E U RO P E AN URO LOGY F O CU S 3 ( 2 017 ) 7 2 – 8 1

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Review – Stone Disease

Genetic Risk Factors for Idiopathic Urolithiasis: A SystematicReview of the Literature and Causal Network Analysis

Kazumi Taguchi a [114_TD$DIFF],b, Takahiro Yasui a, Dawn Schmautz Milliner c, Bernd Hoppe d, Thomas Chi b,*

aDepartment of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; bDepartment of Urology, University of

California, San Francisco, CA, USA; cDivision of Nephrology, Departments of Pediatrics and Internal Medicine, Mayo Clinic, Rochester, MN, USA; dDivision of

Pediatric Nephrology, Department of Pediatrics, University Hospital Bonn, Bonn, Germany

Article info

Article history:

Accepted April 29, 2017

Associate Editor: James Catto

Keywords:

UrolithiasisNephrolithiasisGenome-wide association studySingle-nucleotide polymorphismIngenuity Pathway AnalysisCalciumPhosphateInflammationRandall’s plaque

Abstract

Context: Urolithiasis has a high prevalence and recurrence rate. Prevention is key topatient management, but risk stratification is challenging. In particular, genetic predis-position for urinary stones is not fully understood.Objective: To review current evidence of potential causative genes for idiopathic uro-lithiasis and map their relationships to one another. This evidence is essential for futureestablishment of molecular targeted therapy.Evidence acquisition: A systematic literature review from 2007 to 2017 was performedin accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. The search was restricted to human studies conducted as eithercase–control or genome-wide association studies, and published in English. We alsoperformed a causal network analysis of candidate genes gained from the systematicreview using Ingenuity Pathway Analysis (IPA).Evidence synthesis: During the systematic screening of literature, 30 papers wereselected for the review. A total of 20 genes with 42 polymorphisms/variants were foundto be associated with urolithiasis risk. Their functional roles were mainly categorized asstonematrix, calcium and phosphate regulation, urinary concentration and constitution,and inflammation/oxidative stress. IPA network analysis revealed that these genesconnected via signaling pathways and a proinflammatory/oxidative environment.Conclusions: This systematic review provides an updated gene list and novel causalnetworks for idiopathic urolithiasis risk. Although some genes such as SPP1, CASR, VDR,CLDN14, and SLC34A1were identified by several studies and recognized by prior reviews,further investigation elucidating their roles in stone formation will be essential forfuture studies.Patient summary: In this review, we summarized recent literature regarding genesresponsible for kidney stone risk. Based on a detailed review of 30 articles andcomputational network analysis, we concluded that disorder of mineral regulationwithlocal inflammation in the kidney may cause kidney stone disease.

© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.

* Corresponding author. Department of Urology, University of California, 400 Parnassus Ave., SixthFloor, Suite A610, San Francisco, CA 94143, USA. Tel. +1-415-353-2200; Fax: +1-415-353-2641.

@ucsf.edu (T. Chi).

E-mail address: tom.chi

http://dx.doi.org/10.1016/j.euf.2017.04.0102405-4569/© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.

[(Fig._1)TD$FIG]

758

621

552

257

237

Nonhuman studies

Manuscripts not written in English

Not published within the last 10 yr

Abstract and full text not available

Case reports, meta-analyses, reviews, cohort studies

148

Patients with no evidence of urolithiasis or nephrolithiasis

30

Exclusions Number of papers

Fig. 1 – Flow chart of the methods used to formulate this systematicliterature review in accordance with PRISMA guidelines.PRISMA = Preferred Reporting Items for Systematic Review and Meta-analyses.

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1. Introduction

Urolithiasis has a high prevalence worldwide rangingbetween 7% and 13% in North America, 5% and 9% in Europe,and 1% and 5% in Asia [1]. Owing to the high recurrence rateof urolithiasis, both the American Urological Association [42_TD$DIFF][2]and European Association of Urology [43_TD$DIFF][3] recommend man-aging and preventing future recurrences by dietary andmedical assessments. Single gene mutation states such ascystinuria are known to cause nephrolithiasis in a smallproportion of stone patients [44_TD$DIFF][4]. However, in the largemajority of patients who have idiopathic stone forma-tion, less is known about contributing genetic factors.While numerous research efforts have been performedto elucidate the pathophysiology of lithogenesis [45_TD$DIFF][5], theexact mechanism of stone formation is still not fullyunderstood.

Identifying genetic predisposition may lead to new pre-vention strategies for urolithiasis. For example, studies havedemonstrated that a family history of urolithiasis increasesrelative risk by 2.57-fold in men [46_TD$DIFF][6]. In addition, the con-cordance rate of the disease in monozygotic twins is highercompared with that in dizygotic twins (32.4% vs 17.3%) [47_TD$DIFF]

[7]. These lines of evidence suggest that genetic factors forurolithiasis play a pivotal role in its etiology. By extension,elucidation of responsible genes could lead to future tar-geted gene therapy and better prevention.

