Genetic variants associated with gastrointestinal symptoms in Fabry disease

// Maria Teresa Di Martino 1, * , Francesca Scionti 1, * , Simona Sestito 2 , Angela Nicoletti 2 , Mariamena Arbitrio 3 , Pietro Hiram Guzzi 4 , Valentina Talarico 2 , Federica Altomare 2 , Maria Teresa Sanseviero 2 , Giuseppe Agapito 4 , Antonio Pisani 5 , Eleonora Riccio 5 , Osvaldo Borrelli 6 , Daniela Concolino 2, ** , Licia Pensabene 2, 6, ** 1 Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, 88100 Italy 2 Department of Medical and Surgical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, 88100 Italy 3 ISN-CNR, Roccelletta di Borgia, Catanzaro, 88100 Italy 4 Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, 88100 Italy 5 Departement of Nephrology University Federico II, Naples, 80138 Italy 6 Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Sick Children, University College of London (UCL), London, WC1E 6BT, UK * These authors have contributed equally to this work ** These authors have contributed equally to this work and share senior authorship Correspondence to: Licia Pensabene, email: Pensabene@gosh.nhs.uk Maria Teresa Di Martino, email: teresadm@unicz.it Keywords: Fabry disease, gastrointestinal symptoms, bile acids, DMET, genetic polymorphisms Received: June 08, 2016 Accepted: October 29, 2016 Published: November 05, 2016 ABSTRACT Gastrointestinal symptoms (GIS) are often among the earliest presenting events in Fabry disease (FD), an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A. Despite recent advances in clinical and molecular characterization of FD, the pathophysiology of the GIS is still poorly understood. To shed light either on differential clinical presentation or on intervariability of GIS in FD, we genotyped 1936 genetic markers across 231 genes that encode for drug-metabolizing enzymes and drug transport proteins in 49 FD patients, using the DMET Plus platform. All nine single nucleotide polymorphisms (SNPs) mapped within four genes showed statistically significant differences in genotype frequencies between FD patients who experienced GIS and patients without GIS: ABCB11 (odd ratio (OR) = 18.07, P = 0,0019; OR = 8.21, P = 0,0083; OR=8.21, P = 0,0083; OR = 8.21, P = 0,0083),SLCO1B1 (OR = 9.23, P = 0,0065; OR = 5.08, P = 0,0289; OR = 8.21, P = 0,0083), NR1I3 (OR = 5.40, P = 0,0191) and ABCC5 (OR = 14.44, P = 0,0060). This is the first study that investigates the relationships between genetic heterogeneity in drug absorption, distribution, metabolism and excretion (ADME) related genes and GIS in FD. Our findings provide a novel genetic variant framework which warrants further investigation for precision medicine in FD.