD$IF]intron 2
216/216 65/85
Thailand Turkey
2012 31_TD$IF][[ 35] 2013 [103_TD$IF][36]
7q21.3
rs854560
158/138
Turkey
2016 [3_TD$IF][37]
CARD8 (caspase recruitment domain family member 8)
19q13.33
rs2043211
[93_TD$IF]exon 5
396/403
China
2015 [104_TD$IF][39]
UGT1A1 (UDP glucuronosyltransferase family 1 member A1)
2q37.1
rs10929303
[93_TD$IF]exon 5
31/47
Japan
2014 [35_TD$IF][41]
rs1042640 rs8330
[93_TD$IF]exon 5 exon 5
31/47 31/47
Japan Japan
2014 105_TD$IF][[ 41] 2014 106_TD$IF][[ 41]
FGF23 (fibroblast growth factor 23) CALCR (calcitonin receptor)
Urinary inhibitor of stone formation Anti-inflammatory and [102_TD$IF]-oxidative stress
SLC13A2 (Na+/dicarboxylate cotransporter-1) F2 (prothrombin) IL-RN VNTR (interleukin 1 receptor antagonist) PON 1 (paraoxonase-1)
7q21.3
Uric acid stone
Atazanavir containing stone
associated with calcium-containing stones, whereas only two papers examined rare stone patients: uric acid– and atazanavir-containing stones. For calcium-containing stones, the following genes were reported to have a possible causative role in urolithiasis: osteopontin (OPN) coding gene (SPP1) related to the stone matrix, calcium-sensing receptor (CASR)/claudin 14 (CLDN14)/calcium release-activated calcium modulator 1 (ORAI1) related to calcium regulation, vitamin D receptor (VDR)/klotho (KL)/sodium hydrogen antiporter 3 regulator 1 (NHERF1)/fibroblast growth factor 23 (FGF23)/calcitonin receptor (CALCR) related to phosphate as well as calcium regulation, solute carrier family 13 member 2 (SLC13A2)/prothrombin (F2)
related to urinary inhibition of stone formation, and interleukin 1 receptor antagonist (IL-RN VNTR)/paranoxonase-1 (PON1) related to anti-inflammatory and antioxidative stress. Additionally, four GWASs including a validation case– control study were conducted during the study review period (Table 2). The SNPs of phosphate carrier NPT2a (SLC34A1) and CLDN14 were identified from two different GWASs. SLC34A1, CLDN14, AQP1, diacyl glycerol kinase (DGKH), CASR, and transient receptor potential cation channel subfamily V member 5 (TRPV5) were also associated with other SNPs related to urolithiasis prevalence in case– control studies.
75
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
Table 2 – Genes related to urolithiasis identified by a systematic review of GWAS [107_TD$IF]studies published between 2007 and 2017. Gene ([68_TD$IF]Coded protein)
Locus
SNP
Cases ([108_TD$IF]n)/controls (n)
Markers (n)
Origin
Year [ref.]
SLC34A1 (phosphate carrier NPT2a)
5q35.3
rs11746443a[93_TD$IF] rs12654812a
CLDN14 (claudin 14)
21q22.13
rs219780b[10_TD$IF]
[109_TD$IF]5,892/17,809 5,892/17,809 5,419/279,870 [1_TD$IF]3,773/42,510
712,726 712,726 28,300,000 303,120
2012 [43] 2012 [43] 2015 [37_TD$IF][23] 2009 [12_TD$IF][24]
AQP1 (aquaporin 1)
7q14.3
DGKH (diacyl glycerol kinase) ALPL (alkaline phosphatase) CASR (calcium-sensing receptor) TRPV5 (transient receptor potential cation channel subfamily V member 5)
13q14.1 1p36.12 3q21.1 7q34
rs199565725 rs1000597 rs12669187 rs4142110c rs1256328 rs7627468 p.L530A
5,419/279,870 [13_TD$IF]5,892/17,809 5,892/17,809 5,892/17,809 [15_TD$IF]5,419/279,870 [15_TD$IF]5,419/279,870 [15_TD$IF]5,419/279,870
28,300,000 712,726 712,726 712,726 28,300,000 28,300,000 28,300,000
Japan Japan Iceland Iceland, The Netherlands Iceland Japan Japan Japan Iceland Iceland Iceland
a b c
2015 2012 2012 2012 2015 2015 2015
[37_TD$IF][23] [43] [43] [43] [37_TD$IF][23] [37_TD$IF][23] [18_TD$IF][23]
Validated by a case–control study (601 cases vs 201 controls, Japan) [39_TD$IF][42]. Validated by a case–control study (200 cases vs 200 controls, India) [21_TD$IF][18]. Validated by a case–control study (507 cases vs 505 controls, China) [40_TD$IF][44].
3.1.