Genome-wide association studies havewidely been usedfor identifying genetic risk factors for various diseases. Thisapproach facilitates examining entire DNA sequences todetect mutations, variants, and single-nucleotide polymor-phisms (SNPs). SNPs play a crucial role in determining genesassociated with urolithiasis that may serve as future diag-nostic markers [48_TD$DIFF][8]. Understanding how these SNPs linktogether could potentially help unveil the genomic driversof lithogenesis.

In this review, we focus on SNPs and genome-wideassociation studies (GWASs) conducted for urolithiasis.We present a systematic review of genetic risk factors forstone formation and a network analysis of candidate genes.Our aim is to provide an update on genes associated withnephrolithiasis and how they may interact with oneanother.

2. Evidence acquisition

We performed a systematic literature review in accordancewith the Preferred Reporting Items for Systematic Reviewand Meta-analyses guidelines [49_TD$DIFF][9]. In PubMed and Medlinedatabases, the following search keywords were used:((“genome”[MeSH]) OR (“mutation”[MeSH]) OR (“genet-ic”[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 restrictedto human studies with both an abstract and the full textavailable; published in English during the last 10 yr. Studieswere considered only if patient cases were confirmed as

having either renal or ureteral stones diagnosed previously.A total of 237 papers were reviewed; 54 case reports and33 reviewswere excluded. Cohort studies; negative studies;and studies irrelevant to urolithiasis and nephrolithiasiswere screened. After exclusions; 30 papers were selectedfor this review (Fig. 1).

Existing networks among candidate genes for urolithia-sis development were also analyzed. Ingenuity PathwayAnalysis (IPA; QIAGEN, Hilden, Germany) uses computer-ized analysis with a mega knowledge base of reviewedscientific literature [50_TD$DIFF][10]. The use of IPA methodologyallowed a causal network analysis for the candidate genes.

3. Evidence synthesis

From the selected 30 papers, 20 genes were identified with42 SNPs/variants reported in case–control and/or GWASs.Most investigations consisted of Asian and Europeanpatients. Table 1 summarizes the genes associated withurolithiasis risk factors. The majority of genes were

Table 1 – Genes related to urolithiasis summarized by a systematic review of manuscripts published between 2007 and 2017.

Function Gene ([68_TD$DIFF]Coded protein) Locus SNP, variant Region Cases/controls[69_TD$DIFF](n) origin Year [ref.]

Calcium stoneStone matrix SPP1 (osteopontin) 4p22.1 144 and 145 [70_TD$DIFF]promoter 126/214 Japan 2007 [71_TD$DIFF][13]

T-593A promoter 121/100 Turkey 2010 [72_TD$DIFF][16]rs1126616 exon 7 121/100 Turkey 2010 [73_TD$DIFF][16]rs17524488 promoter 249/247 Taiwan 2010 [74_TD$DIFF][14]c.240T>C exon 6 65/50 Turkey 2012 [75_TD$DIFF][17]c.708C>T exon 7 65/50 Turkey 2012 [76_TD$DIFF][17]rs11439060 prompter 230/250 China 2016 [15_TD$DIFF][15]

Calcium regulation CASR (calcium-sensing receptor) 3q13.33-q21.1 rs1042636 [77_TD$DIFF]exon 7 99/107,115/141, 200/200

Iran,[78_TD$DIFF]Italy, India

2010 [79_TD$DIFF][21],2014 [22],2015 [18]

rs1801725 exon 7 99/107, 200/200 Iran, India 2010 [80_TD$DIFF][22],2015 [18]

E1011Q exon 7 99/107 Iran 2010 [81_TD$DIFF][21]rs6776158 promoter 1 165/208 Italy 2013 [82_TD$DIFF][19]rs1501899 promoter 1 155/141 Italy 2014 [83_TD$DIFF][22]

CLDN14 (claudin 14) 21q22.13 rs219780 [84_TD$DIFF]intron 1 200/200 India 2015 [85_TD$DIFF][18]rs219778 intron 1 200/200 India 2015 [86_TD$DIFF][18]

ORAI1 (calcium release-activated calcium modulator)

12q24.31 rs12313273 [84_TD$DIFF]intron 1 136/500 China 2011 [22_TD$DIFF][25]

Phosphate (and calcium)regulation

VDR[87_TD$DIFF](vitamin D receptor)

12q12-14 rs2228570 [88_TD$DIFF]start codon 106/109 Iran 2012 [89_TD$DIFF][27]

rs1544410 intron 8 98/70 Turkey 2016 [90_TD$DIFF][28]KL (klotho) 13q13.1 G395A [70_TD$DIFF]promoter 108/51 Turkey 2011 [91_TD$DIFF][29]

rs3752472 exon 3 426/282 China 2013 [92_TD$DIFF][30]NHERF1 (sodium-hydrogenantiporter 3 regulator 1)

17q25.1 L110V [93_TD$DIFF]exon 1 92/63 France 2008 [94_TD$DIFF][31]

