New study links DNA methylation in GLP1R gene to obesity without metabolic disorders

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Nov 20 2023

Obesity is associated with multiple metabolic conditions, including insulin resistance, high blood sugar levels, hypertension, and lipid abnormalities. However, a significant proportion of technically obese people are metabolically normal, a state called metabolically healthy obesity (MHO).

While MHO is still associated with a higher risk of death from all causes as compared to metabolically healthy normal-weight (MHNW) people, the mechanisms that underlie the increased risk are unclear. A recent study published in the International Journal of Obesity explores how epigenetic changes in glucagon-like peptide-1 receptor (GLP1R) gene polymorphisms affect the risk of obesity.

Study: Integrated genetic and epigenetic analyses uncovered GLP1R association with metabolically healthy obesity. Image Credit: Somchai_shock / Shutterstock.com

What is GLP1R?

GLP1 is the incretin-like metabolic hormone glucagon-like peptide 1 that binds to the GLP1R receptor. Incretins stimulate the synthesis and subsequent release of insulin when glucose levels are high; however, some incretins also suppress glucagon release.

GLP1 also slows gastric motility, thereby keeping food in the stomach for longer while increasing the feeling of fullness and suppressing food intake. Together, these functions lead to a stable body state with weight loss.

Some gene variants of GLP1R are associated with obesity, such as the rs2268641 allele, which has been linked to the body mass index (BMI) in Americans of European origin. Likewise, rs6923761 alleles that show differential associations with body fat mass in Hispanics, as rs6923761 A allele carriers have a lower fat mass, waist circumference, and BMI than non-carriers.

In addition to these genetic associations, epigenetic modifications can alter gene expression, thus affecting the likelihood of obesity. Little is known about GLP1R methylation in relation to the risk of obesity, especially among those with MHO.

About the study

The current study examines the links between genetic and epigenetic variation in MHO and how epigenetic changes contribute to the association between GLP1R variants and MHO.

The study included participants from a community cohort in Shangdong province, China, who did not have normal triglyceride levels or were not prescribed lipid-lowering agents, normal blood pressure and normal blood sugar levels or not prescribed anti-diabetic drugs, low levels of ‘good’ or high-density lipoprotein (HDL) cholesterol, or normal BMI and waist-hip ratio (WHR) values.

There were 120 participants and 180 controls in this study. About 44% of the study cohort were male, with about two-thirds below the age of 60 years. Both groups had similar rates of drinking, smoking, and activity.

What did the study show?

When examined for co-dominant inheritance, the single nucleotide polymorphism (SNP) rs4714211 was associated with MHO. The risk of MHO was 66% lower with GG compared to the AA allele set.

The likelihood of MHO increased in those with a higher GLP1R gene score. Increased methylation at four sites in the GLP1R intronic region or before the transcription start site was associated with a higher risk of MHO, even after compensating for rs4714211 and other possible confounding factors.

When the gene score was adjusted, MHO was associated with five methylation sites, four of them positively. The methylation risk score (MRS) also showed a positive association with MHO, even after compensating for rs4714211 or the GRS.

Moreover, there was a link between GLP1R polymorphisms and the level of methylation at two sites, as well as between the polymorphisms and MRS. GRS showed association with the MRS, as well as with another GLP1R site.

Upon analyzing the role of epigenetics in this observed association of polymorphisms with MHO, methylation was found to be partly responsible.

What are the implications?

This is the first study integrating the multiomics data to investigate the causality of genetic and epigenetic variations at the GLP1R locus in relation to the risk of obesity.”

The study findings demonstrate that apart from gene polymorphisms, DNA methylation is a factor in the occurrence of MHO. This emphasizes the network of interactions between genetic and epigenetic factors in the origin of MHO.

The association of rs6923761 with MHO has not been observed in other populations, with CT allele carriers of the rs2268641 variant among Polish individuals at a 56% higher risk for overweight or obesity than TT carriers. Similarly, the risk was increased for A carriers of rs6923761 than for non-carriers.

Further research is needed, as this is the first time that GLP1R GRS has been linked to MHO. Nevertheless, the association is plausible, as CpG methylation effects may vary depending on the region in which it occurs due to variations in the pattern of methylation. Thus, exon and intron region hyper-methylation might result in upregulation of the involved genes, while in the gene promoters or adjacent regions, hyper-methylation may prohibit gene expression.

The method used here is superior to Mendelian randomization (MR), as it is capable of assessing the directionality of genetic regulation on MHO mediated by DNA methylation. Different alleles may alter the binding of regulatory proteins like transcription factors to sequences containing methylation sites. Such changes in binding may lead to worse outcomes by their effects on gene expression.

Thus, gene methylation might partly account for the effect of the gene variant on MHO. This observation offers a novel perspective on the effects of GLP1R variants on MHO susceptibility.