title: Computational Analysis of Single Nucleotide Polymorphisms Associated with Altered Drug Responsiveness in Type 2 Diabetes.
abstract: Type 2 diabetes (T2D) is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual variability is principally due to single nucleotide polymorphisms, and differential drug responsiveness has been correlated to alteration in genes involved in drug metabolism (CYP2C9) or insulin signaling (IRS1, ABCC8, KCNJ11 and PPARG). However, most genome-wide association studies did not provide clues about the contribution of DNA variations to impaired drug responsiveness. Thus, characterizing T2D drug responsiveness variants is needed to guide clinicians toward tailored therapeutic approaches. Here, we extensively investigated polymorphisms associated with altered drug response in T2D, predicting their effects in silico. Combining different computational approaches, we focused on the expression pattern of genes correlated to drug resistance and inferred evolutionary conservation of polymorphic residues, computationally predicting the biochemical properties of polymorphic proteins. Using RNA-Sequencing followed by targeted validation, we identified and experimentally confirmed that two nucleotide variations in the CAPN10 gene-currently annotated as intronic-fall within two new transcripts in this locus. Additionally, we found that a Single Nucleotide Polymorphism (SNP), currently reported as intergenic, maps to the intron of a new transcript, harboring CAPN10 and GPR35 genes, which undergoes non-sense mediated decay. Finally, we analyzed variants that fall into non-coding regulatory regions of yet underestimated functional significance, predicting that some of them can potentially affect gene expression and/or post-transcriptional regulation of mRNAs affecting the splicing.
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy. valerio.costa@igb.cnr.it.
authors.forename: Valerio
authors.initials: V
authors.lastname: Costa
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy. antonio.federico@igb.cnr.it.|DiST, Department of Science and Technology, University of Naples "Parthenope", 80134 Naples, Italy. antonio.federico@igb.cnr.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy. carla.pollastro@igb.cnr.it.|DiST, Department of Science and Technology, University of Naples "Parthenope", 80134 Naples, Italy. carla.pollastro@igb.cnr.it.
authors.forename: Carla
authors.initials: C
authors.lastname: Pollastro
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy. ziviello@gmail.com.
authors.forename: Carmela
authors.initials: C
authors.lastname: Ziviello
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy. simona.cataldi@igb.cnr.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Cataldi
authors.affiliation: Department of Translational Medical Sciences, University of Naples "Federico II", 80131 Naples, Italy. pietro.formisano@unina.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy. alfredo.ciccodicola@igb.cnr.it.|DiST, Department of Science and Technology, University of Naples "Parthenope", 80134 Naples, Italy. alfredo.ciccodicola@igb.cnr.it.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ciccodicola
mesh_terms: D002154:Calpain / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D020641:Polymorphism, Single Nucleotide; D012323:RNA Processing, Post-Transcriptional; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: C111379:GPR35 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D008687:Metformin; D002154:Calpain; C415197:calpain 10
keywords: RNA-sequencing; computational predictions; drug responsiveness; personalized medicine; pharmacogenomics; type 2 diabetes