3'-UTR SNP rs2229611 in G6PC1 affects mRNA stability, expression and Glycogen Storage Disease type-Ia risk

Clin Chim Acta. 2017 Aug:471:46-54. doi: 10.1016/j.cca.2017.05.016. Epub 2017 May 11.

Abstract

The frequency of rs2229611, previously reported in Chinese, Caucasians, Japanese and Hispanics, was investigated for the first time in Indian ethnicity. We analyzed its role in the progression of Glycogen Storage Disease type-Ia (GSD-Ia) and breast cancer. Genotype data on rs2229611 revealed that the risk of GSD-Ia was higher (P=0.0195) with CC compared to TT/TC genotypes, whereas no such correlation was observed with breast cancer cases. We observed a strong linkage disequilibrium (LD) among rs2229611 and other disease causing G6PC1 variants (|D'|=1, r2=1). Functional validation performed in HepG2 cells using luciferase constructs showed significant (P<0.05) decrease in expression than wild-type 3'-UTR due to curtailed mRNA stability. Furthermore, AU-rich elements (AREs) mediated regulation of G6PC1 expression characterized using 3'-UTR deletion constructs showed a prominent decrease in mRNA stability. We then examined whether miRNAs are involved in controlling G6PC1 expression using pmirGLO-UTR constructs, with evidence of more distinct inhibition in the reporter function with rs2229611. These data suggests that rs2229611 is a crucial regulatory SNP which in homozygous state leads to a more aggressive disease phenotype in GSD-Ia patients. The implication of this result is significant in predicting disease onset, progression and response to disease modifying treatments in patients with GSD-Ia.

Keywords: 3’UTR; Breast cancer; GSD-Ia; Linkage disequilibrium; Polymorphism; rs2229611.

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Glucose-6-Phosphatase / genetics*
  • Glycogen Storage Disease Type I / enzymology
  • Glycogen Storage Disease Type I / genetics*
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Male
  • Polymorphism, Single Nucleotide*
  • RNA Stability / genetics*
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • Suppression, Genetic / genetics*

Substances

  • 3' Untranslated Regions
  • RNA, Messenger
  • G6PC1 protein, human
  • Glucose-6-Phosphatase

Supplementary concepts

  • Hepatorenal form of glycogen storage disease