R153Q exon 2 92/63 France 2008 [95_TD$DIFF][31]E225K exon 3 92/63 France 2008 [96_TD$DIFF][31]

FGF23 (fibroblast growthfactor 23)

12p13.32 rs7955866 [93_TD$DIFF]exon 3 106/87 Italy 2012 [97_TD$DIFF][32]

CALCR (calcitonin receptor) 7q21.3 [98_TD$DIFF]3’UTR+18C>T 3’UTR 105/101 Iran 2013 [99_TD$DIFF][33]rs72570683 intron 1 105/101 Iran 2013 [100_TD$DIFF][33]rs3214144 intron 1 105/101 Iran 2013 [29_TD$DIFF][33]

Urinary inhibitor ofstone formation

SLC13A2 (Na+/dicarboxylatecotransporter-1)

17q11.2 1550V exon 12 105/107 Japan 2007 [101_TD$DIFF][34]

F2 (prothrombin) 11p11.2 rs5896 [93_TD$DIFF]exon 6 216/216 Thailand 2012 [31_TD$DIFF][35]Anti-inflammatory

and [102_TD$DIFF]-oxidative stressIL-RN VNTR (interleukin1 receptor antagonist)

2q14.1 2/2 genotype [84_TD$DIFF]intron 2 65/85 Turkey 2013 [103_TD$DIFF][36]

PON 1 (paraoxonase-1) 7q21.3 rs854560 158/138 Turkey 2016 [33_TD$DIFF][37]Uric acid stone

CARD8 (caspase recruitmentdomain family member 8)

19q13.33 rs2043211 [93_TD$DIFF]exon 5 396/403 China 2015 [104_TD$DIFF][39]

Atazanavircontaining stone

UGT1A1 (UDPglucuronosyltransferase family1 member A1)

2q37.1 rs10929303 [93_TD$DIFF]exon 5 31/47 Japan 2014 [35_TD$DIFF][41]

rs1042640 [93_TD$DIFF]exon 5 31/47 Japan 2014 [105_TD$DIFF][41]rs8330 exon 5 31/47 Japan 2014 [106_TD$DIFF][41]

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associated with calcium-containing stones, whereas onlytwo papers examined rare stone patients: uric acid– andatazanavir-containing stones. For calcium-containingstones, the following geneswere reported to have a possiblecausative role in urolithiasis: osteopontin (OPN) codinggene (SPP1) related to the stone matrix, calcium-sensingreceptor (CASR)/claudin 14 (CLDN14)/calcium release-acti-vated calcium modulator 1 (ORAI1) related to calciumregulation, vitamin D receptor (VDR)/klotho (KL)/sodiumhydrogen antiporter 3 regulator 1 (NHERF1)/fibroblastgrowth factor 23 (FGF23)/calcitonin receptor (CALCR)related to phosphate as well as calcium regulation, solutecarrier family 13 member 2 (SLC13A2)/prothrombin (F2)

related to urinary inhibition of stone formation, and inter-leukin 1 receptor antagonist (IL-RN VNTR)/paranoxonase-1(PON1) related to anti-inflammatory and antioxidativestress.

Additionally, four GWASs including a validation case–control study were conducted during the study reviewperiod (Table 2). The SNPs of phosphate carrier NPT2a(SLC34A1) and CLDN14 were identified from two differentGWASs. SLC34A1, CLDN14, AQP1, diacyl glycerol kinase (-DGKH), CASR, and transient receptor potential cation chan-nel subfamily V member 5 (TRPV5) were also associatedwith other SNPs related to urolithiasis prevalence in case–control studies.

Table 2 – Genes related to urolithiasis identified by a systematic review of GWAS [107_TD$DIFF]studies published between 2007 and 2017.

Gene ([68_TD$DIFF]Coded protein) Locus SNP Cases ( [108_TD$DIFF]n)/controls (n) Markers (n) Origin Year [ref.]

SLC34A1 (phosphate carrier NPT2a) 5q35.3 rs11746443a [93_TD$DIFF] [109_TD$DIFF]5,892/17,809 712,726 Japan 2012 [43]rs12654812a 5,892/17,809 712,726 Japan 2012 [43]

5,419/279,870 28,300,000 Iceland 2015 [37_TD$DIFF][23]CLDN14 (claudin 14) 21q22.13 rs219780b [110_TD$DIFF] [111_TD$DIFF]3,773/42,510 303,120 Iceland,