Stone macromolecule, matrix
OPN is a highly phosphorylated glycoprotein originally identified in bone that functions as an adhesion motif of protein to integrins and CD44. It was also identified as one of the organic (matrix) components of calcium-based urinary stones. Some reported that OPN knockout mice produce calcium oxalate crystals [51_TD$IF][11], whereas others indicate that OPN facilitates crystal development by mineralization and inflammation processes mediated by other cytokines and immune cells including macrophages [52_TD$IF][12]. Three studies from eastern Asia demonstrated SNPs of SPP1 related to urolithiasis patients. Gao et al [1_TD$IF][13] reported that the SPP1 haplotype SNP carrier with G-T-T-G in the 145 and 144 positions had a higher risk of developing nephrolithiasis compared with other haplotypes (odds ratio [OR] = 1.676), whereas the haplotype T-G-T-G carrier in the same position has a lower risk (OR = 0.351). Liu et al [13_TD$IF][14] showed that the delG/delG genotype of SNP rs17524488 was also associated with a significantly higher risk of developing calcium urolithiasis (OR = 1.95) and a higher urinary calcium to OPN ratio than those with G/G genotype. Xiao et al [15_TD$IF] [15] demonstrated that carriers with the SPP1 rs11439060 insertion types were over-represented in urolithiasis patients compared with controls (OR = 1.55). In addition, two Turkish studies reported that the SPP1 haplotypes between SNPs T-593A and rs1126616 demonstrated a significant lower or higher OR for developing kidney stones; CA haplotype had a lower (OR = 0.283), whereas TT haplotype had a higher (OR = 1.963) risk for kidney stones [12_TD$IF] [16]. Among the pediatric population, C allele frequency of c.240T>C polymorphism (OR = 2.13) and T allele frequency of c.708C>T polymorphism (OR = 2.183) were higher in nephrolithiasis patients than in controls [14_TD$IF][17]. 3.2.
Genes related to calcium regulation
3.2.1.
Calcium-sensing receptor
CASR is located on chromosome 3q13.33-q21.1 and consists of 11 exons. It is a G protein–coupled receptor that
modulates cell activity according to the extracellular calcium concentration. This protein is expressed in the parathyroid gland and the thick ascending limb of the Henle loop. Its activation induces increased calcium excretion in the kidney via regulation of parathyroid hormone (PTH) production and renal tubular calcium reabsorption [53_TD$IF] [18,19]. Earlier studies summarized that activating the Arg990Gly polymorphism (rs1042636) may predispose to nephrolithiasis by increasing calcium excretion [54_TD$IF][20]. Four case–control studies and one GWAS have investigated CASR SNPs. The G allele of rs1042636 was associated with a significant risk of stone disease (OR = 8.06) [18_TD$IF][21], and the variant genotype GG was associated with 20-fold increased risk for kidney stone disease (OR = 20.76) [21_TD$IF] [18]. Stone risk of patients with primary hyperparathyroidism was also higher in patients carrying a G allele at rs1042636 [20_TD$IF][22]. An S allele of rs1801725 was reported to confer an OR = 2.55 [18_TD$IF][21] and a T allele was reported with OR = 2.54 [21_TD$IF][18] for risk of stone disease. Moreover, one study reported that a GG genotype for rs6776158 demonstrated an increased risk of nephrolithiasis (OR = 5.8) by multinomial logistic regression analysis [19_TD$IF][19]. In addition to the risk for kidney stone development, a QQ genotype with respect to the 1011 locus was related to significantly lower serum total calcium in patients [18_TD$IF][21]. Furthermore, Oddsson et al [37_TD$IF][23] found SNP rs7627468 of CASR associated with kidney stones (OR = 1.21) from a GWAS comparing 5419 kidney stone cases with 279 870 controls during examination of 28.3 million sequence variants. 3.2.2.
Claudin 14
CLDN14 is a member of the claudin family of membrane proteins that regulate paracellular passage of ions and small solutes at epithelial tight junctions. CLDN14 is expressed in the kidney, both in the loop of Henle and in proximal tubules, as well as in the epithelia of several other organs, and has been observed to selectively decrease permeability of Ca2+[41_TD$IF] through tight junctions [38_TD$IF][24]. Earlier studies indicated that CLDN14 expression is strongly upregulated by activation of CASR, and dysregulation of the renal CASR-
76
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
CLDN14 pathway could contribute to the development of kidney stones [21_TD$IF][18]. Thorleifsson et al [38_TD$IF][24] found the SNP rs219780 in exon 7 associated with kidney stone incidence (OR = 1.25) by conducting a GWAS in 3773 cases and 42 150 controls from Iceland and the Netherlands. The homozygous carriers of rs219780 were estimated to have 1.64 times greater risk of developing kidney stone compared with noncarriers. This SNP was validated by a GWAS from a different population: patients with two base pair deletion correlating with rs219780 had a strong association with kidney stones (r2 = 0.82, OR = 0.81) [23]. Additionally, a case–control study demonstrated that SNPs rs219778 and rs219780 were significantly associated with kidney stone disease (OR = 3.46 and OR = 2.63, respectively) [21_TD$IF][18]. 3.2.3.
