Domenico Rendina1, Gianpaolo De Filippo2, Fernando Gianfrancesco3, Riccardo Muscariello4, Michele Schiano di Cola4, Pasquale Strazzullo4, Teresa Esposito3,5. 1. Department of Clinical Medicine and Surgery, Federico II University of Naples, via Pansini 5, 80131, Naples, Italy. domenico.rendina@unina.it. 2. Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", Italian National Research Council, Naples, Italy. 3. AP-HP, CHU Bicêtre, Service de Médecine des Adolescents, Le Kremlin-Bicêtre, France. 4. Department of Clinical Medicine and Surgery, Federico II University of Naples, via Pansini 5, 80131, Naples, Italy. 5. IRCCS INM Neuromed, Pozzilli, IS, Italy.
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 VDR rs731236and SLC13A2 rs11567842 allelic 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 VDR TT and SLC13A2 GG genotypes was higher in hypocitraturic SF compared to C (odds ratio [OR] 3.24, 95 % confidence interval [CI] 1.38-7.60 for VDR TT vs. VDR tt and OR 4.06, 95 % CI 1.75-9.42 for SLC13A2 GG vs. SLC13A2 AA ). MDR analysis indicated a significant interaction between VDR TT and SLC13A2 GG in hypocitraturic SF compared to C [OR 3.81 (2.11-6.88)]. These data are compatible with an epistatic interaction between the VDR TT and SLC13A2 GG genotypes 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.
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 VDR rs731236and SLC13A2rs11567842 allelic 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 VDR TT and SLC13A2 GG genotypes was higher in hypocitraturic SF compared to C (odds ratio [OR] 3.24, 95 % confidence interval [CI] 1.38-7.60 for VDR TT vs. VDR tt and OR 4.06, 95 % CI 1.75-9.42 for SLC13A2 GG vs. SLC13A2 AA ). MDR analysis indicated a significant interaction between VDR TT and SLC13A2 GG in hypocitraturic SF compared to C [OR 3.81 (2.11-6.88)]. These data are compatible with an epistatic interaction between the VDR TT and SLC13A2 GG genotypes 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: Jan Halbritter; Michelle Baum; Ann Marie Hynes; Sarah J Rice; David T Thwaites; Zoran S Gucev; Brittany Fisher; Leslie Spaneas; Jonathan D Porath; Daniela A Braun; Ari J Wassner; Caleb P Nelson; Velibor Tasic; John A Sayer; Friedhelm Hildebrandt Journal: J Am Soc Nephrol Date: 2014-10-08 Impact factor: 10.121
Authors: D Rudman; J L Dedonis; M T Fountain; J B Chandler; G G Gerron; G A Fleming; M H Kutner Journal: N Engl J Med Date: 1980-09-18 Impact factor: 91.245
Authors: G Mossetti; P Vuotto; D Rendina; F G Numis; R Viceconti; F Giordano; M Cioffi; F Scopacasa; V Nunziata Journal: J Intern Med Date: 2003-02 Impact factor: 8.989