How a mutation in introns affect the gene expression. if a SNP is not present in any downstream regulatory elements but in somewhere intermediate region of intron and how those polymorphism differentiate a response of those patients against drugs? eg. How rs7903146 polymorphism in TCF7L2 gene lead to risk of T2DM and how they differentiate in response against drugs like metformin or gliptin?
Mutations in intronic regions might not be significant if no association has been found to a disease state. In this case, several genome-wide association studies conducted in heterogenoeus populations have shown that the rs7903146 polymorphism is associated with T2D. The reasons behind the precise molecular mechanisms are still unclear; it is thought that this intronic variant induces disregulation in the WNT pathway, with impairment of beta-cell function and incretin-mediated insulin response after an increase in glucose concentration. A recent study conducted as a part of SUGAR-MGH, demosntrated that carriers of the rs7903146 polymorphism in TCF7L2 had a steeper glipizide response and lower fasting glucose levels after metformin administration. They were also able to show that glucose-mediated incretin-stimulated insulin response is impaired in carriers of the rs7903146 variant in TCF7L2, which could potentially indicate that DPP-IV inhibition or GLP-1 therapies in carriers of this risk allele might not be the better alternative; nevertheless, this still remains an area of opportunity for research.
Article TCF7L2 Genetic Variation Augments Incretin Resistance and In...
Thanks for ur reply Omar Yaxmehen Bello-Chavolla. But if molecular mechanisms is unclear. I wish to know what may be a reason or hypothesis for these disregulations.
TCF7L2 is a transcription factor of wnt signaling pathway, which transcribe wnt targeted genes such as GLP-1, VEGF, e-NOS and ICAM, whose aberration/polymorphisms were found to be directly associated with T2DM cited in different articles of population genetics. SNPs of TCF7L2 of disease associated are not only linked to T2DM, but also cancer, and diseases of neovascularization, based on the wnt targeted genes it regulates.
Although the mechanism is unclear of how intronic variants (i.e. rs7901346 and rs12255372) of TCF7L2 are associated with disease. it was identified using softwares such as Bioinformatic tool such as Alumut visual to identify that these variants are found in the region where splicing process occur which in a nutshell are presumed to play crucial role in deregulation of TCF7L2 expression, thereby also affecting the expression levels of wnt targeted genes which are directly associated to T2DM, cancer and other diseases of neovascularization.
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