Calcium release-activated calcium modulator 1
ORAI1 is located on chromosome 12q24.31 and consists of two exons. ORAI1 is a membrane calcium channel subunit that is activated when calcium stores are depleted. Mutation of this gene resulted in a deficiency of store-operated calcium-dependent signaling pathways, leading to immune system dysfunction [5_TD$IF][25]. Chou et al [25] reported that two SNPs, rs12313273 and rs6486795, of the ORAI1 gene were associated with nephrolithiasis risk (p = 0.006 and 0.035, respectively). The CC and CT genotypes of rs12313273 carried an increased risk of nephrolithiasis compared with the TT genotype (OR = 2.10 and 1.82, respectively). Moreover, the CC and CT genotypes conferred an increased risk for stone recurrence compared with the TT genotype (OR = 3.73 and 2.31, respectively). 3.3.
Genes related to calcium/phosphate regulation
3.3.1.
Vitamin D receptor
VDR is a 50- to 60-kDa cellular polypeptide whose gene is located on 12q13.11 consisting of 11 exons. This gene encodes the nuclear hormone receptor for vitamin D3. It plays a central role in mineral metabolism, including intestinal calcium absorption and renal calcium absorption. A prior meta-analysis of VDR polymorphisms indicated that the f allele and ff + Ff genotype in Fokl as well as the t allele and tt + Tt genotype in Taql were related to an increased risk of urolithiasis [56_TD$IF][26]. Two case–control studies of VDR SNPs were reported from Iran and Turkey. Basiri et al [23_TD$IF][27] indicated that the C allele of rs2228570 was more prevalent in male active stone formers (OR = 11.1 for TC genotype, OR = 10.7 for CC genotype). On the contrary, the B allele of rs1544410 was found to increase the risk of nephrolithiasis by approximately 1.5fold (OR = 1.55) [24_TD$IF][28]. 3.3.2.
Klotho
Klotho is a type-I transmembrane protein related to betaglucosidase, a novel regulator of renal calcium and phosphate homeostasis. Its coding gene, KL, is located on chromosome 13q13.1, consisting of six exons. Klotho is expressed in tissues responsible for calcium homeostasis including the kidney, parathyroid gland, and epithelium of the choroid plexus in the
brain. Klotho also plays an important role in increased calcium uptake in the kidneys via TRPV5 and regulation of phosphate homeostasis via FGF23 [57_TD$IF][29,30]. A Turkish study indicated that patients with a GG genotype of the G395A KL polymorphism had a two-fold increased kidney stone risk compared with AA and GA genotypes (OR = 1.849). They also found that a GG genotype had a significantly higher risk of stone-related metabolic abnormalities such as hypercalcemia (OR = 33.05) and hypophosphatemia (OR = 0.07) [25_TD$IF][29]. The CT + TT genotype of rs3752472 was found to be associated with nephrolithiasis risk when compared with a CC genotype (OR = 1.512) in the Chinese population [26_TD$IF][30]. 3.3.3.
Sodium hydrogen antiporter 3 regulator 1
NHERF1, also known as SLC9A3R1, is located on chromosome 17q25.1 and consists of six exons. NHERF1 binds renal tubular transporters including the Na+[37_TD$IF] phosphate cotransporter 2a (NPT2a) and the PTH type 1 receptor. NHERF1 knockout mice demonstrate increased urinary calcium, phosphate, and uric acid excretion, with resultant renal calcium phosphate crystal deposits [58_TD$IF][11]. Karim et al [31] identified three mutations of NHERF1— L110 V, R153Q, and E225K—from 158 patients, 95 cases of which were located in France. In addition, NHERF1 appeared to cause renal phosphate loss by increasing cyclic AMP generation via PTH in an in vitro model. 3.3.4.
Fibroblast growth factor 23
FGF23 is located on 12q13.32 and consists of three exons. This recently identified growth factor regulates renal phosphate homeostasis by decreasing renal reabsorption and intestinal absorption of phosphate. FGF23 reduces phosphate by downregulating NPT2 cotransporters, resulting in urinary phosphate wasting. It also acts to decrease serum phosphorus levels by reducing the bioavailability of vitamin D3 [59_TD$IF][29,32]. The SNP rs7955856 in FGF23 was reported in stone formers with a renal phosphate leak. The T allele and CT genotype rates within rs7955856 in those patients were significantly higher compared with those in controls (p < 0.03). Moreover, the T allele of rs7955856 carriers showed significantly lower levels of serum phosphate and TmPi/GFR compared with noncarriers (p < 0.03) [28_TD$IF][32]. 3.3.5.