The Netherlands2009 [112_TD$DIFF][24]

rs199565725 5,419/279,870 28,300,000 Iceland 2015 [37_TD$DIFF][23]AQP1 (aquaporin 1) 7q14.3 rs1000597 [113_TD$DIFF]5,892/17,809 712,726 Japan 2012 [43]

rs12669187 5,892/17,809 712,726 Japan 2012 [43]DGKH (diacyl glycerol kinase) 13q14.1 rs4142110c 5,892/17,809 712,726 Japan 2012 [43]ALPL (alkaline phosphatase) 1p36.12 rs1256328 [115_TD$DIFF]5,419/279,870 28,300,000 Iceland 2015 [37_TD$DIFF][23]CASR (calcium-sensing receptor) 3q21.1 rs7627468 [115_TD$DIFF]5,419/279,870 28,300,000 Iceland 2015 [37_TD$DIFF][23]TRPV5 (transient receptor potential

cation channel subfamily V member 5)7q34 p.L530A [115_TD$DIFF]5,419/279,870 28,300,000 Iceland 2015 [118_TD$DIFF][23]

a Validated by a case–control study (601 cases vs 201 controls, Japan) [39_TD$DIFF][42].b Validated by a case–control study (200 cases vs 200 controls, India) [21_TD$DIFF][18].c Validated by a case–control study (507 cases vs 505 controls, China) [40_TD$DIFF][44].

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3.1. Stone macromolecule, matrix

OPN is a highly phosphorylated glycoprotein originallyidentified in bone that functions as an adhesion motif ofprotein to integrins and CD44. It was also identified as oneof the organic (matrix) components of calcium-based uri-nary stones. Some reported that OPN knockout mice pro-duce calcium oxalate crystals [51_TD$DIFF][11], whereas others indicatethat OPN facilitates crystal development by mineralizationand inflammation processes mediated by other cytokinesand immune cells including macrophages [52_TD$DIFF][12].

Three studies from eastern Asia demonstrated SNPs ofSPP1 related to urolithiasis patients. Gao et al [11_TD$DIFF][13] reportedthat the SPP1 haplotype SNP carrier with G-T-T-G in the�145 and �144 positions had a higher risk of developingnephrolithiasis comparedwith other haplotypes (odds ratio[OR] = 1.676), whereas the haplotype T-G-T-G carrier in thesame position has a lower risk (OR = 0.351). Liu et al [13_TD$DIFF][14]showed that the delG/delG genotype of SNP rs17524488 wasalso associatedwith a significantly higher risk of developingcalcium urolithiasis (OR = 1.95) and a higher urinary cal-cium to OPN ratio than those with G/G genotype. Xiao et al [15_TD$DIFF][15] demonstrated that carriers with the SPP1 rs11439060insertion types were over-represented in urolithiasispatients compared with controls (OR = 1.55). In addition,two Turkish studies reported that the SPP1 haplotypesbetween SNPs T-593A and rs1126616 demonstrated a sig-nificant lower or higher OR for developing kidney stones;CA haplotype had a lower (OR = 0.283), whereas TT haplo-type had a higher (OR = 1.963) risk for kidney stones [12_TD$DIFF]

[16]. Among the pediatric population, C allele frequencyof c.240T>C polymorphism (OR = 2.13) and T allele fre-quency of c.708C>T polymorphism (OR = 2.183) were higherin nephrolithiasis patients than in controls [14_TD$DIFF][17].

3.2. Genes related to calcium regulation

3.2.1. Calcium-sensing receptor

CASR is located on chromosome 3q13.33-q21.1 and consistsof 11 exons. It is a G protein–coupled receptor that

modulates cell activity according to the extracellular cal-cium concentration. This protein is expressed in the para-thyroid gland and the thick ascending limb of the Henleloop. Its activation induces increased calcium excretion inthe kidney via regulation of parathyroid hormone (PTH)production and renal tubular calcium reabsorption [53_TD$DIFF]

[18,19]. Earlier studies summarized that activating theArg990Gly polymorphism (rs1042636) may predispose tonephrolithiasis by increasing calcium excretion [54_TD$DIFF][20].

Four case–control studies and one GWAS have investi-gated CASR SNPs. The G allele of rs1042636 was associatedwith a significant risk of stone disease (OR = 8.06) [18_TD$DIFF][21], andthe variant genotype GG was associated with 20-foldincreased risk for kidney stone disease (OR = 20.76) [21_TD$DIFF]

[18]. Stone risk of patients with primary hyperparathyroid-ism was also higher in patients carrying a G allele atrs1042636 [20_TD$DIFF][22]. An S allele of rs1801725 was reported toconfer an OR = 2.55 [18_TD$DIFF][21] and a T allele was reported withOR = 2.54 [21_TD$DIFF][18] for risk of stone disease. Moreover, one studyreported that a GG genotype for rs6776158 demonstrated anincreased risk of nephrolithiasis (OR = 5.8) by multinomiallogistic regression analysis [19_TD$DIFF][19]. In addition to the risk forkidney stone development, a QQ genotype with respect tothe 1011 locus was related to significantly lower serum totalcalcium in patients [18_TD$DIFF][21].

Furthermore, Oddsson et al [37_TD$DIFF][23] found SNP rs7627468 ofCASR associated with kidney stones (OR = 1.21) from aGWAScomparing5419kidneystone caseswith 279870con-trols during examination of 28.3 million sequence variants.

