A Genome-Wide Association Study of Nephrolithiasis in the Japanese Population Identifies Novel Susceptible Loci at 5q35.3, 7p14.3, and 13q14.1

Urabe, Yuji; Tanikawa, Chizu; Takahashi, Atsushi; Okada, Yukinori; Morizono, Takashi; Tsunoda, Tatsuhiko; Kamatani, Naoyuki; Kohri, Kenjiro; Chayama, Kazuaki; Kubo, Michiaki; Nakamura, Yusuke; Matsuda, Koichi

doi:10.1371/journal.pgen.1002541

Cited by 73 publications

(82 citation statements)

References 33 publications

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“…A study indicated that DGK might be involved in transplasmalemmal calcium ion influx of platelets22. In GWAS study by Urabe et al 6,. SNP rs4142110 on DGKH was one of the three novel loci for nephrolithiasis.…”

Section: Discussionmentioning

confidence: 99%

Association Study of Reported Significant Loci at 5q35.3, 7p14.3, 13q14.1 and 16p12.3 with Urolithiasis in Chinese Han Ethnicity

Wang

Feng

Ding

et al. 2017

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In this study, we aimed to validate the association of 8 reported significant loci at 5q35.3, 7p14.3, 13q14.1 and 16p12.3 with urolithiasis in Chinese Han population. We performed case-control association analysis using 624 patients with nephrolithiasis and 1008 control subjects. We selected single-nucleotide polymorphism (SNPs) including rs12654812 and rs11746443 from 5q32.3; rs12669187 and rs1000597 from 7q14.3; rs7981733, rs4142110 and rs17646069 from 13q14.1 and rs4293393 from 16p12.3 which were previously reported to be associated with nephrolithiasis. We found none of these eight reported SNPs were significant associated with urolithiasis risk in Chinese Han population, which suggested that differences could exist in the mechanisms of calcium urolithiasis between Chinese and Japanese Ethnics. The A allele of rs12669187 was significantly correlated with increased level of serum magnesium. The C allele of rs1000597 was associated with higher levels of serum creatinine, uric acid, calcium and lower urine pH level. The T allele of rs4142110 was correlated with higher levels of serum magnesium, phosphorus, and lower AKP level. The G alleles of rs4293393 was associated with higher serum CO2 level. The risk alleles of these SNPs were proved to be associated with the electrolytes metabolism that may result in the formation of urolithiasis.

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Section: Discussionmentioning

confidence: 99%

Association Study of Reported Significant Loci at 5q35.3, 7p14.3, 13q14.1 and 16p12.3 with Urolithiasis in Chinese Han Ethnicity

Wang

Feng

Ding

et al. 2017

Sci Rep

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“…In 2012, a GWAS of urolithiasis in the Japanese population, including 5796 patients with urolithiasis and 17 344 healthy controls, was carried out . This study identified three novel loci for urolithiasis at 5q35.3 ( RGS14‐SLC34A1‐PFN3‐F12 ), 7p14.3 ( INMT‐FAM188B‐AQP1 ) and 13q14.1 ( DGKH ).…”