Calcitonin receptor
Calcitonin, a 32-amino-acid protein, binds its receptor, CALCR, on bone osteoclasts as well as within renal tubular cells. Calcitonin acts as a renal calcium-conserving hormone by increasing Ca2+ and Mg2+ reabsorption and decreasing phosphate reabsorption in kidneys. While CALCR polymorphisms were reported to be associated with bone mineral density changes in different populations, few studies have established the association of its SNPs with urolithiasis [29_TD$IF][33]. Shakhssalim et al [29_TD$IF][33] detected nine polymorphisms from a cohort of 105 male recurrent calcium stone patients and 101 controls. Among these SNPs, the T allele of the 30 UTR + 18C > T polymorphism, as well as the C and A7
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
alleles of rs72570683 and rs3214144 conferred a significant risk for stone disease (OR = 36.72 and 1.95, respectively). 3.4.
Genes related to urinary inhibitors of stone formation
3.4.1.
Solute carrier family 13 member 2
SLC13A2 is located on chromosome 17q11.2, consists of 14 exons, and encodes Na+/dicarboxylate cotransporter-1 (NaDC-1). NaDC-1 plays an important role in citrate reabsorption in the apical membrane of the proximal tubule; thus, this protein is a major determinant of urinary citrate excretion. Genetic predisposition rather than metabolic abnormality may thus be a major cause for idiopathic hypocitraturia generating interest in NaDC-1 [30_TD$IF][34]. From a Japanese cohort of 105 recurrent renal calcium stone formers and 107 controls, 1550 polymorphisms were detected. Although no significant differences in allele frequencies were observed (p = 0.47), individuals with the BB genotype of 1550 V showed significantly lower urinary citrate excretion than those with bb genotype (p = 0.005) [30_TD$IF][34]. 3.4.2.
Prothrombin
F2 controls synthesis of prothrombin, also known as coagulation factor II, a serine-protease coagulation protein in the blood stream that converts soluble fibrinogen into insoluble strands of fibrin and catalyzes many other coagulationrelated reactions. F2 is located on chromosome 11p11.2, consists of 14 exons, and encodes urinary prothrombin fragment 1 (UPTF1). UPTF1 was initially detected as a crystal matrix protein within calcium oxalate crystals, and it is considered to be a potent inhibitor of calcium oxalate growth and aggregation in urine [31_TD$IF][35]. The SNP rs5896 was found in exon 6 using whole exon sequencing of F2. Furthermore, the frequency of the C allele of rs5896 in kidney stone patients was significantly lower than that of the controls (OR = 0.68). Particularly in female patients, genotype (OR = 0.49) and allele frequencies (OR = 0.59) were significantly different between stone patients and controls [31_TD$IF][35], suggesting a potential protective role of F2 against stone formation. 3.5.
Genes related to anti-inflammatory and antioxidative
stress 3.5.1.
Interleukin 1 receptor antagonist
Interleukin (IL)-1 is one of the major proinflammatory cytokines facilitating tissue inflammation. Its receptor, IL1 receptor antagonist, is coded by IL-RN and exhibits an anti-inflammatory function by binding to the same receptor with IL-1a and IL-1b. IL-RN is located on chromosome 2q14.1 and consists of 11 exons. A penta-allelic polymorphic site in intron 2 of this gene consisting of variable number tandem repeats has been investigated extensively in relation to a variety of pathological conditions [32_TD$IF][36]. A Turkish study examined its polymorphisms associated with urolithiasis. A significant genotype distribution of ILRN polymorphisms between urolithiasis and control groups was seen (p = 0.047), and urolithiasis patients had a higher frequency of allele 2 in IL-RN (p = 0.007) [32_TD$IF][36].
3.5.2.
77
Paraoxonase-1
PON1 is a serum high-density lipoprotein–bound enzyme with an antioxidant function. Its activity is reduced in environments of high oxidative stress and associated with increased lipid peroxidation, which might be a factor for determining predisposition to stone formation. PON1 clusters with three related paraoxonase genes at chromosome 7q21.3 [60_TD$IF][37]. Atar et al [37] reported that the PON1 L55M polymorphism was significantly more prevalent in urolithiasis patients (p = 0.002). Those with an MM genotype showed a greater risk for urolithiasis compared with those with an LM genotype (OR = 9.88). 3.6.
Genes for uric acid stones
While a number of researches have sought SNPs associated with hyperuricemia and/or gout by GWASs [61_TD$IF][38], few studies have reported the association between SNPs and uric acid stone formers for the past 10 yr. One study reported the possible association of an SNP in caspase activation and recruitment domain 8 (CARD8) gene in stone formers with gout [34_TD$IF][39]. CARD8 is a component of innate immunity involved in the suppression of nuclear factor kB activation. CARD8 suppresses the immune response and inflammatory activities. It is located on chromosome 19q13.33 and consists of 22 exons. Gout patients carrying a TT genotype of the CARD8 rs2043211 polymorphism had an increased risk of kidney stone compared with those carrying the AA genotype (p = 0.03). 3.7.
