title: Evidence for epistatic interaction between VDR and SLC13A2 genes in the pathogenesis of hypocitraturia in recurrent calcium oxalate stone formers.
abstract: BACKGROUND
  Genetic factors play a key role in the pathogenesis of hypocitraturia, a common risk factor for nephrolithiasis. The Na+-dicarboxylate cotransporter NaDC1, encoded by the sodium-dicarboxylate cotransporter (SLC13A2) gene, is a major determinant of urinary citrate excretion and its biological functions are regulated also by the vitamin D/Vitamin D receptor (VDR) biological system. The aim of this case-control study was to evaluate the possible epistatic interaction between VDRrs731236and SLC13A2rs11567842allelic variants in the pathogenesis of hypocitraturia.
  
  
  METHODS
  Recurrent calcium-oxalate stone formers (SF) with or without hypocitraturia and healthy controls (C) were genotyped. Gene-gene interactions were estimated by the 1.0 software package of multifactor dimensionality reduction (MDR).
  
  
  RESULTS
  The prevalence of VDRTTand SLC13A2GGgenotypes was higher in hypocitraturic SF compared to C (odds ratio [OR] 3.24, 95 % confidence interval [CI] 1.38-7.60 for VDRTTvs. VDRttand OR 4.06, 95 % CI 1.75-9.42 for SLC13A2GGvs. SLC13A2AA). MDR analysis indicated a significant interaction between VDRTTand SLC13A2GGin hypocitraturic SF compared to C [OR 3.81 (2.11-6.88)]. These data are compatible with an epistatic interaction between the VDRTTand SLC13A2GGgenotypes with a significant impact on the magnitude of the effect (suppressive effect).
  
  
  CONCLUSIONS
  These results point to an epistatic interaction between the VDR and the SLC13A2 alleles in the pathogenesis of idiopathic hypocitraturia in calcium-oxalate SF.
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University of Naples, via Pansini 5, 80131, Naples, Italy. domenico.rendina@unina.it.
authors.forename: Domenico
authors.identifier: http://orcid.org/0000-0002-0331-0392
authors.initials: D
authors.lastname: Rendina
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", Italian National Research Council, Naples, Italy.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: De Filippo
authors.affiliation: AP-HP, CHU Bicêtre, Service de Médecine des Adolescents, Le Kremlin-Bicêtre, France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Gianfrancesco
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University of Naples, via Pansini 5, 80131, Naples, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Muscariello
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University of Naples, via Pansini 5, 80131, Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Schiano di Cola
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University of Naples, via Pansini 5, 80131, Naples, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Strazzullo
authors.affiliation: AP-HP, CHU Bicêtre, Service de Médecine des Adolescents, Le Kremlin-Bicêtre, France.|IRCCS INM Neuromed, Pozzilli, IS, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Esposito
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000652:urine; D002129:Calcium Oxalate / Q000652:urine*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D019343:Citric Acid / Q000652:urine*; D003430:Cross-Sectional Studies; D029382:Dicarboxylic Acid Transporters / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D053040:Nephrolithiasis / Q000175:diagnosis / Q000235:genetics* / Q000652:urine*; D016017:Odds Ratio; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D012008:Recurrence; D012307:Risk Factors; D027981:Symporters / Q000235:genetics*
chemical_list: D015415:Biomarkers; D029382:Dicarboxylic Acid Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D018167:Receptors, Calcitriol; C092524:SLC13A2 protein, human; D027981:Symporters; C579457:VDR protein, human; D002129:Calcium Oxalate; D019343:Citric Acid
keywords: Epistasis; Hypocitraturia; Nephrolithiasis; SLC13A2; VDR