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.
Highlights
Diabetes is one of the leading causes of mortality in contemporary society [1]
Several reports have so far described the association of Single Nucleotide Polymorphism (SNP) and altered drug responsiveness in Type 2 Diabetes (T2D) [13]
These SNPs fall within genes with a clear relation to drug transport (SLC22A1 and SLC22A2), metabolism (CYP2C9), activity (PPARG and ABCC8), genes that have a direct role in diabetes onset or progression (KCNJ11, IRS1 and TCF7L2) or that have been frequently associated by Genome-Wide Association Studies (GWAS) to T2D and drug response (CAPN10), despite the fact that the exact mechanisms are still unclear
Summary
Diabetes is one of the leading causes of mortality in contemporary society [1]. A recent report by the International Diabetes Federation indicated an onset rate of about 8.4% in adults and a total number of 382 million cases of diabetes worldwide. This number is estimated to critically increase to up to 592 million by 2035 [1]. Type 2 Diabetes (T2D), known as “non insulin-dependent diabetes”, is the most frequent form (with later onset) and occurs because of insulin defective function [3]. T2D affects more than 5% of the population in western countries and its spread is still increasing
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