Genes for atazanavir-containing stones
Atazanavir-induced nephrolithiasis is a rare condition among all uroliths, and the exact mechanism for their formation is not fully understood. Based on a large cohort study [62_TD$IF][40], atazanavir use was significantly associated with renal stones (hazard ratio = 10.44), and the median time from commencement of atazanavir to stone diagnosis was 24.5 mo. Atazanavir is reported to be excreted whole in the urine, leading to the hypothesis that metabolism of atazanavir in the human body may be related to developing stones. UDP glucuronosyltransferase family 1 member A1 (UGT1A1) is expressed primarily in the liver and gastrointestinal tract, and plays a role in bilirubin elimination. Given that UGT1A1 is known for its association with atazanavirinduced unconjugated hyperbilirubinemia, it is also thought to be involved in atazanavir metabolism. Nishijima et al [35_TD$IF][41] reported that the TC genotype of rs10929303, GC genotype of rs1042640, and G allele of rs8330 of UGT1A-30 UTR were independent risk factors for atazanavir-induced nephrolithiasis among HIV-positive patients (OR = 3.7, 5.8, and 5.8, respectively). 3.8.
Other genes identified by GWASs
3.8.1.
Phosphate carrier NPT2a
SLC34A1 located on chromosome 5q35.3 encodes NPT2a, a member of the type IIa sodium phosphate cotransporter
78
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
family. NPT2a is responsible for phosphate absorption at the apical membrane of renal proximal tubular cells [39_TD$IF][42]. Npt2a knockout mice demonstrate hypercalciuria and renal calcium phosphate crystal deposits [51_TD$IF][11]. Mutations of SLC34A1 appear to be associated with hypophosphatemic nephrolithiasis and osteoporosis in humans [39_TD$IF][42]. Two GWASs detected SLC34A1 polymorphisms associated with kidney stone, and one case–control study validated these results. Rs1176443 was identified as a novel locus for nephrolithiasis (OR = 1.19) from 5892 Japanese nephrolithiasis patients. Subsequent analyses in 21 842 Japanese individuals revealed that the risk allele of rs11746443 was associated with a reduction in the estimated glomerular filtration rate [36_TD$IF][43]. SNP rs12654812 was found to be associated with kidney stones from 5892 Japanese and 5419 Icelander kidney stone patients (OR = 1.16 and 1.18, respectively) [36_TD$IF][43]. This SNP was also associated with decreased serum PTH and phosphate levels [37_TD$IF][23]. A separate population study validated its association with nephrolithiasis (OR = 1.43) and decreased serum phosphorus level (p = 0.0353) [39_TD$IF][42]. 3.8.2.
Aquaporin-1
Aquaporin-1 is abundantly expressed in the kidney, mainly in the proximal tubule, functioning as a water channel. Aqp1 knockout mice show reduced osmotic permeability and developed hydration after water deprivation. AQP1 is located on chromosome 7p14.3 and consists of seven exons. Rs100597 and rs12669187 were detected as the SNPs significantly associated with nephrolithiasis (each OR = 1.22). These SNPs are thought to affect the urine concentration process and thereby increase the risk of nephrolithiasis [36_TD$IF][43]. 3.8.3.
Diacyl glycerol kinase
DGKH is expressed in the brain and is known to be related to psychiatric disorders such as bipolar and major depressive disease. DGKH belongs to the DGK family, which is involved in transplasmalemmal calcium ion influx [40_TD$IF][44]. Its coding gene, DGKH, is located on chromosome 13q.14.11 and consists of 38 exons. A Japanese GWAS detected the SNP rs4142110 associated with nephrolithiasis (OR = 1.14) [36_TD$IF][43]. A case–control study further indicated that rs4142110 was associated with a risk of calcium oxalate stones and hypercalciuria (p < 0.05). The CT, TT, and CT + TT genotypes of rs4142110 were significantly correlated with decreased calcium oxalate stone risk (OR = 0.666, 0.562, and 0.466, respectively). In addition, the CT, TT, and CT + TT genotypes showed a significant decrease in hypercalciuria (OR = 0.666, 0.562, and 0.466, respectively) [40_TD$IF][44]. 3.8.4.
Alkaline phosphatase
Alkaline phosphatase (ALPL) is a member of the alkaline phosphatase family as a tissue nonspecific form and a membrane-bound glycosylated enzyme. ALPL is expressed in the proximal tubules of the kidney and hydrolyzes pyrophosphate to free phosphate, suggesting its facilitative role in kidney stone formation. ALPL is located on chromosome 1p36.12 and consists of 14 exons. The SNP rs1256328 of ALPL was found to be associated with both incident (OR = 1.21)
and recurrent (OR = 1.23) kidney stones. Rs1256328 also had a significant association with increased serum alkaline phosphatase levels (p < 0.001) [37_TD$IF][23]. 3.8.5.