3.2.2. Claudin 14

CLDN14 is a member of the claudin family of membraneproteins that regulate paracellular passage of ions and smallsolutes at epithelial tight junctions. CLDN14 is expressed inthe kidney, both in the loop of Henle and in proximaltubules, as well as in the epithelia of several other organs,and has been observed to selectively decrease permeabilityof Ca2+ [41_TD$DIFF] through tight junctions [38_TD$DIFF][24]. Earlier studies indi-cated that CLDN14 expression is strongly upregulated byactivation of CASR, and dysregulation of the renal CASR-

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CLDN14 pathway could contribute to the development ofkidney stones [21_TD$DIFF][18].

Thorleifsson et al [38_TD$DIFF][24] found the SNP rs219780 in exon7 associated with kidney stone incidence (OR = 1.25) byconducting a GWAS in 3773 cases and 42 150 controls fromIceland and the Netherlands. The homozygous carriers ofrs219780 were estimated to have 1.64 times greater risk ofdeveloping kidney stone compared with noncarriers. ThisSNP was validated by a GWAS from a different population:patients with two base pair deletion correlating withrs219780 had a strong association with kidney stones(r2 = 0.82, OR = 0.81) [23]. Additionally, a case–controlstudy demonstrated that SNPs rs219778 and rs219780were significantly associated with kidney stone disease(OR = 3.46 and OR = 2.63, respectively) [21_TD$DIFF][18].

3.2.3. Calcium release-activated calcium modulator 1

ORAI1 is located on chromosome 12q24.31 and consists oftwo exons. ORAI1 is a membrane calcium channel subunitthat is activated when calcium stores are depleted. Muta-tion of this gene resulted in a deficiency of store-operatedcalcium-dependent signaling pathways, leading to immunesystem dysfunction [55_TD$DIFF][25].

Chou et al [25] reported that two SNPs, rs12313273and rs6486795, of the ORAI1 gene were associated withnephrolithiasis risk (p = 0.006 and 0.035, respectively). TheCCandCTgenotypesof rs12313273carriedan increased riskofnephrolithiasis comparedwith the TTgenotype (OR = 2.10and1.82, respectively). Moreover, the CC and CT genotypes con-ferred an increased risk for stone recurrence compared withthe 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 islocated on 12q13.11 consisting of 11 exons. This geneencodes the nuclear hormone receptor for vitamin D3. Itplays a central role in mineral metabolism, including intes-tinal calcium absorption and renal calcium absorption. Aprior meta-analysis of VDR polymorphisms indicated thatthe f allele and ff + Ff genotype in Fokl as well as the t alleleand tt + Tt genotype in Taqlwere related to an increased riskof urolithiasis [56_TD$DIFF][26].

Two case–control studies of VDR SNPs were reportedfrom Iran and Turkey. Basiri et al [23_TD$DIFF][27] indicated that the Callele of rs2228570wasmore prevalent in male active stoneformers (OR = 11.1 for TC genotype, OR = 10.7 for CC geno-type). On the contrary, the B allele of rs1544410 was foundto increase the risk of nephrolithiasis by approximately 1.5-fold (OR = 1.55) [24_TD$DIFF][28].

3.3.2. Klotho

Klotho is a type-I transmembrane protein related to beta-glucosidase, a novel regulatorof renal calciumandphosphatehomeostasis. Its coding gene, KL, is located on chromosome13q13.1, consisting of sixexons. Klotho is expressed in tissuesresponsible for calcium homeostasis including the kidney,parathyroidgland,andepitheliumof thechoroidplexus inthe

brain. Klotho also plays an important role in increased cal-cium uptake in the kidneys via TRPV5 and regulation ofphosphate homeostasis via FGF23 [57_TD$DIFF][29,30].

A Turkish study indicated that patients with a GG geno-type of the G395A KL polymorphism had a two-foldincreased kidney stone risk compared with AA and GAgenotypes (OR = 1.849). They also found that a GG genotypehad a significantly higher risk of stone-related metabolicabnormalities such as hypercalcemia (OR = 33.05) andhypophosphatemia (OR = 0.07) [25_TD$DIFF][29]. The CT + TT genotypeof rs3752472 was found to be associated with nephrolithia-sis risk when compared with a CC genotype (OR = 1.512) inthe Chinese population [26_TD$DIFF][30].

3.3.3. Sodium hydrogen antiporter 3 regulator 1

NHERF1, also known as SLC9A3R1, is located on chromosome17q25.1 and consists of six exons. NHERF1 binds renaltubular transporters including the Na+ [37_TD$DIFF] phosphate cotran-sporter 2a (NPT2a) and the PTH type 1 receptor. NHERF1knockout mice demonstrate increased urinary calcium,phosphate, and uric acid excretion, with resultant renalcalcium phosphate crystal deposits [58_TD$DIFF][11].

Karim et al [31] identified three mutations of NHERF1—L110 V, R153Q, and E225K—from 158 patients, 95 cases ofwhichwere located in France. In addition,NHERF1 appearedto cause renal phosphate loss by increasing cyclic AMPgeneration 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 phos-phate homeostasis by decreasing renal reabsorption andintestinal absorption of phosphate. FGF23 reduces phos-phate by downregulating NPT2 cotransporters, resulting inurinary phosphate wasting. It also acts to decrease serumphosphorus levels by reducing the bioavailability of vitaminD3 [59_TD$DIFF][29,32].

