Genetic variants associated with gastrointestinal symptoms in Fabry disease.

Maria Teresa Di Martino,Pietro Hiram Guzzi,Angela Nicoletti,Federica Altomare,Eleonora Riccio,Maria Teresa Sanseviero,Giuseppe Agapito,Valentina Talarico,Licia Pensabene,Daniela Concolino,Antonio Pisani,Simona Sestito,Osvaldo Borrelli,Mariamena Arbitrio,Francesca Scionti

doi:10.18632/oncotarget.13135

Maria Teresa Di Martino, Pietro Hiram Guzzi + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.13135

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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.

Highlights

Fabry disease (FD [MIM:301500]), or AndersonFabry disease, is a rare X-linked lipid storage disorder caused by mutations in the GLA gene (MIM: 300644), encoding the lysosomal enzyme α-galactosidase A (α-Gal A)
Abdominal pain was present in 12 patients (24.5%) while diarrhea was reported in 11 patients (22.4%)
Four ABCB11 polymorphisms, in linkage disequilibrium (LD), significantly correlated with Gastrointestinal symptoms (GIS), and the frequencies of the heterozygous genotypes CT were significantly higher in FD patients with GIS (CT = 84% versus 38% P = 0.0083, 92% versus 38% P = 0.0019, 84% versus 38% P = 0.0083 and 82% versus 38% P = 0.0083, respectively)

Summary

Introduction

Fabry disease (FD [MIM:301500]), or AndersonFabry disease, is a rare X-linked lipid storage disorder caused by mutations in the GLA gene (MIM: 300644), encoding the lysosomal enzyme α-galactosidase A (α-Gal A). The clinical presentation of FD varies from a classical phenotype (null or minimal α-Gal A activity), including childhoodwww.impactjournals.com/oncotarget onset angiokeratoma, acroparesthesias, gastrointestinal disorders, hypohidrosisand characteristic corneal and lenticular opacities [2, 3] to adult-onset variants (residual α-GalA activity) with only cardiac [4] or renal [5] symptoms. Published data showed a high degree of intra-familial phenotypic variability in patients carrying the same mutation [7]. Gastrointestinal symptoms (GIS) are reported in approximately 60% of FD patients and have a profound negative effect on their quality of life. Despite recent advances in clinical and molecular characterization of FD, the pathophysiology of the GIS is still poorly understood

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