Transient receptor potential cation channel subfamily V
member 5
TRPV5 is a highly selective epithelial calcium channel expressed at the apical membrane of the distal renal tubule epithelial cells, which mediates calcium transport in the kidney and constitutes the rate-limiting step of active calcium reabsorption. TRPV5 is located on chromosome 7q34 and consists of 15 exons, and Trpv5 knockout mice exhibited severe hypercalciuria. The TRPV5 p.Leu530Arg variant was detected to be significantly associated with recurrent kidney stones (OR = 3.62) [37_TD$IF][23]. 3.9.
Causal gene networks for lithogenesis
Fig. 2 illustrates the result of gene network analysis among the candidate genes listed in Tables 1 and 2. Each gene has been categorized by its location in the kidney and function. Genes related to stone matrix, calcium and phosphate regulation, and inflammation are connected via c-Jun Nterminal kinase signaling pathways, beta-estradiol, leptin, caspase, and proinflammatory cytokines. In particular, FGF23, VDR, SPP1, and IL1RN play primarily roles, interfacing with other genes for lithogenesis. Interestingly, these networks are relatively similar to the gene networks surrounding Randall’s plaques (RPs), which are considered potential origin nidi for calcium stone. A recent microarray study reported that cellular transporters and ion channels also formed networks with proinflammatory cytokines and signaling pathways, indicating that RPs develop by urothelial/ interstitial/tubular cellular apoptosis followed by OPN aggregation, mediated by tissue inflammation and oxidative stress [63_TD$IF][45]. In addition, several genes shown in this systematic review and gene network analysis in RP [63_TD$IF][45] are known to be responsible for hereditary developed kidney stone disease, which are typically expressed in pediatric patients. CASR is associated with autosomal dominant hypocalcemic hypercalciuria and Bartter syndrome. CASR and VDR are related to hypercalcemia in the context of hypercalciuriafamilial isolated hyperparathyroidism and idiopathic hypercalciuria. SLC34A1 is associated with persistent hypophosphatemia in urolithiasis and osteoporosis. Moreover, genes significantly expressed around RPs, including SLC12A1 and potassium voltage-gated channel subfamily J (KCNJ) [63_TD$IF][45], are associated with Bartter syndrome, a genetic disorder with an extremely high incidence of urinary stones [64_TD$IF][46]. While multiple studies have demonstrated these genes to be closely associated with a risk for urolithiasis, the complexities of their interactions have yet to be completely determined. As a result, the exact pathogenesis of idiopathic kidney stones is still unknown with regard to genetic factors. Further investigation, combining GWASs and omics analyses, will be essential for improving the understanding of the genetic causes of idiopathic urolithiasis.
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
[(Fig._2)TD$IG]
79
Fig. 2 – Causal networks of genes associated with urolithiasis revealed from the current systematic review. Different shapes and their relationship are as follows: red molecules = stone matrix genes; yellow molecules = calcium regulation genes; green molecules = phosphate (and calcium) regulation genes; cyan molecule = urinary inhibitor of stone formation genes; purple molecules = inflammation genes; gray molecules = other genes. ALPL = alkaline phosphatase; AQP1 = aquaporin-1; CALCR = calcitonin receptor; CASR = calcium-sensing receptor; CLDN14 = claudin 14; DGKH = diacyl glycerol kinase; FGF23 = fibroblast growth factor 23; IL = interleukin; Jnk = c-Jun N-terminal kinase; KL = klotho; LEP = leptin; SLC = solute carrier; TRPV5 = potential cation channel subfamily V member 5; UGT1A1 = UDP glucuronosyltransferase family 1 member A1; VDR = vitamin D receptor.
Limitations should be recognized for this study. Since we limited our inclusion to literature for last 10 yr, earlier similar studies in other populations may implicate somewhat different genes, and may convey a different impression of geographic distribution of the risk factors and incidence of idiopathic urolithiasis. Additionally, excluding studies related to monogenic causes of urolithiasis without appropriate control cases may result in a selection bias of articles, reflecting limited analysis result for current specific literature.
Author contributions: Thomas Chi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Taguchi, Yasui, Chi. Acquisition of data: Taguchi. Analysis and interpretation of data: Taguchi, Chi. Drafting of the manuscript: Taguchi, Hoppe, Milliner, Chi. Critical revision of the manuscript for important intellectual content: Yasui, Hoppe, Milliner, Chi. Statistical analysis: None. Obtaining funding: Taguchi, Yasui. Administrative, technical, or material support: None.
4.
Conclusions
Supervision: Chi. Other: None.