The SNP rs7955856 in FGF23 was reported in stoneformers with a renal phosphate leak. The T allele and CTgenotype rates within rs7955856 in those patients weresignificantly higher compared with those in controls (p< 0.03). Moreover, the Tallele of rs7955856 carriers showedsignificantly lower levels of serum phosphate and TmPi/GFRcompared with noncarriers (p < 0.03) [28_TD$DIFF][32].

3.3.5. Calcitonin receptor

Calcitonin, a 32-amino-acid protein, binds its receptor,CALCR, on bone osteoclasts as well as within renal tubularcells. Calcitonin acts as a renal calcium-conserving hormoneby increasing Ca2+ and Mg2+ reabsorption and decreasingphosphate reabsorption in kidneys. While CALCR polymor-phisms were reported to be associated with bone mineraldensity changes in different populations, few studieshave established the association of its SNPswith urolithiasis[29_TD$DIFF][33].

Shakhssalim et al [29_TD$DIFF][33] detected nine polymorphismsfrom a cohort of 105 male recurrent calcium stone patientsand 101 controls. Among these SNPs, the T allele of the30UTR + 18C > T polymorphism, as well as the C and A7

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alleles of rs72570683 and rs3214144 conferred a significantrisk 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 of14 exons, and encodes Na+/dicarboxylate cotransporter-1(NaDC-1). NaDC-1 plays an important role in citrate reab-sorption in the apical membrane of the proximal tubule;thus, this protein is a major determinant of urinary citrateexcretion. Genetic predisposition rather than metabolicabnormality may thus be a major cause for idiopathichypocitraturia generating interest in NaDC-1 [30_TD$DIFF][34].

From a Japanese cohort of 105 recurrent renal calciumstone formers and 107 controls, 1550 polymorphisms weredetected. Although no significant differences in allele fre-quencies were observed (p = 0.47), individuals with the BBgenotypeof1550 Vshowedsignificantly lowerurinarycitrateexcretion than those with bb genotype (p = 0.005) [30_TD$DIFF][34].

3.4.2. Prothrombin

F2 controls synthesis of prothrombin, also known as coag-ulation factor II, a serine-protease coagulation protein in theblood stream that converts soluble fibrinogen into insolublestrands of fibrin and catalyzes many other coagulation-related reactions. F2 is located on chromosome 11p11.2,consists of 14 exons, and encodes urinary prothrombinfragment 1 (UPTF1). UPTF1was initially detected as a crystalmatrix protein within calcium oxalate crystals, and it isconsidered to be a potent inhibitor of calcium oxalategrowth and aggregation in urine [31_TD$DIFF][35].

The SNP rs5896 was found in exon 6 using whole exonsequencing of F2. Furthermore, the frequency of the C alleleof rs5896 in kidney stone patients was significantly lowerthan that of the controls (OR = 0.68). Particularly in femalepatients, genotype (OR = 0.49) and allele frequencies(OR = 0.59) were significantly different between stonepatients and controls [31_TD$DIFF][35], suggesting a potential protectiverole 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 proinflammatorycytokines facilitating tissue inflammation. Its receptor, IL-1 receptor antagonist, is coded by IL-RN and exhibits ananti-inflammatory function by binding to the same receptorwith IL-1a and IL-1b. IL-RN is located on chromosome2q14.1 and consists of 11 exons. A penta-allelic polymorphicsite in intron 2 of this gene consisting of variable numbertandem repeats has been investigated extensively in rela-tion to a variety of pathological conditions [32_TD$DIFF][36].

A Turkish study examined its polymorphisms associatedwith urolithiasis. A significant genotype distribution of IL-RN polymorphisms between urolithiasis and control groupswas seen (p = 0.047), and urolithiasis patients had a higherfrequency of allele 2 in IL-RN (p = 0.007) [32_TD$DIFF][36].

3.5.2. Paraoxonase-1

PON1 is a serum high-density lipoprotein–bound enzymewith an antioxidant function. Its activity is reduced inenvironments of high oxidative stress and associated withincreased lipid peroxidation, which might be a factor fordetermining predisposition to stone formation. PON1 clus-ters with three related paraoxonase genes at chromosome7q21.3 [60_TD$DIFF][37].

Atar et al [37] reported that the PON1 L55M polymor-phism was significantly more prevalent in urolithiasispatients (p = 0.002). Those with an MM genotype showeda greater risk for urolithiasis compared with those with anLM genotype (OR = 9.88).

