Genetic variants associated with gastrointestinal symptoms in Fabry disease.
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.
Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, 88100 Italy.
Maria Teresa
MT
Di Martino
Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, 88100 Italy.
Francesca
F
Scionti
Department of Medical and Surgical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, 88100 Italy.
Simona
S
Sestito
Department of Medical and Surgical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, 88100 Italy.
Angela
A
Nicoletti
ISN-CNR, Roccelletta di Borgia, Catanzaro, 88100 Italy.
Mariamena
M
Arbitrio
Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, 88100 Italy.
Pietro
P
Hiram Guzzi
Department of Medical and Surgical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, 88100 Italy.
Valentina
V
Talarico
Department of Medical and Surgical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, 88100 Italy.
Federica
F
Altomare
Department of Medical and Surgical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, 88100 Italy.
Maria Teresa
MT
Sanseviero
Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, 88100 Italy.
Giuseppe
G
Agapito
Departement of Nephrology University Federico II, Naples, 80138 Italy.
Antonio
A
Pisani
Departement of Nephrology University Federico II, Naples, 80138 Italy.
Eleonora
E
Riccio
Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Sick Children, University College of London (UCL), London, WC1E 6BT, UK.
Osvaldo
O
Borrelli
Department of Medical and Surgical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, 88100 Italy.
Daniela
D
Concolino
Department of Medical and Surgical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, 88100 Italy.|Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Sick Children, University College of London (UCL), London, WC1E 6BT, UK.
Licia
L
Pensabene
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11 / Q000235:genetics; D000328:Adult; D000090702:Constitutive Androstane Receptor; D000795:Fabry Disease / Q000150:complications / Q000235:genetics*; D005260:Female; D005767:Gastrointestinal Diseases / Q000235:genetics*; D014644:Genetic Variation; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human
DMET; Fabry disease; bile acids; gastrointestinal symptoms; genetic polymorphisms