This systematic review demonstrates that genes related to stone matrix, calcium and phosphate regulation, inflammation, and oxidative stress are associated with modulating risk for idiopathic urolithiasis. These results are consistent with previous gene expression profiling of RPs and appear to be linked to some hereditary renal diseases. Translational research studies have tried to elucidate the mechanisms by which these genes are involved in a variety of approaches [51_TD$IF] [11]. With continued study, multimodal efforts by researchers may result in the development of feasible gene targeting therapy for urolithiasis in the future.
Financial disclosures: Thomas Chi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Kazumi Taguchi has received JSPS KAKENHI Grant #16K11054, the Naito Foundation Research Grant, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research Grant. Thomas Chi has received NIH grant funding (P20-DK100863 and R21-DK-109433). Funding/Support and role of the sponsor: None.
80
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
References
[24] Thorleifsson G, Holm H, Edvardsson V, et al. Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral
[1] Sorokin I, Mamoulakis C, Miyazawa K, Rodgers A, Talati J, Lotan Y.
density. Nat Genet 2009;41:926–30.
Epidemiology of stone disease across the world. World J Urol 2017.
[25] Chou Y-H, Juo S-HH, Chiu Y-C, et al. A Polymorphism of the ORAI1
http://dx.doi.org/10.1007/s00345-017-2008-6, PMID:28213860 [Epub
gene is associated with the risk and recurrence of calcium nephro-
ahead of print].
lithiasis. J Urol 2011;185:1742–6.
[2] Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of
[26] Lin Y, Mao Q, Zheng X, Chen H, Yang K, Xie L. Vitamin D receptor
kidney stones: AUA guideline. J Urol 2014;192:316–24. [3] Türk C, Petrík A, Sarica K, et al. EAU guidelines on diagnosis and
genetic polymorphisms and the risk of urolithiasis: a meta-analysis.
conservative management of urolithiasis. Eur Urol 2016;69:468–74.
[27] Basiri A, Shakhssalim N, Houshmand M, et al. Coding region analysis
[4] Monico CG, Milliner DS. Genetic determinants of urolithiasis. Nat
of vitamin D receptor gene and its association with active calcium
Rev Nephrol 2011;8:151–62. [5] Khan SR, Pearle MS, Robertson WG, et al. Kidney stones. Nat Rev Dis Prim 2016;2:16008. [6] Curhan GC, Willett WC, Rimm EB, Stampfer MJ. Family history and risk of kidney stones. J Am Soc Nephrol 1997;8:1568–73.
Urol Int 2011;86:249–55.
stone disease. Urol Res 2012;40:35–40. [28] Cakir OO, Yilmaz A, Demir E, Incekara K, Kose MO, Ersoy N. Association of the BsmI, ApaI, TaqI, Tru9I and FokI polymorphisms of the vitamin D receptor gene with nephrolithiasis in the Turkish population. Urol J 2016;13:2509–18.
[7] Goldfarb DS, Fischer ME, Keich Y, Goldberg J. A twin study of genetic
[29] Telci D, Dogan AU, Ozbek E, et al. KLOTHO gene polymorphism of
and dietary influences on nephrolithiasis: a report from the Viet-
G395A is associated with kidney stones. Am J Nephrol 2011;
nam Era Twin (VET) Registry. Kidney Int 2005;67:1053–61. [8] Yasui T, Okada A, Hamamoto S, et al. Pathophysiology-based treatment of urolithiasis. Int J Urol 2017;24:32–8. [9] Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1. [10] Krä Mer A, Green J, Pollard J, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 2014; 30:523–30. [11] Tzou DT, Taguchi K, Chi T, Stoller ML. Animal models of urinary stone disease. Int J Surg 2016;36:596–606.
33:337–43. [30] Xu C, Song R, Yang J, et al. Klotho gene polymorphism of rs3752472 is associated with the risk of urinary calculi in the population of Han nationality in eastern China. Gene 2013;526:494–7. [31] Karim Z, Gérard B, Bakouh N, et al. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 2008;359: 1128–35. [32] Rendina D, Esposito T, Mossetti G, et al. A functional allelic variant of the FGF23 gene is associated with renal phosphate leak in calcium nephrolithiasis. J Clin Endocrinol Metab 2012;97: E840–4.
[12] Kohri K, Yasui T, Okada A, et al. Biomolecular mechanism of urinary
[33] Shakhssalim N, Basiri A, Houshmand M, et al. Genetic polymor-
stone formation involving osteopontin. Urol Res 2012;40:623–37.
phisms in calcitonin receptor gene and risk for recurrent kidney
[13] Gao B, Yasui T, Itoh Y, et al. Association of osteopontin gene haplotypes with nephrolithiasis. Kidney Int 2007;72:592–8.
calcium stone disease. Urol Int 2014;92:356–62. [34] Okamoto N, Aruga S, Matsuzaki S, Takahashi S, Matsushita K,
[14] Liu C-C, Huang S-P, Tsai L-Y, et al. The impact of osteopontin
Kitamura T. Associations between renal sodium-citrate cotranspor-
promoter polymorphisms on the risk of calcium urolithiasis. Clin
ter (hNaDC-1) gene polymorphism and urinary citrate excretion in
Chim Acta 2010;411:739–43.