3.6. Genes for uric acid stones

While a number of researches have sought SNPs associatedwith hyperuricemia and/or gout by GWASs [61_TD$DIFF][38], few studieshave reported the association between SNPs and uric acidstone formers for the past 10 yr. One study reported thepossible association of an SNP in caspase activation andrecruitment domain 8 (CARD8) gene in stone formers withgout [34_TD$DIFF][39]. CARD8 is a component of innate immunityinvolved in the suppression of nuclear factor kB activation.CARD8 suppresses the immune response and inflammatoryactivities. It is located on chromosome 19q13.33 and con-sists of 22 exons. Gout patients carrying a TTgenotype of theCARD8 rs2043211 polymorphism had an increased risk ofkidney stone compared with those carrying the AA geno-type (p = 0.03).

3.7. Genes for atazanavir-containing stones

Atazanavir-induced nephrolithiasis is a rare conditionamong all uroliths, and the exact mechanism for theirformation is not fully understood. Based on a large cohortstudy [62_TD$DIFF][40], atazanavir use was significantly associated withrenal stones (hazard ratio = 10.44), and themedian time fromcommencementofatazanavir tostonediagnosiswas24.5mo.Atazanavir is reported to be excreted whole in the urine,leading to the hypothesis that metabolism of atazanavir inthe human body may be related to developing stones.

UDP glucuronosyltransferase family 1 member A1(UGT1A1) is expressed primarily in the liver and gastroin-testinal tract, and plays a role in bilirubin elimination. Giventhat UGT1A1 is known for its association with atazanavir-induced unconjugated hyperbilirubinemia, it is alsothought to be involved in atazanavir metabolism. Nishijimaet al [35_TD$DIFF][41] reported that the TC genotype of rs10929303, GCgenotype of rs1042640, and G allele of rs8330 of UGT1A-30-UTR were independent risk factors for atazanavir-inducednephrolithiasis 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, amember of the type IIa sodium phosphate cotransporter

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family. NPT2a is responsible for phosphate absorption at theapical membrane of renal proximal tubular cells [39_TD$DIFF][42]. Npt2aknockout mice demonstrate hypercalciuria and renal cal-cium phosphate crystal deposits [51_TD$DIFF][11]. Mutations of SLC34A1appear to be associated with hypophosphatemic nephro-lithiasis and osteoporosis in humans [39_TD$DIFF][42].

Two GWASs detected SLC34A1 polymorphisms associ-ated with kidney stone, and one case–control study vali-dated these results. Rs1176443 was identified as a novellocus for nephrolithiasis (OR = 1.19) from 5892 Japanesenephrolithiasis patients. Subsequent analyses in 21842 Jap-anese individuals revealed that the risk allele of rs11746443was associated with a reduction in the estimated glomeru-lar filtration rate [36_TD$DIFF][43]. SNP rs12654812 was found to beassociated with kidney stones from 5892 Japanese and5419 Icelander kidney stone patients (OR = 1.16 and 1.18,respectively) [36_TD$DIFF][43]. This SNP was also associated withdecreased serum PTH and phosphate levels [37_TD$DIFF][23]. A separatepopulation study validated its association with nephro-lithiasis (OR = 1.43) and decreased serum phosphorus level(p = 0.0353) [39_TD$DIFF][42].

3.8.2. Aquaporin-1

Aquaporin-1 is abundantly expressed in the kidney, mainlyin the proximal tubule, functioning as awater channel. Aqp1knockout mice show reduced osmotic permeability anddeveloped hydration after water deprivation. AQP1 islocated on chromosome 7p14.3 and consists of seven exons.Rs100597 and rs12669187 were detected as the SNPs sig-nificantly associated with nephrolithiasis (each OR = 1.22).These SNPs are thought to affect the urine concentrationprocess and thereby increase the risk of nephrolithiasis [36_TD$DIFF][43].

3.8.3. Diacyl glycerol kinase

DGKH is expressed in the brain and is known to be related topsychiatric disorders such as bipolar and major depressivedisease. DGKH belongs to the DGK family, which is involvedin transplasmalemmal calcium ion influx [40_TD$DIFF][44]. Its codinggene, DGKH, is located on chromosome 13q.14.11 and con-sists of 38 exons. A Japanese GWAS detected the SNPrs4142110 associated with nephrolithiasis (OR = 1.14) [36_TD$DIFF][43].A case–control study further indicated that rs4142110 wasassociated with a risk of calcium oxalate stones and hyper-calciuria (p < 0.05). The CT, TT, and CT + TT genotypes ofrs4142110 were significantly correlated with decreased cal-cium oxalate stone risk (OR = 0.666, 0.562, and 0.466,respectively). In addition, the CT, TT, and CT + TT genotypesshowed a significant decrease in hypercalciuria (OR = 0.666,0.562, and 0.466, respectively) [40_TD$DIFF][44].

3.8.4. Alkaline phosphatase

Alkaline phosphatase (ALPL) is a member of the alkalinephosphatase family as a tissue nonspecific form and amembrane-bound glycosylated enzyme. ALPL is expressedin the proximal tubules of the kidney and hydrolyzes pyro-phosphate to free phosphate, suggesting its facilitative rolein kidney stone formation. ALPL is located on chromosome1p36.12 and consists of 14 exons. The SNP rs1256328 of ALPLwas found to be associated with both incident (OR = 1.21)

and recurrent (OR = 1.23) kidney stones. Rs1256328 alsohad a significant association with increased serum alkalinephosphatase levels (p < 0.001) [37_TD$DIFF][23].