Section: Genetic Factors Of Kidney Stone Diseasementioning

confidence: 99%

Pathophysiology‐based treatment of urolithiasis

et al. 2016

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Abbreviations & Acronyms CHD = coronary heart disease EPA = eicosapentaenoic acid GWAS = genome-wide association studies MCP-1 = monocyte chemoattractant protein 1 MPT = mitochondrial permeability transition NADPH = nicotinamide adenine dinucleotide phosphate NIM811 = N-methyl-4-isoleucine cyclosporine OPN = osteopontin OS = oxidative stress PPAR = peroxisome proliferator-activated receptor ROS = reactive oxygen species SNP = single nucleotide polymorphism Abstract: Urolithiasis, a complex multifactorial disease, results from interactions between environmental and genetic factors. Epidemiological studies have shown the association of urolithiasis with a number of lifestyle-related diseases, including cardiovascular diseases, hypertension, chronic kidney disease, diabetes and metabolic syndrome. Elucidation of the mechanisms underlying urinary stone formation will enable development of new preventive treatments. The present article reviews the epidemiology, pathophysiology and potential treatment of urolithiasis. Recent literature has shown that oxidative stress and reactive oxygen species could be one such mechanistic pathway. Calcium oxalate crystals adhering to renal tubular cells are incorporated into the cells through the involvement of osteopontin. Stimulation of crystal-cell adhesion impairs acceleration of the mitochondrial permeability transition pore in tubular cells, resulting in mitochondrial collapse, oxidative stress and activation of the apoptotic pathway in the initial steps of renal calcium crystallization. With regard to genetic factors, studies show that single nucleotide polymorphisms in genes encoding calcium-sensing receptor, vitamin D receptor and osteopontin are correlated with urolithiasis. Genome-wide association studies have shown that CLDN14 and NPT2 are associated with urolithiasis in Caucasian and Japanese populations, respectively. Thus, single nucleotide polymorphism analysis would aid in the prediction of urolithiasis risk and recurrence. New diagnostic methods and preventive approaches, along with complete removal of stones, will improve the management of urolithiasis.

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“…Three loci, 5q35.3, 7p14.3, and 13q14.1, were associated with calcium nephrolithiasis in a Japanese GWAS including 5,892 cases and 17,809 controls [34]. Three genes at these loci are candidates to explain these associations.…”

Section: Slc34a1 and Aqp1 Genesmentioning

confidence: 99%

Idiopathic Calcium Nephrolithiasis: A Review of Pathogenic Mechanisms in the Light of Genetic Studies

et al. 2014

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Background: Calcium nephrolithiasis is a multifactorial disease with a polygenic milieu. Association studies identified genetic polymorphisms potentially implicated in the pathogenesis of calcium nephrolithiasis. The present article reviews the mechanisms of calcium stone formation and the potential contribution of gene polymorphisms to lithogenic mechanisms. Summary: Endoscopy observations suggested that precipitation of calcium-oxalate on the Randall's plaque at the papilla surface may cause idiopathic calcium-oxalate stones. The Randall's plaque is a hydroxyapatite deposit in the interstitium of the kidney medulla, which resembles a soft tissue calcification. Conversely, calcium-phosphate stones may develop from crystalline deposits located at the tip of the Bellini duct. Polymorphisms of eleven genes have been associated with stones in genome-wide association studies and replicated candidate-gene association studies: VDR, SLC34A1, SLC34A4, CLDN14, and CaSR genes coding for proteins regulating tubular phosphate and calcium reabsorption; CaSR, MGP, OPN, PLAU, and UMOD genes coding for proteins preventing calcium salt precipitation; AQP1 gene coding for a water channel in the proximal tubule. The renal activity of the last gene, DGKH, is unknown. Polymorphisms in these genes may predispose to calcium-oxalate and -phosphate stones by increasing the risk of calcium-phosphate precipitation in the tubular fluid. Key Messages: Genetic findings suggest that tubular fluid supersaturation with respect to calcium and phosphate predisposes to calcium-oxalate stones by triggering cellular mechanisms that lead to the Randall's plaque formation. © 2014 S. Karger AG, Basel

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A Genome-Wide Association Study of Nephrolithiasis in the Japanese Population Identifies Novel Susceptible Loci at 5q35.3, 7p14.3, and 13q14.1

Cited by 73 publications

References 33 publications

Association Study of Reported Significant Loci at 5q35.3, 7p14.3, 13q14.1 and 16p12.3 with Urolithiasis in Chinese Han Ethnicity

Association Study of Reported Significant Loci at 5q35.3, 7p14.3, 13q14.1 and 16p12.3 with Urolithiasis in Chinese Han Ethnicity

Pathophysiology‐based treatment of urolithiasis

Idiopathic Calcium Nephrolithiasis: A Review of Pathogenic Mechanisms in the Light of Genetic Studies

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