recurrent renal calcium stone formers and normal controls. Int J
[15] Xiao X, Dong Z, Ye X, et al. Association between OPN genetic variations and nephrolithiasis risk. Biomed Rep 2016;5:321–6. [16] Gögebakan B, Igci YZ, Arslan A, et al. Association between the T593A and C6982T polymorphisms of the osteopontin gene and risk of developing nephrolithiasis. Arch Med Res 2010;41:442–8. [17] Tekin G, Ertan P, Horasan G, Berdeli A. SPP1 gene polymorphisms associated with nephrolithiasis in Turkish pediatric patients. Urol J 2012;9:640–7.
Urol 2007;14:344–9. [35] Rungroj N, Sudtachat N, Nettuwakul C, et al. Association between human prothrombin variant (T165M) and kidney stone disease. PLoS One 2012;7:e45533. [36] Çoker Gurkan A, Arisan S, Arisan ED, Sönmez NC, Palavan Ünsal N. Association between IL-1RN VNTR, IL-1b -511 and IL-6 (-174, -572, -597) gene polymorphisms and urolithiasis. Urol Int 2013;91: 220–6.
[18] Guha M, Bankura B, Ghosh S, et al. Polymorphisms in CaSR and CLDN14
[37] Atar A, Gedikbasi A, Sonmezay E, et al. Serum paraoxonase-1 gene
genes associated with increased risk of kidney stone disease in
polymorphism and enzyme activity in patients with urolithiasis.
patients from the eastern part of India. PLoS One 2015;10:e0130790. [19] Vezzoli G, Terranegra A, Aloia A, et al. Decreased transcriptional activity of calcium-sensing receptor gene promoter 1 is associated with calcium nephrolithiasis. J Clin Endocrinol Metab 2013;98: 3839–47. [20] Vezzoli G, Terranegra A, Soldati L. Calcium-sensing receptor gene polymorphisms in patients with calcium nephrolithiasis. Curr Opin Nephrol Hypertens 2012;21:355–61. [21] Shakhssalim N, Kazemi B, Basiri A, et al. Association between calcium-sensing receptor gene polymorphisms and recurrent calcium kidney stone disease: a comprehensive gene analysis. Scand J Urol Nephrol 2010;44:406–12.
Ren Fail 2016;38:378–82. [38] Merriman TR. An update on the genetic architecture of hyperuricemia and gout. Arthritis Res Ther 2015;17:98. [39] Chen Y, Ren X, Li C, et al. CARD8 rs2043211 polymorphism is associated with gout in a Chinese male population. Cell Physiol Biochem 2015;35:1394–400. [40] Hamada Y, Nishijima T, Watanabe K, et al. High incidence of renal stones among HIV-infected patients on ritonavir-boosted atazanavir than in those receiving other protease inhibitor-containing antiretroviral therapy. Clin Infect Dis 2012;55:1262–9. [41] Nishijima T, Tsuchiya K, Tanaka N, et al. Single-nucleotide polymorphisms in the UDP-glucuronosyltransferase 1A-30 untranslated
[22] Vezzoli G, Scillitani A, Corbetta S, et al. Risk of nephrolithiasis in
region are associated with atazanavir-induced nephrolithiasis in
primary hyperparathyroidism is associated with two polymorphisms
patients with HIV-1 infection: a pharmacogenetic study. J Antimi-
of the calcium-sensing receptor gene. J Nephrol 2015;28:67–72.
crob Chemother 2014;69:3320–8.
[23] Oddsson A, Sulem P, Helgason H, et al. Common and rare variants
[42] Yasui T, Okada A, Urabe Y, et al. A replication study for three
associated with kidney stones and biochemical traits. Nat Commun
nephrolithiasis loci at 5q35.3, 7p14.3 and 13q14.1 in the Japanese
2015;6:7975.
population. J Hum Genet 2013;58:588–93.
E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 7 2 – 8 1
[43] Urabe Y, Tanikawa C, Takahashi A, et al. A genome-wide association
81
[45] Taguchi K, Hamamoto S, Okada A, et al. Genome-wide gene expres-
study of nephrolithiasis in the Japanese population identifies novel
sion profiling of Randall’s plaques in calcium oxalate stone formers.
susceptible loci at 5q35.3, 7p14.3, and 13q14.1. PLoS Genet 2012;8:
J Am Soc Nephrol 2017;28:333–47.
e1002541. [44] Xu Y, Zeng G, Mai Z, Ou L. Association study of DGKH gene polymorphisms with calcium oxalate stone in Chinese population. Urolithiasis 2014;42:379–85.
[46] Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and urolithiasis in children. Kidney Int 2011;80:1278–91.