3.8.5. Transient receptor potential cation channel subfamily V

member 5

TRPV5 is a highly selective epithelial calcium channelexpressed at the apical membrane of the distal renal tubuleepithelial cells, which mediates calcium transport in thekidney and constitutes the rate-limiting step of active cal-cium reabsorption. TRPV5 is located on chromosome 7q34and consists of 15 exons, and Trpv5 knockoutmice exhibitedsevere hypercalciuria. The TRPV5 p.Leu530Arg variant wasdetected to be significantly associated with recurrent kid-ney stones (OR = 3.62) [37_TD$DIFF][23].

3.9. Causal gene networks for lithogenesis

Fig. 2 illustrates the result of gene network analysis amongthe candidate genes listed in Tables 1 and 2. Each gene hasbeen categorized by its location in the kidney and function.Genes related to stone matrix, calcium and phosphateregulation, and inflammation are connected via c-Jun N-terminal kinase signaling pathways, beta-estradiol, leptin,caspase, and proinflammatory cytokines. In particular,FGF23, VDR, SPP1, and IL1RN play primarily roles, interfacingwith other genes for lithogenesis. Interestingly, these net-works are relatively similar to the gene networks surround-ing Randall’s plaques (RPs), which are considered potentialorigin nidi for calcium stone. A recent microarray studyreported that cellular transporters and ion channels alsoformed networks with proinflammatory cytokines and sig-naling pathways, indicating that RPs develop by urothelial/interstitial/tubular cellular apoptosis followed by OPNaggregation, mediated by tissue inflammation and oxida-tive stress [63_TD$DIFF][45].

In addition, several genes shown in this systematicreview and gene network analysis in RP [63_TD$DIFF][45] are knownto be responsible for hereditary developed kidney stonedisease, which are typically expressed in pediatric patients.CASR is associated with autosomal dominant hypocalcemichypercalciuria and Bartter syndrome. CASR and VDR arerelated to hypercalcemia in the context of hypercalciuria-familial isolated hyperparathyroidism and idiopathichypercalciuria. SLC34A1 is associated with persistent hypo-phosphatemia in urolithiasis and osteoporosis. Moreover,genes significantly expressed around RPs, includingSLC12A1 and potassium voltage-gated channel subfamilyJ (KCNJ) [63_TD$DIFF][45], are associated with Bartter syndrome, agenetic disorder with an extremely high incidence of uri-nary stones [64_TD$DIFF][46].

While multiple studies have demonstrated these genesto be closely associated with a risk for urolithiasis, thecomplexities of their interactions have yet to be completelydetermined. As a result, the exact pathogenesis of idiopathickidney stones is still unknown with regard to genetic fac-tors. Further investigation, combining GWASs and omicsanalyses, will be essential for improving the understandingof the genetic causes of idiopathic urolithiasis.

[(Fig._2)TD$FIG]

Fig. 2 – Causal networks of genes associated with urolithiasis revealed from the current systematic review. Different shapes and their relationship areas follows: red molecules = stone matrix genes; yellow molecules = calcium regulation genes; green molecules = phosphate (and calcium) regulationgenes; 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 = diacylglycerol 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.

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Limitations should be recognized for this study. Since welimited our inclusion to literature for last 10 yr, earliersimilar studies in other populations may implicate some-what different genes, and may convey a different impres-sion of geographic distribution of the risk factors and inci-dence of idiopathic urolithiasis. Additionally, excludingstudies related to monogenic causes of urolithiasis withoutappropriate control cases may result in a selection bias ofarticles, reflecting limited analysis result for current specificliterature.

4. Conclusions

This systematic review demonstrates that genes related tostonematrix, calcium and phosphate regulation, inflamma-tion, and oxidative stress are associated with modulatingrisk for idiopathic urolithiasis. These results are consistentwith previous gene expression profiling of RPs and appearto be linked to some hereditary renal diseases. Translationalresearch studies have tried to elucidate the mechanisms bywhich these genes are involved in a variety of approaches [51_TD$DIFF]

[11]. With continued study, multimodal efforts by research-ers may result in the development of feasible gene targetingtherapy for urolithiasis in the future.

Author contributions: Thomas Chi had full access to all the data in thestudy and takes responsibility for the integrity of the data and theaccuracy 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.Supervision: Chi.Other: None.

Financial disclosures: Thomas Chi certifies that all conflicts of interest,including specific financial interests and relationships and affiliationsrelevant 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 receivedJSPS KAKENHI Grant #16K11054, the Naito Foundation Research Grant,and the Mochida Memorial Foundation for Medical and PharmaceuticalResearch Grant. Thomas Chi has received NIH grant funding (P20-DK-100863 and R21-DK-109433).

Funding/Support and role of the sponsor: None.

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