Methylation status of vault RNA 2-1 promoter is a predictor of glycemic response to glucagon-like peptide-1 analog therapy in type 2 diabetes mellitus

Abstract

IntroductionTherapeutic efficiency of glucagon-like peptide-1 (GLP-1) analog is about 50%–70% in type 2 diabetes mellitus (T2DM). Discovery of potential genetic biomarkers for prediction of treatment efficiency of GLP-1 analog before therapy is still necessary. We assess whether DNA methylation was associated with glycemic response to GLP-1 analog therapy in patients with poorly controlled T2DM.Research design and methodsGenomic DNA was extracted from the peripheral blood of training (n=10) and validation (n=128) groups of patients with T2DM receiving GLP-1 analogs. DNA methylome was analyzed using Infinium Human Methylation EPIC Bead Chip in the training group. The candidate genes were examined using a pyrosequencing platform in the validation group. The association between DNA methylation status and glycemic response to GLP-1 was analyzed in these patients.ResultsThe most differential methylation region between those with a good (responsive) and poor (unresponsive) glycemic response to GLP-1 analog therapy was located on chromosome 5q31.1 (135415693 to 135416613), the promoter of VTRNA2-1 in the training group. The methylation status of the VTRNA2-1 promoter was examined in the validation group via pyrosequencing reaction, and the hypomethylation of VTRNA2-1 (<40% methylation) was significantly associated with poor glycemic response to GLP-1 treatment (OR 2.757, 95% CI 1.240 to 6.130, p=0.011). Since the VTRNA2-1 promoter region was previously reported maternal imprinting extended to the adjacent centromeric CCCTC-binding factor site that contained an A/C polymorphism (rs2346018), which was associated with methylation density of VTRNA2-1, this A/C polymorphism was also integrated to analyze association with glycemic response to GLP-1 analog therapy. In patients with the A allele of rs2346018 and hypomethylation (<40%) on the VTRNA2-1 promoter, the OR increased to 4.048 (95% CI 1.438 to 11.389, p=0.007).ConclusionsThe glycemic response to GLP-1 analog treatment is associated with the methylation status of the VTRNA2-1 promoter and polymorphism of rs2346018.

Determinants in Tailoring Antidiabetic Therapies: A Personalized Approach

“…Also, A allele of a polymorphism in the same gene, that is, rs2346018, correlated with hypomethylation and thus reduced responsiveness to GLP-1 analogs. 88 miRNAs have a role in posttranscriptional regulation of expression. These are 20 to 30 nucleotides-long noncoding RNAs which bind to 3′-UTR of the target primary transcript causing its destabilization and repression of translation.…”

“…Also, A allele of a polymorphism in the same gene, that is, rs2346018, correlated with hypomethylation and thus reduced responsiveness to GLP-1 analogs. 88 …”

Methylation pattern of polymorphically imprinted nc886 is not conserved across mammalia

“…The methylation status of this epiallele has also been associated with allergies [ 24 ], asthma [ 25 ], infections [ 26 ], and inflammation [ 27 ]. We and others have also shown that both the nc886 methylation status and RNA expression are associated with indicators of glucose metabolism [ 16 , 28 ].…”

Methylation status of VTRNA2-1/nc886 is stable across human populations, monozygotic twin pairs and in majority of somatic tissues

“…Furthermore, the methylation level or status of nc886 or level of nc886 RNAs transcribed from the locus have been associated with childhood BMI (19), adiposity and cholesterol levels (11), as well as allergies (20), asthma (21), infections (22) and inflammation (23). Interestingly, the nc886 methylation status and the level of nc886 RNAs have also been associated with indicators of glucose metabolism (11,24). These findings suggest that the methylation status of nc886 is a potential molecular mediator of the Developmental Origins of Health and Disease (DOHaD) hypothesis (also known as the Barker hypothesis) (25).…”