HNF1 alpha upregulation and promoter hypermethylation as a cause of glucose dysregulation: a case-control study of Kashmiri MODY population

摘要

Aim HNF1 alpha transcription factor regulates a network of genes involved in the development of beta-cells and also serves as a model for transcription defects in pancreatic beta-cells; mutations in this gene cause MODY. The goal of this study was to assess the promoter methylation and expression profile of the most common MODY causing gene, HNF1 alpha, in Kashmiri MODY patients, as factors responsible for glucose dysregulation, as no such study had been performed on MODY patients in Kashmir previously. Methods The study included 85 Kashmiri subjects. Samples were extracted for DNA and RNA using standard protocols. The HNF1 alpha promoter methylation profile was assessed by bisulfite conversion of the DNA followed by MSP, whereas qPCR was used for expression analysis. Results The expression of HNF1 alpha was found to be upregulated (p value 0.0349*) in majority of MODY (60%) and T1D (72%) cases (p value 0.0349*). HNF1 alpha expression was 1.33-fold higher in MODY cases with hypermethylated HNF1 alpha promoters (p value 0.0360*). HNF1 alpha expression was upregulated by 2.3-fold in MODY patients with HbA1c levels > 7% (p value 0.0025**). MODY cases with FBS levels > 7.7 mmol/l were upregulated by 0.646-fold than those with FBS levels <= 7.7 mmol/l (p value 0.0161*). Conclusion In this study, we found that as glucose dysregulation progresses, blood FBS, RBS, and HbA1c levels rise, and that at higher levels, HNF1 alpha expression rises as well. From the results obtained, we may conclude that HNF1 alpha is strongly upregulated in MODY, thus indicating the deleterious effect of over expression of HNF1 alpha gene on glucose regulation.