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

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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 individuals are metabolically normal, a condition termed metabolically healthy obesity (MHO).

Although MHO is still associated with a higher risk of death from all causes than metabolically healthy normal-weight (MHNW) people, the mechanisms underlying the increased risk are clear. A recent study published International Journal of Obesity Investigates how epigenetic changes in glucagon-like peptide-1 receptor (GLP1R) gene polymorphisms influence obesity risk.

Study: Integrated genetic and epigenetic analyzes uncover GLP1R association with metabolically healthy obesity.  Image credit: Somchai_shock/ Study: Integrated genetic and epigenetic analyzes uncover GLP1R association with metabolically healthy obesity. Image credit: Somchai_shock/

What is GLP1R?

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

GLP1 also slows gastric motility, thus keeping food in the stomach longer and increasing feelings of fullness and suppressing food intake. Together, these functions lead to a stable body condition with weight loss.

Some gene variants of GLP1R are associated with obesity, such as the rs2268641 allele, which is associated with body mass index (BMI) in Americans of European descent. Similarly, rs6923761 alleles show differential association with body fat mass in Hispanics, such that rs6923761 allele carriers have lower fat mass, waist circumference, and BMI than non-carriers.

In addition to these genetic associations, epigenetic changes can alter gene expression, thus influencing obesity susceptibility. Little is known about GLP1R methylation in relation to obesity risk, particularly in those with MHO.

About the study

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

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

This study had 120 participants and 180 controls. About 44% of the study group was male, with almost two-thirds under the age of 60. Both groups had similar rates of drinking, smoking and activity.

What does the study show?

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

Those with higher GLP1R gene scores are more likely to develop MHO. Methylation increased with higher risk of MHO even after compensating for rs4714211 and other potential confounding factors at four sites in the GLP1R intronic region or before the transcription start site.

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

Furthermore, there was a link between GLP1R polymorphisms and methylation levels at the two sites as well as polymorphisms and MRS. GRS showed binding to other GLP1R sites with MRS.

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

What are the effects?

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

The results of the study show that apart from gene polymorphism, DNA methylation is a factor in the occurrence of MHO. This emphasizes the network of interactions between genetic and epigenetic factors in the genesis of MHO.

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

Further research is needed, as this is the first time GLP1R GRS has been linked to MHO. Nevertheless, the connection is plausible, as CpG methylation effects may vary depending on the region in which they occur due to variations in methylation patterns. Thus, hyper-methylation in exon and intron regions can promote the genes involved, while in gene promoters or adjacent regions, hyper-methylation can inhibit gene expression.

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

Thus, gene methylation may partially account for the effect of gene variants on MHO. This observation provides a novel perspective on the effects of GLP1R variants on MHO sensitivity.

Journal Reference:

  • Han, F., Zhu, S., Kong, X., et al. (2023). Integrated genetic and epigenetic analyzes uncover GLP1R association with metabolically healthy obesity. International Journal of Obesity. doi:10.1038/s41366-023-01414-1.

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